Tone Tønjum

• Barouti, Angeliki; Herfindal, Lars; Vagolu, Siva Krishna; Homberset, Håvard; Tonjum, Tone & Kopplin, Georg [Show all 7 contributors for this article] (2024). Evaluation of the cytotoxic and antimicrobial potential of epiphytic biomass obtained from Laminaria hyperborea biorefinery side-streams. Frontiers in Marine Science. ISSN 2296-7745. 11. doi: 10.3389/fmars.2024.1384136.
• Cao, Dan; Jiang, Xiuzhi; Wu, Tiantian; Xiang, Yanghui; Liu, Jiaying & Li, Zhen [Show all 12 contributors for this article] (2024). Identification of essential oils with strong activity against stationary phase Mycobacterium abscessus. Heliyon. ISSN 2405-8440. 10(5). doi: 10.1016/j.heliyon.2024.e27073.
• Girase, Rukaiyya T.; Ahmad, Iqrar; Oh, Jong Min; Kim, Hoon; Mathew, Bijo & Vagolu, Siva Krishna [Show all 11 contributors for this article] (2023). Repurposing Azoles to Resolve Serotogenic Toxicity Associated with Linezolid to Combat Multidrug-Resistant Tuberculosis. ACS Medicinal Chemistry Letters. ISSN 1948-5875. 14(12), p. 1754–1759. doi: 10.1021/acsmedchemlett.3c00406.
• Özcan, Esma; Vagolu, Siva Krishna; Gündüz, Miyase Gözde; Stevanovic, Milena; Kökbudak, Zülbiye & Tonjum, Tone [Show all 9 contributors for this article] (2023). Novel Quinoline-Based Thiosemicarbazide Derivatives: Synthesis, DFT Calculations, and Investigation of Antitubercular, Antibacterial, and Antifungal Activities. ACS Omega. ISSN 2470-1343. 8(43), p. 40140–40152. doi: 10.1021/acsomega.3c03018. Full text in Research Archive
• Sarkar, Souvik; Mayer Bridwell, Anne E.; Good, James A. D.; Wang, Erin R.; McKee, Samuel R. & Valenta, Joy [Show all 18 contributors for this article] (2023). Design, Synthesis, and Evaluation of Novel Δ²-Thiazolino 2-Pyridone Derivatives That Potentiate Isoniazid Activity in an Isoniazid-Resistant Mycobacterium tuberculosis Mutant. Journal of Medicinal Chemistry. ISSN 0022-2623. 66(16), p. 11056–11077. doi: 10.1021/acs.jmedchem.3c00358. Full text in Research Archive
• Koçak Aslan, Ebru; Han, Muhammed İhsan; Vagolu, Siva Krishna; Tamhaev, Rasoul; Dengiz, Cagatay & Doğan, Şengül Dilem [Show all 10 contributors for this article] (2022). Isoniazid Linked to Sulfonate Esters via Hydrazone Functionality: Design, Synthesis, and Evaluation of Antitubercular Activity. Pharmaceuticals. ISSN 1424-8247. 15:1301(10), p. 1–15. doi: 10.3390/ph15101301. Full text in Research Archive
• Tapera, Michael; Kekeçmuhammed, Hüseyin; Sahin, Kader; Vagolu, Siva Krishna; Lherbet, Christian & Homberset, Håvard [Show all 12 contributors for this article] (2022). Synthesis, characterization, anti-tuberculosis activity and molecular modeling studies of thiourea derivatives bearing aminoguanidine moiety. Journal of Molecular Structure. ISSN 0022-2860. 1270:133899, p. 1–17. doi: 10.1016/j.molstruc.2022.133899.
• Keleş Atıcı, Rüveyde; Doğan, Şengül Dilem; Gündüz, Miyase Gözde; Vagolu, Siva Krishna; Chebaiki, Melina & Homberset, Håvard [Show all 9 contributors for this article] (2022). Urea derivatives carrying a thiophenylthiazole moiety: Design, synthesis, and evaluation of antitubercular and InhA inhibitory activities. Drug development research (Print). ISSN 0272-4391. 83(6), p. 1292–1304. doi: 10.1002/ddr.21958.
• Koçak Aslan, Ebru; Vagolu, Siva Krishna; Armaković, Sanja J.; Armaković, Stevan; Şahin, Onur & Tonjum, Tone [Show all 7 contributors for this article] (2022). Linking azoles to isoniazid via hydrazone bridge: Synthesis, crystal structure determination, antitubercular evaluation and computational studies. Journal of Molecular Liquids. ISSN 0167-7322. 354. doi: 10.1016/j.molliq.2022.118873.
• Birhanu, Alemayehu Godana; Gomez Munoz, Marta; Kalayou, Shewit; Riaz, Tahira; Lutter, Timo & Yimer, Solomon Abebe [Show all 8 contributors for this article] (2022). Proteome Profiling of Mycobacterium tuberculosis Cells Exposed to Nitrosative Stress. ACS Omega. ISSN 2470-1343. 7(4), p. 3470–3482. doi: 10.1021/acsomega.1c05923. Full text in Research Archive
• Arenas, Jesús; Szabo, Zalan; van der Wal, Jelle; Maas, Coen; Riaz, Tahira & Tonjum, Tone [Show all 7 contributors for this article] (2021). Serum proteases prevent bacterial biofilm formation: role of kallikrein and plasmin. Virulence. ISSN 2150-5594. 12(1), p. 2902–2917. doi: 10.1080/21505594.2021.2003115. Full text in Research Archive
• Welekidan, Letemichael Negash; Yimer, Solomon Abebe; Skjerve, Eystein; Dejene, Tsehaye Asmelash; Homberset, Håvard & Tonjum, Tone [Show all 7 contributors for this article] (2021). Whole Genome Sequencing of Drug Resistant and Drug Susceptible Mycobacterium tuberculosis Isolates From Tigray Region, Ethiopia. Frontiers in Microbiology. ISSN 1664-302X. 12. doi: 10.3389/fmicb.2021.743198. Full text in Research Archive
• Mekonnen, Daniel; Derbie, Awoke; Mihret, Adane; Yimer, Solomon Abebe; Tonjum, Tone & Gelaw, Baye [Show all 10 contributors for this article] (2021). Lipid droplets and the transcriptome of Mycobacterium tuberculosis from direct sputa: a literature review. Lipids in Health and Disease. ISSN 1476-511X. 20:129(1), p. 1–13. doi: 10.1186/s12944-021-01550-5. Full text in Research Archive
• Welekidan, Letemichael Negash; Skjerve, Eystein; Dejene, Tsehaye Asmelash ; Gebremichael, Mengistu Welday ; Brynildsrud, Ola Brønstad & Tonjum, Tone [Show all 7 contributors for this article] (2020). Frequency and patterns of first- and second-line drug resistance-conferring mutations in Mycobacterium tuberculosis isolated from pulmonary tuberculosis patients in a cross-sectional study in Tigray Region, Ethiopia. Journal of Global Antimicrobial Resistance. ISSN 2213-7165. 24, p. 6–13. doi: 10.1016/j.jgar.2020.11.017. Full text in Research Archive
• Welekidan, Letemichael Negash; Skjerve, Eystein; Dejene, Tsehaye Asmelash; Gebremichael, Mengistu Welday; Brynildsrud, Ola Brønstad & Agdestein, Angelika [Show all 9 contributors for this article] (2020). Characteristics of pulmonary multidrug-resistant tuberculosis patients in Tigray Region, Ethiopia: A cross-sectional study. . PLOS ONE. ISSN 1932-6203. 15(8). doi: 10.1371/journal.pone.0236362. Full text in Research Archive Show summary

  Background: Tuberculosis (TB) is among the top 10 causes of mortality and the first killer among infectious diseases worldwide. One of the factors fuelling the TB epidemic is the global rise of multidrug resistant TB (MDR-TB). The aim of this study was to determine the magnitude and factors associated with MDR-TB in the Tigray Region, Ethiopia. Method: This study employed a facility-based cross-sectional study design, which was conducted between July 2018 and August 2019. The inclusion criteria for the study participants were GeneXpert-positive who were not under treatment for TB, PTB patients' ≥15 years of age and who provided written informed consent. A total of 300 participants were enrolled in the study, with a structured questionnaire used to collect data on clinical, sociodemographic and behavioral factors. Sputum samples were collected and processed for acid-fast bacilli staining, culture and drug susceptibility testing. Drug susceptibility testing was performed using a line probe assay. Logistic regression was used to analyze associations between outcome and predictor variables. Results: The overall proportion of MDR-TB was 16.7% (11.6% and 32.7% for new and previously treated patients, respectively). Of the total MDR-TB isolates, 5.3% were pre-XDR-TB. The proportion of MDR-TB/HIV co-infection was 21.1%. A previous history of TB treatment AOR 3.75; 95% CI (0.7-2.24), cigarette smoking AOR 6.09; CI (1.65-2.50) and patients who had an intermittent fever (AOR = 2.54, 95% CI = 1.21-5.4) were strongly associated with MDR-TB development. Conclusions: The magnitude of MDR-TB observed among new and previously treated patients is very alarming, which calls for an urgent need for intervention. The high proportion of MDR-TB among newly diagnosed cases indicates ongoing transmission, which suggests the need for enhanced TB control program performance to interrupt transmission. The increased proportion of MDR-TB among previously treated cases indicates a need for better patient management to prevent the evolution of drug resistance. Assessing the TB control program performance gaps and an optimal implementation of the WHO recommended priority actions for the management of drug-resistant TB, is imperative to help reduce the current high MDR-TB burden in the study region.

• Andersson, Dan I.; Balaban, Nathalie Q.; Baquero, Fernando; Courvalin, Patrice; Glaser, Philippe & Gophna, Uri [Show all 9 contributors for this article] (2020). Antibiotic resistance: turning evolutionary principles into clinical reality. FEMS Microbiology Reviews. ISSN 0168-6445. 44(2), p. 171–188. doi: 10.1093/femsre/fuaa001. Full text in Research Archive Show summary

  Antibiotic resistance is one of the major challenges facing modern medicine worldwide. The past few decades have witnessed rapid progress in our understanding of the multiple factors that affect the emergence and spread of antibiotic resistance at the population level and the level of the individual patient. However, the process of translating this progress into health policy and clinical practice has been slow. Here, we attempt to consolidate current knowledge about the evolution and ecology of antibiotic resistance into a roadmap for future research as well as clinical and environmental control of antibiotic resistance. At the population level, we examine emergence, transmission and dissemination of antibiotic resistance, and at the patient level, we examine adaptation involving bacterial physiology and host resilience. Finally, we describe new approaches and technologies for improving diagnosis and treatment and minimizing the spread of resistance.

• Fernández Navarro, José; Croteau, Deborah L; Jurek, Aleksandra; Andrusivova, Zaneta; Yang, Beimeng & Wang, Yue [Show all 15 contributors for this article] (2020). Spatial Transcriptomics Reveals Genes Associated with Dysregulated Mitochondrial Functions and Stress Signaling in Alzheimer Disease. iScience. ISSN 2589-0042. 23:101556(10), p. 1–19. doi: 10.1016/j.isci.2020.101556. Full text in Research Archive
• Yimer, Solomon Abebe; Kalayou, Shewit; Homberset, Håvard; Birhanu, Alemayehu Godana; Riaz, Tahira & Zegeye, Ephrem Debebe [Show all 11 contributors for this article] (2020). Lineage-specific proteomic signatures in the Mycobacterium tuberculosis complex reveal differential abundance of proteins involved in virulence, DNA repair, CRISPR-Cas, bioenergetics and lipid metabolism. Frontiers in Microbiology. ISSN 1664-302X. 11. doi: 10.3389/fmicb.2020.550760. Full text in Research Archive
• Shi, Wanliang; Cui, Peng; Niu, Hongxia; Zhang, Shuo; Tonjum, Tone & Zhu, Bingdong [Show all 7 contributors for this article] (2019). Introducing RpsA point mutations ∆438A and D123A into the chromosome of M. tuberculosis confirms their role in causing resistance to pyrazinamide. Antimicrobial Agents and Chemotherapy. ISSN 0066-4804. 63:e02681-18(6), p. 1–6. doi: 10.1128/AAC.02681-18. Show summary

  Pyrazinamide (PZA) is a unique frontline drug for shortening tuberculosis (TB) treatment, but its mechanisms of action are elusive. We previously found one PZA-resistant strain that harbors an alanine deletion at position 438 (Δ438A) in RpsA, a target of PZA associated with PZA resistance, but its role in causing PZA resistance has been inconclusive. Here, we introduced the RpsA Δ438A mutation along with the D123A mutation into the Mycobacterium tuberculosis chromosome and demonstrated that these RspA mutations are indeed responsible for PZA resistance.

• Tonjum, Tone (2019). Molecular epidemiology of M. tuberculosis in Ethiopia: A systematic review and meta-analysis. Tuberculosis. ISSN 1472-9792. 118. doi: 10.1016/j.tube.2019.101858. Show summary

  The molecular epidemiology of Mycobacterium tuberculosis (M. tuberculosis, Mtb) is poorly documented in Ethiopia. The data that exists has not yet been collected in an overview metadata form. Thus, this review summarizes available literature on the genomic diversity, geospatial distribution and transmission patterns of Mtb lineages (L) and sublineages in Ethiopia. Spoligotyping and Mycobacterial Interspersed Repetitive Units-Variable Number Tandem Repeats (MIRU-VNTR) based articles were identified from MEDLINE via PubMed and Scopus. The last date of article search was done on 12th February 2019. Articles were selected following the PRISMA flow diagram. The proportion of (sub)lineages was summarized at national level and further disaggregated by region. Clustering and recent transmission index (RTI) were determined using metan command and random effect meta-analysis model. The meta-analysis was computed using Stata 14 (Stata Corp. College Station, TX, USA). Among 4371 clinical isolates, 99.5% were Mtb and 0.5% were M. bovis. Proportionally, L4, L3, L1 and L7 made up 62.3%, 21.7%, 7.9% and 3.4% of the total isolates, respectively. Among sublineages, L4.2. ETH/SIT149, L4.10/SIT53, L3. ETH1/SIT25 and L4.6/SIT37 were the leading clustered isolates accounting for 14.4%, 9.7%, 7.2% and 5.5%, respectively. Based on MIRU-VNTR, the rate of clustering was 41% and the secondary case rate from a single source case was estimated at 29%. Clustering and recent transmission index was higher in eastern and southwestern Ethiopia compared with the northwestern part of the country. High level of genetic diversity with a high rate of clustering was noted which collectively mirrored the phenomena of micro-epidemics and super-spreading. The largest set of clustered strains deserves special attention and further characterization using whole genome sequencing (WGS) to better understand the evolution, genomic diversity and transmission dynamics of Mtb.

• Mekonnen, Daniel; Derbie, Awoke; Chanie, Asmamaw; Shumet, Abebe; Biadglegne, Fantahun & Kassahun, Yonas [Show all 14 contributors for this article] (2019). Molecular epidemiology of M. tuberculosis in Ethiopia: A systematic review and meta-analysis. Tuberculosis. ISSN 1472-9792. 118:101858, p. 1–10. doi: 10.1016/j.tube.2019.101858. Show summary

  The molecular epidemiology of Mycobacterium tuberculosis (M. tuberculosis, Mtb) is poorly documented in Ethiopia. The data that exists has not yet been collected in an overview metadata form. Thus, this review summarizes available literature on the genomic diversity, geospatial distribution and transmission patterns of Mtb lineages (L) and sublineages in Ethiopia. Spoligotyping and Mycobacterial Interspersed Repetitive Units-Variable Number Tandem Repeats (MIRU-VNTR) based articles were identified from MEDLINE via PubMed and Scopus. The last date of article search was done on 12th February 2019. Articles were selected following the PRISMA flow diagram. The proportion of (sub)lineages was summarized at national level and further disaggregated by region. Clustering and recent transmission index (RTI) were determined using metan command and random effect meta-analysis model. The meta-analysis was computed using Stata 14 (Stata Corp. College Station, TX, USA). Among 4371 clinical isolates, 99.5% were Mtb and 0.5% were M. bovis. Proportionally, L4, L3, L1 and L7 made up 62.3%, 21.7%, 7.9% and 3.4% of the total isolates, respectively. Among sublineages, L4.2. ETH/SIT149, L4.10/SIT53, L3. ETH1/SIT25 and L4.6/SIT37 were the leading clustered isolates accounting for 14.4%, 9.7%, 7.2% and 5.5%, respectively. Based on MIRU-VNTR, the rate of clustering was 41% and the secondary case rate from a single source case was estimated at 29%. Clustering and recent transmission index was higher in eastern and southwestern Ethiopia compared with the northwestern part of the country. High level of genetic diversity with a high rate of clustering was noted which collectively mirrored the phenomena of micro-epidemics and super-spreading. The largest set of clustered strains deserves special attention and further characterization using whole genome sequencing (WGS) to better understand the evolution, genomic diversity and transmission dynamics of Mtb.

• Shi, Wanliang; Cui, Peng; Niu, Hongxia; Zhang, Shuo; Tonjum, Tone & Zhu, Bingdong [Show all 7 contributors for this article] (2019). Introducing RpsA Point Mutations Δ438A and D123A into the Chromosome of Mycobacterium tuberculosis Confirms Their Role in Causing Resistance to Pyrazinamide. Antimicrobial Agents and Chemotherapy. ISSN 0066-4804. 63:e02681-18(6), p. 1–6. doi: 10.1128/AAC.02681-18. Show summary

  Pyrazinamide (PZA) is a unique frontline drug for shortening tuberculosis (TB) treatment, but its mechanisms of action are elusive. We previously found one PZA-resistant strain that harbors an alanine deletion at position 438 (Δ438A) in RpsA, a target of PZA associated with PZA resistance, but its role in causing PZA resistance has been inconclusive. Here, we introduced the RpsA Δ438A mutation along with the D123A mutation into the Mycobacterium tuberculosis chromosome and demonstrated that these RspA mutations are indeed responsible for PZA resistance.

• Birhanu, Alemayehu Godana; Solomon, Abebe Yimer; Kalayou, Shewit; Riaz, Tahira; Zegeye, Ephrem Debebe & Holm-Hansen, Carol J C [Show all 10 contributors for this article] (2019). Ample glycosylation in membrane and cell envelope proteins may explain the phenotypic diversity and virulence in the Mycobacterium tuberculosis complex. Scientific Reports. ISSN 2045-2322. 9:2927, p. 1–15. doi: 10.1038/s41598-019-39654-9. Full text in Research Archive Show summary

  Multiple regulatory mechanisms including post-translational modifications (PTMs) confer complexity to the simpler genomes and proteomes of Mycobacterium tuberculosis (Mtb). PTMs such as glycosylation play a significant role in Mtb adaptive processes. The glycoproteomic patterns of clinical isolates of the Mycobacterium tuberculosis complex (MTBC) representing the lineages 3, 4, 5 and 7 were characterized by mass spectrometry. A total of 2944 glycosylation events were discovered in 1325 proteins. This data set represents the highest number of glycosylated proteins identified in Mtb to date. O-glycosylation constituted 83% of the events identified, while 17% of the sites were N-glycosylated. This is the first report on N-linked protein glycosylation in Mtb and in Gram-positive bacteria. Collectively, the bulk of Mtb glycoproteins are involved in cell envelope biosynthesis, fatty acid and lipid metabolism, two-component systems, and pathogen-host interaction that are either surface exposed or located in the cell wall. Quantitative glycoproteomic analysis revealed that 101 sites on 67 proteins involved in Mtb fitness and survival were differentially glycosylated between the four lineages, among which 64% were cell envelope and membrane proteins. The differential glycosylation pattern may contribute to phenotypic variabilities across Mtb lineages. The study identified several clinically important membrane-associated glycolipoproteins that are relevant for diagnostics as well as for drug and vaccine discovery

• Alfsnes, Kristian; Frye, Stephan Alfons; Eriksson, Jens; Eldholm, Vegard; Brynildsrud, Ola Brønstad & Bohlin, Jon [Show all 11 contributors for this article] (2018). A genomic view of experimental intraspecies and interspecies transformation of a rifampicin-resistance allele into Neisseria meningitidis. Microbial Genomics. ISSN 2057-5858. 4(11), p. 1–14. doi: 10.1099/mgen.0.000222. Full text in Research Archive Show summary

  The spread of antibiotic resistance within and between different bacterial populations is a major health problem on a global scale. The identification of genetic transformation in genomic data from Neisseria meningitidis, the meningococcus (Mc), and other bacteria is problematic, since similar or even identical alleles may be involved. A particular challenge in naturally transformable bacteria generally is to distinguish between common ancestry and true recombined sites in sampled genome sequences. Furthermore, the identification of recombination following experimental transformation of homologous alleles requires identifiable differences between donor and recipient, which in itself influences the propensity for homologous recombination (HR). This study identifies the distribution of HR events following intraspecies and interspecies Mc transformations of rpoB alleles encoding rifampicin resistance by whole-genome DNA sequencing and single nucleotide variant analysis. The HR events analysed were confined to the genomic region surrounding the single nucleotide genetic marker used for selection. An exponential length distribution of these recombined events was found, ranging from a few nucleotides to about 72 kb stretches. The lengths of imported sequences were on average found to be longer following experimental transformation of the recipient with genomic DNA from an intraspecies versus an interspecies donor (P<0.001). The recombination events were generally observed to be mosaic, with donor sequences interspersed with recipient sequence. Here, we present four models to explain these observations, by fragmentation of the transformed DNA, by interruptions of the recombination mechanism, by secondary recombination of endogenous self-DNA, or by repair/replication mechanisms.

• Jensen, Helge Leander B.; Lillenes, Meryl Sønderby; Rabano, Alberto; Günther, Clara-Cecilie; Riaz, Tahira & Kalayou, Shewit [Show all 9 contributors for this article] (2018). Expression of nucleotide excision repair in Alzheimer's disease is higher in brain tissue than in blood. Neuroscience Letters. ISSN 0304-3940. 672, p. 53–58. doi: 10.1016/j.neulet.2018.02.043. Full text in Research Archive Show summary

  Age-related changes are increased in patients with Alzheimer's disease (AD), including oxidative stress and DNA damage. We propose that genotoxic stress and DNA repair responses influence neurodegeneration in the pathogenesis of AD. Here, we focus on nucleotide excision repair (NER). Real-time qPCR and mass spectrometry were employed to determine the expression levels of selected NER components. The mRNA levels of the genes encoding the NER proteins RAD23B, RPA1, ERCC1, PCNA and LIG3 as well as the NER-interacting base excision repair protein MPG in blood and brain tissue from four brain regions in patients with AD or mild cognitive impairment and healthy controls (HC), were assessed. NER mRNA levels were significantly higher in brain tissue than in blood. Further, LIG3 mRNA levels in the frontal cortex was higher in AD versus HC, while mRNA levels of MPG and LIG3 in entorhinal cortex and RPA1 in the cerebellum were lower in AD versus HC. In blood, RPA1 and ERCC1 mRNA levels were lower in AD patients than in HC. Alterations in gene expression of NER components between brain regions were associated with AD, connecting DNA repair to AD pathogenesis and suggesting a distinct role for NER in the brain.

• Frye, Stephan Alfons; Beyene, Getachew Tesfaye; Namouchi, Amine; Munoz, Marta Gomez; Homberset, Håvard & Kalayou, Shewit [Show all 9 contributors for this article] (2017). The helicase DinG responds to stress due to DNA double strand breaks. PLOS ONE. ISSN 1932-6203. 12:e0187900(11), p. 1–23. doi: 10.1371/journal.pone.0187900.
• Desler, Claus; Lillenes, Meryl Sønderby; Tonjum, Tone & Juel Rasmussen, Lene (2017). The role of mitochondrial dysfunction in the progression of Alzheimer’s disease. Current Medicinal Chemistry. ISSN 0929-8673. 25(40), p. 5578–5587. doi: 10.2174/0929867324666170616110111.
• Hovland, Eirik; Beyene, Getachew Tesfaye; Frye, Stephan Alfons; Homberset, Håvard; Balasingham, Seetha & Gomez Munoz, Marta [Show all 9 contributors for this article] (2017). DprA from Neisseria meningitidis: properties and role in natural competence for transformation. Microbiology (Reading). ISSN 1350-0872. 163(7), p. 1016–1029. doi: 10.1099/mic.0.000489. Show summary

  DNA processing chain A (DprA) is a DNA-binding protein that is ubiquitous in bacteria and expressed in some archaea. DprA is active in many bacterial species that are competent for transformation of DNA, but its role in Neisseriameningitidis (Nm) is not well characterized. An Nm mutant lacking DprA was constructed, and the phenotypes of the wild-type and ΔdprA mutant were compared. The salient feature of the phenotype of dprA null cells is the total lack of competence for genetic transformation shown by all of the donor DNA substrates tested in this study. Here, Nm wild-type and dprA null cells appeared to be equally resistant to genotoxic stress. The gene encoding DprANm was cloned and overexpressed, and the biological activities of DprANm were further investigated. DprANm binds ssDNA more strongly than dsDNA, but lacks DNA uptake sequence-specific DNA binding. DprANm dimerization and interaction with the C-terminal part of the single-stranded binding protein SSBNmwere demonstrated. dprA is co-expressed with smg, a downstream gene of unknown function, and the gene encoding topoisomerase 1, topA.

• Birhanu, Alemayehu Godana; Solomon, Abebe Yimer; Holm-Hansen, Carol J C; Norheim, Gunnstein; Aseffa, Abraham & Abebe, Markose [Show all 7 contributors for this article] (2017). Nε- and O-Acetylation in Mycobacterium tuberculosis Lineage 7 and Lineage 4 strains: Proteins Involved in Bioenergetics, Virulence and Antimicrobial Resistance are Acetylated. Journal of Proteome Research. ISSN 1535-3893. 16(11), p. 4045–4059. doi: 10.1021/acs.jproteome.7b00429. Full text in Research Archive Show summary

  Increasing evidence demonstrates that lysine acetylation is involved in Mycobacterium tuberculosis (Mtb) virulence and pathogenesis. However, previous investigations in Mtb have only monitored acetylation at lysine residues using selected reference strains. We analyzed the global Nε- and O-acetylation of 3 Mtb isolates; 2 lineage 7 clinical isolates and the lineage 4 H37Rv reference strain. Quantitative acetylome analysis resulted in identification of 2490 class-I acetylation sites, among them 2349 O-acetylation and 141 Nε-acetylation sites, derived from 953 unique proteins. Mtb O-acetylation was thereby significantly more abundant than Nε-acetylation. The acetylated proteins were found to be involved in central metabolism, translation, stress responses and antimicrobial drug resistance. Notably, 261 acetylation sites on 165 proteins were differentially regulated between lineage 7 and lineage 4 strains. A total of 257 acetylation sites on 161 proteins were hypoacetylated in lineage 7 strains. These proteins are involved in Mtb growth, virulence, bioenergetics, host-pathogen interaction and stress responses. This study provides the first global analysis of O-acetylated proteins in Mtb. This quantitative acetylome data expand the current understanding regarding the nature and diversity of acetylated proteins in Mtb, and opens a new avenue of research for exploring the role of protein acetylation in Mtb physiology.

• Yimer, Solomon Abebe; Birhanu, Alemayehu Godana; Kalayou, Shewit; Riaz, Tahira; Zegeye, Ephrem Debebe & Beyene, Getachew Tesfaye [Show all 11 contributors for this article] (2017). Comparative proteomic analysis of Mycobacterium tuberculosis lineage 7 and lineage 4 strains reveals differentially abundant proteins linked to slow growth and virulence. Frontiers in Microbiology. ISSN 1664-302X. 8:795, p. 1–14. doi: 10.3389/fmicb.2017.00795. Full text in Research Archive Show summary

  In order to decipher the nature of the slowly growing Mycobacterium tuberculosis (M.tuberculosis) lineage 7, the differentially abundant proteins in strains ofM. tuberculosis lineage 7 and lineage 4 were defined. Comparative proteomic analysis by mass spectrometry was employed to identify, quantitate and compare the protein profiles of strains from the two M. tuberculosis lineages. Label-free peptide quantification of Whole cells from M. tuberculosis lineage 7 and 4 yielded the identification of 2825 and 2541 proteins, respectively. A combined total of 2867 protein groups covering 71% of the predicted M. tuberculosis proteome were identified. The abundance of 125 proteins in M. tuberculosis lineage 7 and 4 strains was significantly altered. Notably, the analysis showed that a number of M. tuberculosis proteins involved in growth and virulence were less abundant in lineage 7 strains compared to lineage 4. Five ABC transporter proteins, three phosphate binding proteins essential for inorganic phosphate uptake, and six components of the type 7 secretion system ESX-3 involved in iron acquisition were less abundant in M. tuberculosis lineage 7. This proteogenomic analysis provided an insight into the lineage 7-specific protein profile which may provide clues to understanding the differential properties of lineage 7 strains in terms of slow growth, survival fitness, and pathogenesis.

• Norheim, Gunnstein; Seterelv, Siri Schøyen; Arnesen, Trude Margrete; Mengshoel, Anne Torunn; Tonjum, Tone & Rønning, Janne Oseberg [Show all 7 contributors for this article] (2017). Tuberculosis Outbreak in an Educational Institution in Norway. Journal of Clinical Microbiology. ISSN 0095-1137. 55(5), p. 1327–1333. doi: 10.1128/JCM.01152-16. Show summary

  Within 1 week in April 2013, three cases of pulmonary tuberculosis (TB) were reported among students attending training sessions at an educational institution in Oslo, Norway. By the end of October 2013, a total of nine epidemiologically linked cases had been reported. The outbreak encompassed a total of 24 cases from 2009 to 2014, among which all of the 22 Mycobacterium tuberculosis isolates available had identical mycobacterial interspersed repetitive-unit–variable-number tandem-repeat (MIRU-VNTR) profiles (MtbC15-9 code 10287-189) belonging to the Beijing lineage. Whole-genome sequencing (WGS) of the M. tuberculosis isolates revealed 20 variable nucleotide positions within the cluster, indicating a clonal outbreak. The most likely index case was identified and diagnosed in Norway in 2009 but was born in Asia. WGS analyses verified that all of the cases were indeed part of a single transmission chain. However, even when combining WGS and intensified contact tracing, we were unable to fully reconstruct the TB transmission events.

• Beyene, Getachew Tesfaye; Kalayou, Shewit; Riaz, Tahira & Tonjum, Tone (2017). Comparative proteomic analysis of Neisseria meningitidis wildtype and dprA null mutant strains links DNA processing to pilus biogenesis. BMC Microbiology. ISSN 1471-2180. 17:96, p. 1–18. doi: 10.1186/s12866-017-1004-8. Show summary

  Background: DNA processing chain A (DprA) is a DNA binding protein which is ubiquitous in bacteria, and is required for DNA transformation to various extents among bacterial species. However, the interaction of DprA with competence and recombination proteins is poorly understood. Therefore, the proteomes of whole Neisseria meningitidis (Nm) wildtype and dprA mutant cells were compared. Such a comparative proteomic analysis increases our understanding of the interactions of DprA with other Nm components and may elucidate its potential role beyond DNA processing in transformation. Results: Using label-free quantitative proteomics, a total of 1057 unique Nm proteins were identified, out of which 100 were quantified as differentially abundant (P ≤ 0.05 and fold change ≥ |2|) in the dprA null mutant. Proteins involved in homologous recombination (RecA, UvrD and HolA), pilus biogenesis (PilG, PilT1, PilT2, PilM, PilO, PilQ, PilF and PilE), cell division, including core energy metabolism, and response to oxidative stress were downregulated in the Nm dprA null mutant. The mass spectrometry data are available via ProteomeXchange with identifier PXD006121. Immunoblotting and co-immunoprecipitation were employed to validate the association of DprA with PilG. The analysis revealed reduced amounts of PilG in the dprA null mutant and reduced amounts of DprA in the Nm pilG null mutant. Moreover, a number of pilus biogenesis proteins were shown to interact with DprA and /or PilG. Conclusions: DprA interacts with proteins essential for Nm DNA recombination in transformation, pilus biogenesis, and other functions associated with the inner membrane. Inverse downregulation of Nm DprA and PilG expression in the corresponding mutants indicates a link between DNA processing and pilus biogenesis.

• Castañeda-García, Alfredo; Prieto, Anabel I.; Rodríguez-Beltrán, Jerónimo; Alonso, N.; Cantillon, Daire & Costas, Coloma [Show all 17 contributors for this article] (2017). A non-canonical mismatch repair pathway in prokaryotes. Nature Communications. ISSN 2041-1723. 8:14246, p. 1–10. doi: 10.1038/ncomms14246. Show summary

  Mismatch repair (MMR) is a near ubiquitous pathway, essential for the maintenance of genome stability. Members of the MutS and MutL protein families perform key steps in mismatch correction. Despite the major importance of this repair pathway, MutS-MutL are absent in almost all Actinobacteria and many Archaea. However, these organisms exhibit rates and spectra of spontaneous mutations similar to MMR-bearing species, suggesting the existence of an alternative to the canonical MutS-MutL-based MMR. Here we report that Mycobacterium smegmatis NucS/EndoMS, a putative endonuclease with no structural homology to known MMR factors, is required for mutation avoidance and anti-recombination, hallmarks of the canonical MMR. Furthermore, phenotypic analysis of naturally occurring polymorphic NucS in a M. smegmatis surrogate model, suggests the existence of M. tuberculosis mutator strains. The phylogenetic analysis of NucS indicates a complex evolutionary process leading to a disperse distribution pattern in prokaryotes. Together, these findings indicate that distinct pathways for MMR have evolved at least twice in nature.

• Lillenes, Meryl Sønderby; Støen, Mari; Günther, Clara-Cecilie; Selnes, Per; Stenset, Vidar & Espeseth, Thomas [Show all 9 contributors for this article] (2017). Mitochondrial transcription factor A (TFAM) rs1937 and AP endonuclease 1 (APE1) rs1130409 alleles are associated with reduced cognitive performance. Neuroscience Letters. ISSN 0304-3940. 645, p. 46–52. doi: 10.1016/j.neulet.2017.02.062. Show summary

  Mitochondrial dysfunction and DNA damage is intimately connected to ageing and neurodegeneration, including Alzheimer’s disease (AD). A particular culprit in this context is oxidative stress, which is a result of increased reactive oxygen species (ROS) due to hyperactive or dysfunctional mitochondria and/or reduced DNA repair capacity. Base excision repair (BER) is the major pathway for repairing oxidative damage events in chromosomal and mitochondrial DNA. Defects in BER have been detected in ageing and neurodegeneration. Mitochondrial transcription factor A (TFAM) plays an important role in the maintenance of mitochondrial DNA integrity. The present study investigated single nucleotide polymorphisms (SNPs) in the genes encoding the BER components MutYH, OGG1, APE1, PolB and PolG and the gene encoding mitochondrial TFAM in a cohort of 161 AD patients, 96 non-AD patient controls (PC) and 192 healthy controls (HC). Notably, the minor allele carriers of APE1 rs1130409 and the common allele carriers of TFAM rs1937 were associated with reduced mini-mental state examination score in AD patients, PC and HC, with no distinction of SNP frequencies in either of these sub-groups. Collectively, the results suggest an association between DNA maintenance and decline in cognitive function. These studies enlighten the normal brain aging process and point to potential new biomarkers for cognitive function and impairment.

• Zegeye, Nigus; Asrat, Daniel; Woldeamanuel, Yimtubezinash; Habte, Abebe; Gedlu, Etsegenet & Tonjum, Tone [Show all 7 contributors for this article] (2016). Throat culture positivity rate and antibiotic susceptibility pattern of beta-hemolytic streptococci in children on secondary prophylaxis for rheumatic heart disease. BMC Infectious Diseases. ISSN 1471-2334. 16:510, p. 1–8. doi: 10.1186/s12879-016-1841-3. Show summary

  Background: For characterization of clinical isolates of Streptococcus pyogenes and S. dysgalactiae subsp. equisimilis for surveillance studies, emm typing and protein profiling are currently the best available molecular methods. This study determined the emm gene type and protein profile of Streptococcus pyogenes and S. dysgalactiae subsp. equisimilis strains isolated from children with rheumatic heart disease who were receiving on-going prophylaxis. Methods: The emm gene typing of four strains of S. pyogenes and four strains of S. dysgalactiae subsp. equisimilis was performed by PCR followed by DNA sequencing. The protein profile of these strains was also analysed by high end mass spectrometry. Results: Six different emm gene types were identified. These were stGrobn.1, emm 70.0, emm 68.2, emm 77.0, stG4831.0 and stC839.0. StGrobn.1 was the newly discovered subtype which is associated with an S. dysgalactiae subsp. equisimilis isolate expressing Lancefield group A. The phylogenetic tree showed that the inter-strain and intra-strain differences are relatively small. Differences between the emm types from S. dysgalactiae subsp. equisimilis are normally greater than the differences between emm types from S. dysgalactiae subsp. equisimilis and S. pyogenes. The streptococcal glycosyltransferase in strain S. pyogenes emm 68.2 exhibited N-linked glycosylation carrying a unique N-acetylhexoseamine (HexNAc)-deoxyhexose. This is a novel post-translational modification (PTM) not previously recognized. Conclusion:The S. pyogenes and S. dysgalactiae subsp. equisimilis strains assessed here had different emm gene types, proteomic and PTM patterns, enabling distinction of subgroups of these closely related strains with pathogenic potential in rheumatic fever disease. From the current study, only emm77.0 was included in the 26 multivalent Group A streptococcal (GAS) vaccine.

• Beyene, Getachew Tesfaye; Balasingham, Seetha; Frye, Stephan Alfons; Namouchi, Amine; Homberset, Håvard & Kalayou, Shewit [Show all 8 contributors for this article] (2016). Characterization of the Neisseria meningitidis Helicase RecG. PLOS ONE. ISSN 1932-6203. 11:e0164588(10), p. 1–31. doi: 10.1371/journal.pone.0164588. Show summary

  Neisseria meningitidis (Nm) is a Gram-negative oral commensal that opportunistically can cause septicaemia and/or meningitis. Here, we overexpressed, purified and characterized the Nm DNA repair/recombination helicase RecG (RecGNm) and examined its role during genotoxic stress. RecGNm possessed ATP-dependent DNA binding and unwinding activities in vitro on a variety of DNA model substrates including a Holliday junction (HJ). Database searching of the Nm genomes identified 49 single nucleotide polymorphisms (SNPs) in the recGNm including 37 non-synonymous SNPs (nsSNPs), and 7 of the nsSNPs were located in the codons for conserved active site residues of RecGNm. A transient reduction in transformation of DNA was observed in the Nm ΔrecG strain as compared to the wildtype. The gene encoding recGNm also contained an unusually high number of the DNA uptake sequence (DUS) that facilitate transformation in neisserial species. The differentially abundant protein profiles of the Nm wildtype and ΔrecG strains suggest that expression of RecGNm might be linked to expression of other proteins involved in DNA repair, recombination and replication, pilus biogenesis, glycan biosynthesis and ribosomal activity. This might explain the growth defect that was observed in the Nm ΔrecG null mutant.

• Namouchi, Amine; Gomez Munoz, Marta; Frye, Stephan Alfons; Moen, Line Victoria; Rognes, Torbjørn & Tonjum, Tone [Show all 7 contributors for this article] (2016). The Mycobacterium tuberculosis transcriptional landscape under genotoxic stress. BMC Genomics. ISSN 1471-2164. 17:791, p. 1–13. doi: 10.1186/s12864-016-3132-1. Full text in Research Archive Show summary

  Background: As an intracellular human pathogen, Mycobacterium tuberculosis (Mtb) is facing multiple stressful stimuli inside the macrophage and the granuloma. Understanding Mtb responses to stress is essential to identify new virulence factors and pathways that play a role in the survival of the tubercle bacillus. The main goal of this study was to map the regulatory networks of differentially expressed (DE) transcripts in Mtb upon various forms of genotoxic stress. We exposed Mtb cells to oxidative (H2O2 or paraquat), nitrosative (DETA/NO), or alkylation (MNNG) stress or mitomycin C, inducing double-strand breaks in the DNA. Total RNA was isolated from treated and untreated cells and subjected to high-throughput deep sequencing. The data generated was analysed to identify DE genes encoding mRNAs, non-coding RNAs (ncRNAs), and the genes potentially targeted by ncRNAs. Results: The most significant transcriptomic alteration with more than 700 DE genes was seen under nitrosative stress. In addition to genes that belong to the replication, recombination and repair (3R) group, mainly found under mitomycin C stress, we identified DE genes important for bacterial virulence and survival, such as genes of the type VII secretion system (T7SS) and the proline-glutamic acid/proline-proline-glutamic acid (PE/PPE) family. By predicting the structures of hypothetical proteins (HPs) encoded by DE genes, we found that some of these HPs might be involved in mycobacterial genome maintenance. We also applied a state-of-the-art method to predict potential target genes of the identified ncRNAs and found that some of these could regulate several genes that might be directly involved in the response to genotoxic stress. Conclusions: Our study reflects the complexity of the response of Mtb in handling genotoxic stress. In addition to genes involved in genome maintenance, other potential key players, such as the members of the T7SS and PE/PPE gene family, were identified. This plethora of responses is detected not only at the level of DE genes encoding mRNAs but also at the level of ncRNAs and their potential targets.

• Lillenes, Meryl Sønderby; Rabano, Alberto; Støen, Mari; Riaz, Tahira; Misaghian, Dorna & Møllersen, Linda [Show all 12 contributors for this article] (2016). Altered DNA base excision repair profile in brain tissue and blood in Alzheimer’s disease. Molecular Brain. ISSN 1756-6606. 9:61, p. 1–14. doi: 10.1186/s13041-016-0237-z. Show summary

  Background: Alzheimer’s disease (AD) is a progressive, multifactorial neurodegenerative disorder that is the main cause of dementia globally. AD is associated with increased oxidative stress, resulting from imbalance in production and clearance of reactive oxygen species (ROS). ROS can damage DNA and other macromolecules, leading to genome instability and disrupted cellular functions. Base excision repair (BER) plays a major role in repairing oxidative DNA lesions. Here, we compared the expression of BER components APE1, OGG1, PARP1 and Polβ in blood and postmortem brain tissue from patients with AD, mild cognitive impairment (MCI) and healthy controls (HC). Results: BER mRNA levels were correlated to clinical signs and cerebrospinal fluid biomarkers for AD. Notably, the expression of BER genes was higher in brain tissue than in blood samples. Polβ mRNA level was significantly higher in the cerebellum than in the other brain regions, more so in AD patients than in HC. Blood mRNA levels of OGG1 was low and PARP1 high in MCI and AD. Conclusions: These findings suggest that alteration in BER gene expression is an event preceding AD and reflect the oxidative stress-generating energy-consumption in the brain and the importance of BER in repairing these damage events. The results link DNA repair in brain and blood to the etiology of AD at the molecular level and can potentially serve in establishing novel biomarkers, particularly in the AD prodromal phase.

• Yimer, Solomon Abebe; Namouchi, Amine; Zegeye, Ephrem Debebe; Holm-Hansen, Carol J C; Norheim, Gunnstein & Abebe, Markos [Show all 8 contributors for this article] (2016). Deciphering the recent phylogenetic expansion of the originally deeply rooted Mycobacterium tuberculosis lineage 7. BMC Evolutionary Biology. ISSN 1471-2148. 16:146, p. 1–10. doi: 10.1186/s12862-016-0715-z. Full text in Research Archive Show summary

  Background: A deeply rooted phylogenetic lineage of Mycobacterium tuberculosis (M. tuberculosis) termed lineage 7 was discovered in Ethiopia. Whole genome sequencing of 30 lineage 7 strains from patients in Ethiopia was performed. Intra-lineage genome variation was defined and unique characteristics identified with a focus on genes involved in DNA repair, recombination and replication (3R genes). Results: More than 800 mutations specific to M. tuberculosis lineage 7 strains were identified. The proportion of non-synonymous single nucleotide polymorphisms (nsSNPs) in 3R genes was higher after the recent expansion of M. tuberculosis lineage 7 strain started. The proportion of nsSNPs in genes involved in inorganic ion transport and metabolism was significantly higher before the expansion began. A total of 22346 bp deletions were observed. Lineage 7 strains also exhibited a high number of mutations in genes involved in carbohydrate transport and metabolism, transcription, energy production and conversion. Conclusions: We have identified unique genomic signatures of the lineage 7 strains. The high frequency of nsSNP in 3R genes after the phylogenetic expansion may have contributed to recent variability and adaptation. The abundance of mutations in genes involved in inorganic ion transport and metabolism before the expansion period may indicate an adaptive response of lineage 7 strains to enable survival, potentially under environmental stress exposure. As lineage 7 strains originally were phylogenetically deeply rooted, this may indicate fundamental adaptive genomic pathways affecting the fitness of M. tuberculosis as a species.

View all works in Cristin

• Hov, Øystein; Graver, Hans Petter & Tonjum, Tone (2020). Tillit i koronaens tid. Dreyer Forlag A/S. ISBN 978-82-8265-556-9. 148 p.
• Rollag, Halvor; Müller, Fredrik & Tonjum, Tone (2019). Medisinsk mikrobiologi. Gyldendal Akademisk. ISBN 9788205500983. 516 p.
• Tonjum, Tone & Enersen, Morten (2019). Kapittel 8. Normalflora, Medisinsk mikrobiologi 4. utgave. Gyldendal Akademisk. ISBN 9788205500983. 8 p.
• Tonjum, Tone (2016). Neisseria. Elsevier. ISBN 978-0-7020-6285-8. 13 p.

View all works in Cristin

• Tonjum, Tone (2021). Role of Post-translational Modifications in Antimicrobial Resistance . Show summary

  Background: The public health challenge of antimicrobial resistance (AMR) is escalating rapidly throughout the world, while the number of effective antimicrobial drugs continues to decrease. Numerous microbial DNA mutations and horizontal gene transfer events that directly cause or contribute to AMR have been identified and thoroughly characterized. Now we are discovering that additional mechanisms, such as macromolecular decorations of proteins, termed post-translational modifications (PTMs), also are implicated in AMR development. Tuberculosis (TB) is one of the top 10 causes of death worldwide. This devastating infectious disease, caused by Mycobacterium tuberculosis (Mtb), was reported to be the cause of 10 million new cases. and 1.5 million deaths in 2019. Methods: Mtb members of lineages 3, 4, 5 and 7 were investigated to better understand the evolution of virulence and AMR. Unique and shared proteomic signatures, as deduced from quantitative bioinformatics analyses of high-resolution mass spectrometry data, were delineated and related to phenotypic traits. Results: The slow-growing Lineage 7 exhibited increased abundance of proteins involved in DNA repair, secretion and the CRISPR/Cas system as compared to the other lineages. MDR strains of lineage 2 had a reduced abundance of proteins involved in DNA repair and CRISPR/Cas. Notably, protein PTMs such as glycosylation and acetylation were found to play a significant role in Mtb adaptive processes and in AMR. Discussion: The study identified several clinically important glycosylated and acetylated proteins that are applicable for diagnostics as well as for drug and vaccine discovery, highly relevant for improved global health in a next-generation setting.

• Johansen, Truls E. Bjerklund; Cai, Tommaso; Naber, Kurt; Nicolle, Lindsay E.; Tandogdu, Zafer & Tonjum, Tone [Show all 9 contributors for this article] (2021). Gravide bør screenes for asymptomatisk bakteriuri. Tidsskrift for Den norske legeforening. ISSN 0029-2001. 141(11), p. 1–5. doi: 10.4045/tidsskr.21.0379.
• Kaniusaite, Milda; Riaz, Tahira; Lillenes, Meryl Sønderby; Detlie, Trond Espen; Alfredo, Rabano & Tonjum, Tone (2020). On the Brain-Gut axis: The gut microbiome affects the differential expression of DNA repair pathways in the human brain and mucosal gut tissue.
• Tonjum, Tone (2020). Epi-Omics – to the next level.
• Riaz, Tahira & Tonjum, Tone (2020). Resistance mechanisms and novel drug targets.
• Tonjum, Tone (2019). Tuberculosis and Machine learning. Show summary

  Antimicrobial resistance (AMR) represents a health threat that demands joint action globally. At TTA4, we will address bacterial physiology, metabolism, virulence and host adaptation, exemplified by Mycobacterium tuberculosis (Mtb), and how genome dynamics impact on Mtb fitness adaptation in changing environments and on antimicrobial resistance (AMR). The topics addressed will be relevant for mycobacterial pathogenesis and evolution, genome dynamics and AMR in general. Biochemical, genetic, live imaging and ultrastructural approaches are used to probe the interactions between proteins of these pathways. The objective of the meeting is to highlight recent progress, to reveal a more integrated understanding of the architecture of mycobacterial physiology, fitness for survival and AMR. A main part of the meeting is dedicated to machine learning relevant for these topics. Infection biology and biomedicine are prime examples of research fields in swift development, not the least because of integrated approaches and multidisciplinary interactions between different segments of the life sciences. The increasing complexity of microbiological data and emergence of Big Data invigorates a need for deep learning, machine learning (ML) and artificial intelligence (AI). All the new –omics data pave the way for ML and AI. Big Data has become too complex for humans to even try to understand their impact. That's what big data is: It's the realization that there exist piles of data beyond the capacity of the traditional human methods of analysis. ML is a field that combines systematic information, computer programming, and AI, all in one synergistic manner. Big data and ML will have a tremendous influence on our society ahead. This presents a serious challenge and is a tremendous opportunity to apply automated techniques to help solve problems in infection biology in the 21st century.

• Lillenes, Meryl Sønderby; Riaz, Tahira; Støen, Mari; Kalayou, Shewit; Rabano, Alberto & Tonjum, Tone (2019). Proteomic Analysis of Brain Tissue from Patients with Alzheimer’s disease and Healthy Controls Reveals Differential Expression of Proteins Involved in Mitochondrial Dysfunction between Brain Domains.
• Tonjum, Tone; Birhanu, Alemayehu Godana; Riaz, Tahira & Yimer, Solomon Abebe (2019). Abundance of post-translational modifications in Mycobacterium tuberculosis. Show summary

  Background Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), one of the top 10 causes of death worldwide and the leading cause of death from infectious disease. Despite the discovery of a multitude of Mtb strains with a high degree of genetic conservation, only a few sub-groups cause extensive outbreaks and antimicrobial drug resistance (AMR), with different clinical presentations in terms of transmissibility, virulence and elicited immune responses. Various regulatory mechanisms contribute to the complexity of the simpler genomes and proteomes of Mtb, and post-translational modifications (PTMs) play a significant role in this variability. PTMs allow bacteria to rapidly alter protein activity in response to host factors and have been implicated in Mtb virulence and AMR. Our aim is to characterize the global acetylome and glycoproteomic profile of different Mtb lineages, to unveil the role of these PTMs in mycobacterial adaptation, survival and AMR. Materials/methods The global acetylome and glycoproteomic patterns in five Mtb strains, four clinical isolates including the slow-growing lineage 7 and the reference strain H37Rv, were analyzed. Mtb cell lysates were subjected to in-gel trypsin digestion and injected into a Nano LC-MS/MS mass spectrometer (Thermo Scientific). The MaxQuant and Perseus softwares were used peptide search and PTM site identification. Poteins were searched for 57 different glycan residues. The findings on N-linked protein glycosylation were verified by manual inspection. The Cytoscape plug-in MCODE was used to develop protein-protein interaction networks. Results Our analysis resulted in the identification of 2944 glycosylation sites on 1325 proteins and 2490 acetylation sites on 953 proteins. Notably, we report 489 sites that were N-glycosylated at N residues (17% of the total glycosylation events). The study identified strain-specific qualitative and quantitative differences in PTM abundances on proteins involved in virulence, pathogenesis and AMR. Conclusions Notably, this study reports a vast abundance of PTMs in clinical Mtb strains and is the first report on N-linked glycosylation and O-acetylation in Mtb. These novel PTM data also explain the role of protein acetylation and glycosylation in creating phenotypic variability and fitness for survival among the genetically conserved lineages of Mtb.

• Degre, M & Tonjum, Tone (2019). Infeksjoner i sentralnervesystemet. In Rollag, Halvor; Müller, Fredrik & Tonjum, Tone (Ed.), Medisinsk mikrobiologi. Gyldendal Akademisk. ISSN 9788205500983. p. 475–482.
• Kristiansen, Bjørn Erik & Tonjum, Tone (2019). Andre gramnegative bakterier. In Rollag, Halvor; Müller, Fredrik & Tonjum, Tone (Ed.), Medisinsk mikrobiologi. Gyldendal Akademisk. ISSN 9788205500983. p. 233–245.
• Kristiansen, Bjørn Erik & Tonjum, Tone (2019). Neisserier og moraxeller. In Rollag, Halvor; Müller, Fredrik & Tonjum, Tone (Ed.), Medisinsk mikrobiologi. Gyldendal Akademisk. ISSN 9788205500983. p. 197–208.
• Mengshoel, Anne Torunn & Tonjum, Tone (2019). Mykobakterier. In Rollag, Halvor; Müller, Fredrik & Tonjum, Tone (Ed.), Medisinsk mikrobiologi. Gyldendal Akademisk. ISSN 9788205500983. p. 160–170.
• Tonjum, Tone (2019). Introduksjon til medisinsk bakteriologi. In Rollag, Halvor; Müller, Fredrik & Tonjum, Tone (Ed.), Medisinsk mikrobiologi. Gyldendal Akademisk. ISSN 9788205500983. p. 32–55.
• Zegeye, Ephrem Debebe; Gómez-Muñoz, Marta; Namouchi, Amine; Balasingham, Seetha; Szpinda, Irena & Förstner, Konrad [Show all 8 contributors for this article] (2019). A nutrient supplement promotes the rapid detection and improved sensitivity of mycobacteria in clinical samples via the differential regulation of dormancy genes and noncoding RNAs.
• Tonjum, Tone; Homberset, Håvard; Eriksson, Jens & kussell, edo (2018). Update on neisserial transformation . Show summary

  The pathogenic Neisseria species, N. meningitidis and N. gonorrhoeae are readily transformed in vitro by exogenous heterologous DNA, such as antibiotic resistance cassettes. The closely related and generally harmless commensal species N. lactamica (Nla) is less tolerant of DNA heterology and has previously not been described to be competent for natural transformation. A possible explanation for this observation is that Nla-specific restriction endonucleases limit the transformability of Nla. Here, we provide evidence to support this hypothesis, including bioinformatics data consistent with the presence of an abundance of restriction-modification (RM) systems in Nla. Bioinformatics studies also demonstrated an aberrantly low frequency of the restriction/modification site CATG in the Nla genome, which can be attributed to restriction site avoidance. Furthermore, inactivation of genes encoding selected endonucleases increased the efficiency of Nla transformation with heterologous DNA. These results suggest that engineered Nla strains in which one or more RM systems are inactivated could be useful tools for developing anti-microbial vaccines.

• Tonjum, Tone (2018). The Brain-Gut Axis: DNA repair and the microbiome.
• Tonjum, Tone (2018). The Brain-Gut axis: Differential expression of DNA repair in human brain and mucosal gut tissue.
• Tonjum, Tone (2018). On the Brain-Gut axis: Impact of DNA repair and the microbiome .
• Tonjum, Tone (2017). News on microbial -omics.
• Tonjum, Tone (2017). Oppdatering - Turning the Tide of AMR.
• Tonjum, Tone (2017). 9 råd til russen. [Internet]. Ekspertsykehuset.
• Tonjum, Tone (2017). Gonore: Sex og lure bakterier. Show summary

  Gonokokker er sosiale bakterier som har noen ville egenskaper. Med sosiale bakterier mener vi at bakteriene lett overføres fra person til person. Siden de trives på slimhinner i kjønnsorganer, urinrør, endetarm og hals skjer dette hovedsakelig via seksuell kontakt, både vaginalt, oralt og analt. De ville egenskapene er at de ligger bak kjønnssykdommen gonoré som i dag er blitt vanskelig å behandle da mange av disse bakteriene er blitt motstandsdyktige mot de fleste av de antibiotika vi har tilgjengelig.

• Tonjum, Tone (2017). Chromosomally mediated antibiotic resistance.
• Tonjum, Tone (2017). Antimicrobial resistance in Mycobacterium tuberculosis.
• Tonjum, Tone (2017). Mycobacterial genome dynamics and evolution.
• Tonjum, Tone (2017). Antimicrobial resistance and the microbiome in a One Health Perspective.
• Tonjum, Tone (2017). Leading multicultural and multidisciplinary research teams.
• Tonjum, Tone (2017). Genome dynamics driving evolution and drug resistance in Mycobacterium tuberculosis .
• Tonjum, Tone (2017). Novel anti-microbial strategies.
• Tonjum, Tone (2017). Turning the tide of antimicrobial resistance.
• Tonjum, Tone (2017). Turning the Tide of Antimicrobial Resistance - an update.
• Tonjum, Tone; Krengel, Ute & Heggelund, Julie Elisabeth (2017). 5 alternativer til antibiotika.
• Tonjum, Tone & Dyrhol-Riise, Anne Ma (2017). Resistent tuberkulose på vei inn i landet. Show summary

  Tuberkulose (TB) er en av verdens 10 mest dødelige sykdommer. TB er forårsaket av tuberkulosebakterien og sprer seg via luft- og dråpesmitte. Hvert år blir ca 500 000 mennesker syke av multiresistente tuberkulosebakterier. Da vil ikke vanlige tuberkulosemedisiner fungere. Disse bakteriene finner også veien til Norge.

• Tonjum, Tone (2017). Antibiotics: What are the alternatives?
• Tonjum, Tone (2017). Fighting the superbugs: Turning the tide of antimicrobial resistance.
• Tonjum, Tone; Birhanu, Alemayehu Godana; Noer, Marie Therese & Szpinda, Irena (2017). Proteomic analysis of Mycobacterium tuberculosis membrane vesicles under stress - EP 0415.
• Yimer, Solomon Abebe; Yimer, Solomon Abebe & Tonjum, Tone (2016). Current knowledge on Mycobacterium tuberculosis lineage 7: the paradox of slow growth and still success.
• Yimer, Solomon Abebe; Birhanu, Alemayehu Godana; Shewit, Kalayou; Riaz, Tahira; Zegeye, Ephrem Debebe & Beyene, Getachew Tesfaye [Show all 11 contributors for this article] (2016). First proteomic analysis of Mycobacterium tuberculosis lineage 7 differentially expressed proteins involved for growth.
• Frye, Stephan Alfons; Balasingham, Seetha; Beyene, Getachew Tesfaye; Homberset, Håvard; Namouchi, Amine & Tonjum, Tone (2016). Meningococcal DNA binding and unwinding proteins. Show summary

  Background: DNA helicases are a ubiquitous group of enzymes that use the energy of nucleoside triphosphate (dNTP) hydrolysis to catalyze the separation of double-stranded DNA (dsDNA). Helicases are involved in essentially every step in DNA metabolism, including replication, DNA repair, recombination, transcription, Holliday junction movement, and displacement of proteins from DNA. We investigated the DNA helicases RecG and DinG from Neisseria meningitidis (NmRecG and NmDinG) and their roles during genotoxic stress, including DNA damage. These helicases belong to superfamily 2, are ATP dependent and exert 5′to 3′ directionality. Our aim was to define the potential roles of NmRecG and NmDinG in DNA repair, recombination and replication (3R). Methods and results: Cell lysates from Nm wildtype and recG and dinG null mutants (NmrecG and dinG) were assessed by quantitative mass spectrometry (MS). In the ∆recG mutant, 16 proteins were differentially expressed as compared to the Nm wildtype. RecN, Ssb and DnaX were upregulated in the Nm∆recG mutant, while the type 4 pilus structural subunit protein PilE as well as pilus biogenesis components (PilF, PilT and PilQ) were downregulated. Global proteomics analysis of Nm wildtype and ∆recG mutant strains thus revealed the most abundant differentially expressed proteins and linked RecG to DNA repair, recombination and replication, pilus biogenesis components and glycan biosynthesis. Notably, when NmdinG cells grown under mitomycin C (MMC) stress, 134 proteins were shown to be differentially abundant compared to the unstressed NmdinG. Most of them are involved in metabolic functions like carbon, amino acid and nucleotide synthesis. Among 3R proteins, polymerase III subunits and recombinational repair proteins RuvA, RuvB, RecB and RecD were significantly downregulated while TopA and SSB were upregulated under stress. Genotoxic stress analysis demonstrated that NmdinG was more sensitive to double-strand DNA breaks (DSB) induced MMC than the Nm wildtype, defining the role of neisserial DinG in DSB repair. An unusually high number of DNA uptake sequences (DUS) that facilitate the transformation in neisserial species were identified in the Nm recG gene, signifying its importance. The genes encoding NmRecG and NmDinG were cloned and overexpressed, the recombinant NmRecG and NmDinG proteins were purified to homogeneity and their enzymatic activity was characterized. NmRecG acts through its ability to process Holliday junction (HJ) intermediates and catalyse branch migration of complex DNA structures. NmRecG and NmDinG possess 5′to3′ directionality and prefer DNA substrates containing a 5′overhang. ATPase activity of NmRecG and NmDinG is strictly DNA-dependent, and DNA unwinding activity requires nucleoside triphosphate in addition to divalent metal cations. This study contributes to understand the overall role of RecG in neisserial genome maintenance and evolution. Conclusions: This study gives new insight into the functional roles and interactions of the helicases RecG and DinG, elucidation their roles in meningococcal DNA repair and recombination, with a link of RecG to transformation also through pilus biogenesis.

• Tonjum, Tone; Riaz, Tahira; Lillenes, Meryl Sønderby; Detlie, Trond Espen & Jensen, Helge Leander B. (2016). The Brain-Gut axis: Differential expression of DNA repair in human brain and mucosal gut tissue . Show summary

  The biology of the neurological and gastrointestinal systems are tightly interconnected, interacting with and influencing each other through multiple bidirectional signaling pathways. The human microbiome strongly influences the physiology of all organs including the central nervous system (CNS), and the CNS in turn modulates gut function, beyond the effects of the vagal nerve. Therefore, imbalance in the brain-gut axis could correlate with incipient pathology in the CNS and/or the gastrointestinal tract. We asked if and how the gut microbiome modulates susceptibility to progressive neurodegenerative Alzheimer’s disease (AD). The primary hypothesis we are testing is that imbalance in the brain-gut axis promotes neurodegeneration or gastrointestinal dysfunction, or both. The proteomic expression profile was tested in post-mortem human brain tissue and gut mucosal biopsies. In terms of DNA repair, predominant base excision repair (BER) was expressed in brain tissue, while nucleotide excision repair (NER) was more highly expressed in the gut mucosa. This differential expression pattern reflects local stress and organ environments, both the nature of non-replicating versus replicating cells as well as the state of a sterile organ versus that of an organ with a rich microbiome. Different DNA repair responses were evident in the prodromal versus late stages of AD and in IBD. We have previously shown that signature reactions in BER patterns in brain appear before AD pathology is evident and may represent a response to increased oxidative stress. These studies extend our findings on DNA repair and bioenergetics in AD and IBD, and will also address the contribution of the gut microbiome.

• Tonjum, Tone (2016). Utvikling av antibiotikaresistens hos Gramnegative og Grampositive bakterier: påvisning og ny behandling .
• Tonjum, Tone (2016). NORBRAIN: The Norwegian Brain Initiative and Infrastructure.
• Tonjum, Tone (2016). The antimicrobial resistance challenge from a Nordic view .
• Birhanu, Alemayehu Godana; Yimer, Solomon Abebe; Riaz, Tahira & Tonjum, Tone (2016). Proteomic Analysis of Mycobacterium tuberculosis Membrane Vesicles. Show summary

  Secreted membrane vesicles (MVs) are abundant in Mycobacterium tuberculosis (Mtb) and are suggested to have important roles in mycobacterial physiology and pathogenesis. MVs may contain varied cargo, including nucleic acids, toxins, lipoproteins and enzymes. In particular, MVs have been shown to serve as a vehicle for the selective packaging and release of virulence factors, such as toxins and immunomodulatory molecules. However, how and why MVs escape the thick cell walls of mycobacteria is still unknown. The aim of this project is characterize the proteomic profile of MVs from selected Mtb lineages and to unveil the role of MVs in mycobacterial adaptation to environmental factors. Mtb cells were cultured with and without oxidative and nitrosative stress. The Mtb cell free culture supernatant was used as a source to isolate enriched MVs by density gradient ultra-centrifugation. The purified membrane vesicles were investigated by mass spectrometry. The MaxQuant and Perseus softwares were used for peptide search, data analysis and quality control, respectively. The functional categories of the proteins identified were grouped using the KEGG pathway database. The mass spectrometry proteomic data revealed that MVs contain enriched packaging of virulence associated mycobacterial proteins. A total of 83 proteins were identified in Mtb MVs, out of which 69 were shared with the cellular proteome and 14 were found exclusively in MVs. The majority of the MV-specific components detected were secreted proteins which are reported to be major virulence factors (antigen-85 complexes, ESAT-6 and PE/PPE, etc). Based on the KEGG pathway functional analysis, the identified proteins were found to be involved in two-component systems, ABC transporters, amino acid and fatty acid metabolism, as well as catalytic and hydrolase activity and hypothetical proteins. Thereby, this study generated new knowledge on the proteomic profile of Mtb MVs. We have characterized Mtb membrane vesicles, which are enriched with surface/secreted antigenic proteins and virulence factors. Further in silico and in vitro/in-vivo studies are required to investigate the adaptive and clinical relevance of the MV proteins identified, including the newly discovered un-characterized proteins.

• Jensen, Helge Leander B.; Lillenes, Meryl Sønderby; Günther, Clara-Cecilie; Rabano, Alberto; Ulstein, Ingun & Bøhmer, Thomas [Show all 7 contributors for this article] (2016). The DNA Nucleotide Excision Repair Profile in Blood and Brain Tissue from Patients with Alzheimer's Disease . Show summary

  Alzheimer’s disease (AD) is a progressive, multifactorial neurodegenerative disorder that is the main cause of dementia globally. AD is clinically well characterized, however, little is known about the early etiology. Aging is the greatest risk factor for the development of dementia including AD, and age-related changes are augmented in patients with AD. Increased oxidative stress, resulting from imbalance in production and clearance of reactive oxygen species (ROS), can damage DNA and other macromolecules, leading to genome instability and disrupted cellular functions. Oxidative DNA damage is primarily repaired by the base excision repair (BER) pathway, however, the nucleotide excision repair (NER) pathway repairing helix distorting damages also seems to be involved. NER is known to be associated with neurodegenerative disorders like Cockayne syndrome and some subtypes of Xeroderma pigmentosum, and may play a role in the early stages of AD. To this end, we addressed the role of the NER pathway in the development of AD by comparing the expression of the DNA repair components RAD23B, RPA1, ERCC1, LIG3, PCNA and MPG in blood and post-mortem brain tissue from patients with AD, mild cognitive impairment (MCI) and healthy controls (HC). mRNA levels of the DNA repair components selected were significantly higher in the brain compared to blood. Notably, the expression of LIG3 (frontal cortex) and RPA1 (cerebellum) was higher in the AD brain than in healthy controls. This suggests an important role of NER in the brain relevant for the etiology of AD.

• Birhanu, Alemayehu Godana; Yimer, Solomon Abebe; Riaz, Tahira & Tonjum, Tone (2016). Proteomic Analysis of Mycobacterium tuberculosis Membrane Vesicles.
• Birhanu, Alemayehu Godana; Yimer, Solomon Abebe; Riaz, Tahira & Tonjum, Tone (2016). Proteomic Analysis of Mycobacterium tuberculosis Membrane Vesicles. Show summary

  Studies in the last decades have demonstrated the importance of secreted proteins in bacterial pathogenesis. Secreted membrane vesicles (MVs), in particular, have been suggested to serve as a vehicle for the selective packaging and release of virulence factors, such as toxins and immunomodulatory molecules (1-2). Previous studies on Mycobacterium tuberculosis (Mtb) pathogenesis have shown that phagocytosed dead bacilli with no secreted proteins lose their ability to hinder phagosome-lysosome fusion (3). Therefore, understanding the contents and mechanism of action of MV proteins will lead to deeper understanding of TB disease. The aim of this project is characterise the proteomic profile of Mtb MVs to unveil their role in host-pathogen interaction. Mtb H37Rv cells were cultured in minimal media (MM) at 37 °C to mid-log phase (OD600 = 0.8) and the filtered cell free supernatant was used as a source to isolate MVs by density gradient ultra-centrifugation (4). The purified membrane vesicles and cellular pellets were loaded on Bis-Tris Protein Gels (4-12%) for in-gel digestion and cleaned up using c-18 zip-tip columns (5) before injection into the Q-Exactive mass spectrometer (Thermo Scientific, Germany) in triplicates. MaxQuant software was used to define the amounts of the various peptides present and the data was analyzed using Perseus software. The functional categories for the differentially expressed proteins identified were grouped using the KEGG database. The concentration and size distribution of membrane vesicles isolated were measured using NanoSight and the size ranges from 70-400 nm in diameter. Next-generation mass spectrometry revealed that there is enriched packaging of virulence associated mycobacterial proteins in MVs. A total of 83 proteins were identified in Mtb MVs out of which 69 are shared with the cellular proteome and 14 found exclusively in MVs. The majority of the MV components detected were secreted proteins which are reported to be major virulence factors (antigen 85 complex, ESAT-6 and PE/PPE). Furthermore, 71 proteins have never been reported in Mtb membrane vesicles before (2, 4), and some of the proteins were uncharacterized. KEGG pathway enrichment analysis showed proteins involved in two-component systems, ABC transporters, amino acid and fatty acid metabolism, and catalytic and hydrolase activity. This study generated new knowledge on the proteomic profile of Mtb MVs and their surface-exposed antigens. We have characterized Mtb membrane vesicles, which are enriched with surface/secreted antigenic proteins and virulence factors. Further in-silico and in-vitro/in-vivo study is needed to investigate the clinical relevance of the MV proteins identified, including the newly discovered un-characterized proteins. References: 1. Kuehn MJ, Kesty NC. Bacterial outer membrane vesicles and the host–pathogen interaction. Genes & development. 2005 Nov 15;19(22):2645-55. 2. Lee J, Kim SH, Choi DS, Lee JS, Kim DK, Go G, Park SM, Kim SH, Shin JH, Chang CL, Gho YS. Proteomic analysis of extracellular vesicles derived from Mycobacterium tuberculosis. Proteomics. 2015 Oct 1;15(19):3331-7. 3. Russell DG, Purdy GE, Owens RM, Rohde KH, Yates RM. Mycobacterium tuberculosis and the four minute phagosome. ASM News. 2005;71:459–463. 4. Prados-Rosales R, Brown L, Casadevall A, Montalvo-Quirós S, Luque-Garcia JL. Isolation and identification of membrane vesicle-associated proteins in Gram-positive bacteria and mycobacteria. MethodsX. 2014 Dec 31;1:124-9 5. Wiśniewski JR, Zougman A, Mann M. Combination of FASP and StageTip-based fractionation allows in-depth analysis of the hippocampal membrane proteome. J Proteome Res 8(12):5674-8, 2009.

• Gomez Munoz, Marta; Namouchi, Amine; Balasingham, Seetha & Tonjum, Tone (2016). Identifiying ncRNAs expressed under genotoxic stress and dormancy in Mycobacterium tuberculosis. Show summary

  Mycobacterium tuberculosis (Mtb) is the intracellular pathogen that causes tuberculosis (TB), an infectious disease responsible for 1.5 million deaths worldwide in 2015. This bacterium is inhaled in aerosol droplets and once in the lung, it is engulfed by alveolar macrophages. Inside the activated macrophage, Mtb is exposed to a hostile environment, including reactive oxygen species (ROS) and reactive nitrogen species (RNS) that cause oxidation, deamination and alkylation of macromolecules. This condition is fatal to most bacterial pathogens, but Mtb has the ability to sense the host environment and eventually enter into a non-replicating, persistent state. The tubercle bacilli can remain in this latent stage for a lifetime without causing disease or, under certain conditions, it can awake resulting in TB disease. In this context, the aim of our study is to identify and characterize non-coding RNAs (ncRNAs) transcribed under genotoxic stress as well as during reactivation from the dormant stage. Here, Mtb strain H37Rv was exposed to various forms of genotoxic stress (oxidative, nitrosative or alkylative stress or double strand DNA breaks) and defined culture supplements. Total RNA from treated and untreated H37Rv cells was isolated and subjected to high-throughput RNA-seq. ncRNAs were identified using Rockhopper. A subset of the ncRNAs detected was selected for a more detailed analysis, including validation by northern blot. The secondary structure of the ncRNAs under study was predicted using mfold and their potential gene targets were predicted using intaRNA and CopraRNA. Ahead, we will combine our molecular and bioinformatics results with in vitro studies, including mapping 5’ and 3’ by RACE, establishing their secondary structure with SHAPE, and detecting sRNA-mRNA interactions by performing EMSA. The potential physiological role of the Mtb ncRNAs predicted will be tested by employing mutants or by repression, deletion or over-expression of the ncRNA of interest and measuring the potential phenotypic outcome by next-generation quantitative mass spectrometry.

• Lillenes, Meryl Sønderby & Tonjum, Tone (2016). Altered DNA base excision repair profile in brain tissue and blood in Alzheimer's disease.
• Lillenes, Meryl Sønderby; Riaz, Tahira; Rabano, Alberto; Fladby, Tormod & Tonjum, Tone (2016). Altered DNA base excision repair profile in brain tissue and blood in Alzheimer's disease. Show summary

  Alzheimer’s disease (AD) is the major contributor to cognitive decline and dementia worldwide. Considering the expanding numbers of elderly in our society, studies of health and disease in the aging population is increasingly important. In order to understand AD, one must understand normal aging. AD is preceded by mild cognitive impairment (MCI), and once MCI occurs, early diagnostics and therapies are urgently needed. MCI/AD is associated with increased oxidative stress, resulting from imbalance in production and clearance of reactive oxygen species (ROS). ROS can damage DNA and other macromolecules, leading to genome instability and disrupted cellular functions. To counteract the harmful effects of oxidative DNA damage, cells use the base excision repair (BER) pathway. We have monitored the expression of the DNA repair profile in human blood and post-mortem brain biopsies from AD and MCI patients and healthy aged individuals by transcriptional profiling and mass spectrometry. In this context, we have a particular a focus on selected BER components, to define if the expression profile varies between AD patients as compared to healthy controls. Notably, BER expression was significantly higher in brain tissue compared to blood. BER mRNA levels were correlated to clinical signs and cerebrospinal fluid biomarkers for AD. Blood mRNA levels of OGG1 was low and PARP1 high in MCI and AD. These findings suggest that alteration in BER gene expression is an event preceding AD and reflect the oxidative stress-generating energy-consumption in the brain and the importance of BER in repairing these damage events. Collectively, these studies provide new keys to understanding early events in the progression of AD and also expand the pool of potential biomarkers for pre-clinical AD

• Tonjum, Tone (2015). Genome dynamics in the brain-gut axis: Vesicles, microbes and DNA repair .
• Tonjum, Tone (2015). Meningococcal recombination and transformation .
• Tonjum, Tone (2015). Neisseria lactamica phylogeny, antigens and vaccine potential.
• Riaz, Tahira; Kubendraraj, Shivani; Sanjeevan, Sharuga; Tonjum, Tone; Støen, Mari & Vagolu, Siva Krishna [Show all 7 contributors for this article] (2022). Nye forbindelser i bekjempelsen mot antibiotikaresistent tuberkulose. OsloMet - storbyuniversitetet.
• Riaz, Tahira; Tønjum, Tone; Støen, Mari; Berge, Tone; Sukenthirarasa, Pravina & Ka Wai Kai, Celina (2021). New Drugs to Combat AMR. OsloMet - storbyuniversitetet.
• Riaz, Tahira; Tonjum, Tone & Olsen, Ingrid (2019). Proteomic approaches to study CD4+ T cells and meningococci: New insight into life science and infection biology. Universitetet i Oslo. ISSN 978-82-8377-448-1.
• Birhanu, Alemayehu Godana; Tonjum, Tone & Abebe, Markos (2019). Unveiling phenotypic differences among the genetically conserved Mycobacterium tuberculosis complex: Characterization of proteomes and post-translational modifications. Universitetet i Oslo. ISSN 978-82-8377-456-6. Full text in Research Archive Show summary

  The Mycobacterium tuberculosis complex (MTBC) is the causative agent of tuberculosis (TB), one of the world's deadliest communicable diseases with 10 million new cases and 1.6 million deaths in 2017. Despite the high degree of genomic conservation among members of the MTBC, TB infections exhibit vast discrepancies in clinical outcomes and epidemiological behavior. Bacterial factors that contribute to this phenotypic variability remain elusive and cannot be explained by MTBC genomics alone. We hypothesize that qualitative and quantitative differences in the abundance of proteins and post-translational modifications (PTMs) may explain the phenotypic diversity across members of the MTBC. This study analyzed the proteomic and PTM (acetylation and glycosylation) profiles among members of the MTBC. These two PTMs are reported to be important determinants of MTBC virulence and pathogenicity. Shotgun-based proteomics yielded the identification of 2867 MTBC proteins. Quantitative proteomic analysis of the MTBC reference strain H37Rv and slow-growing lineage 7 strains demonstrated a differential abundance of proteins involved in virulence growth and bioenergetics. The acetylome analysis identified 2490 class-I acetylation sites on 953 proteins. The MTBC proteins found to be acetylated are involved in core metabolic processes, bioenergetics, virulence,and drug resistance. Notably, O-acetylation of MTBC was described for the first time. Quantitative PTM analysis revealed reduced acetylation on 97.5% of the differentially acetylated virulence factors in MTBC lineage 7 strains as compared to H37Rv. The glycoproteomic analysis of clinical MTBC strains representing lineages 3, 4, 5 and 7 identified 2944 glycosylation events on 1325 proteins. These proteins are involved in MTBC cell envelope biogenesis, pathogen-host interaction, membrane transport, and pathogenesis. The study also provides the first report on Nlinked glycosylation in MTBC and in Gram-positive bacteria. Quantitative analysis revealed differential glycosylation of 67 proteins involved in MTBC fitness and survival. Identification of glycoproteins and their function contributes to a better understanding of the pathogenesis and survival strategies adopted by MTBC, which is fundamental to diseases management. The data represents the highest number of acetylated and glycosylated proteins in MTBC recorded to date. The presence of significant differences in the proteome and PTMs among MTBC lineages may directly influence the strain phenotype. This will enable improved understanding in the adaptive potential of the pathogen with new potential for identification of novel drug targets, vaccine candidates and efficient TB diagnosis.

View all works in Cristin