Publications
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Li, Youxian; Watanabe, Eiichiro; Kawashima, Yusuke; Plichta, Damian R.; Wang, Zhujun & Ujike, Makoto
[Show all 32 contributors for this article]
(2022).
Identification of trypsin-degrading commensals in the large intestine.
Nature.
ISSN 0028-0836.
609(7927),
p. 582–589.
doi:
10.1038/s41586-022-05181-3.
Full text in Research Archive
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Abstract Increased levels of proteases, such as trypsin, in the distal intestine have been implicated in intestinal pathological conditions 1–3 . However, the players and mechanisms that underlie protease regulation in the intestinal lumen have remained unclear. Here we show that Paraprevotella strains isolated from the faecal microbiome of healthy human donors are potent trypsin-degrading commensals. Mechanistically, Paraprevotella recruit trypsin to the bacterial surface through type IX secretion system-dependent polysaccharide-anchoring proteins to promote trypsin autolysis. Paraprevotella colonization protects IgA from trypsin degradation and enhances the effectiveness of oral vaccines against Citrobacter rodentium . Moreover, Paraprevotella colonization inhibits lethal infection with murine hepatitis virus-2, a mouse coronavirus that is dependent on trypsin and trypsin-like proteases for entry into host cells 4,5 . Consistently, carriage of putative genes involved in trypsin degradation in the gut microbiome was associated with reduced severity of diarrhoea in patients with SARS-CoV-2 infection. Thus, trypsin-degrading commensal colonization may contribute to the maintenance of intestinal homeostasis and protection from pathogen infection.
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Loevenich, Simon; Malmo, Jostein; Liberg, Ann Magritt; Sherstova, Tatyana; Li, Youxian & Rian, Kristin
[Show all 8 contributors for this article]
(2019).
Cell-Type-Specific Transcription of Innate Immune Regulators in response to HMPV Infection.
Mediators of Inflammation.
ISSN 0962-9351.
2019,
p. 1–13.
doi:
10.1155/2019/4964239.
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Human metapneumovirus (HMPV) may cause severe respiratory disease. The early innate immune response to viruses like HMPV is characterized by induction of antiviral interferons (IFNs) and proinflammatory immune mediators that are essential in shaping adaptive immune responses. Although innate immune responses to HMPV have been comprehensively studied in mice and murine immune cells, there is less information on these responses in human cells, comparing different cell types infected with the same HMPV strain. The aim of this study was to characterize the HMPV-induced mRNA expression of critical innate immune mediators in human primary cells relevant for airway disease. In particular, we determined type I versus type III IFN expression in human epithelial cells and monocyte-derived macrophages (MDMs) and dendritic cells (MDDCs). In epithelial cells, HMPV induced only low levels of IFN-β mRNA, while a robust mRNA expression of IFN-λs was found in epithelial cells, MDMs, and MDDCs. In addition, we determined induction of the interferon regulatory factors (IRFs) IRF1, IRF3, and IRF7 and critical inflammatory cytokines (IL-6, IP-10, and IL-1β). Interestingly, IRF1 mRNA was predominantly induced in MDMs and MDDCs. Overall, our results suggest that for HMPV infection of MDDCs, MDMs, NECs, and A549 cells (the cell types examined), cell type is a strong determinator of the ability of HMPV to induce different innate immune mediators. HMPV induces the transcription of IFN-β and IRF1 to higher extents in MDMs and MDDCs than in A549s and NECs, whereas the induction of type III IFN-λ and IRF7 is considerable in MDMs, MDDCs, and A549 epithelial cells.
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Li, Youxian; Østerhus, Stine & Johnsen, Ingvild Bjellmo
(2018).
Human Metapneumovirus Infection Inhibits Cathelicidin Antimicrobial Peptide Expression in Human Macrophages.
Frontiers in Immunology.
9(MAY),
p. 1–10.
doi:
10.3389/fimmu.2018.00902.
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Human cathelicidin antimicriobial peptide (CAMP) is a critical component of host innate immunity with both antimicrobial and immunomodulatory functions. Several pathogens have been shown to downregulate CAMP expression, yet it is unclear if such modulation occurs during a viral infection. In this study, we showed that infection with human metapneumovirus (hMPV), one of the leading causes of respiratory tract infections in young children, strongly suppressed basal and vitamin-D induced CAMP expression in human macrophages. hMPV-mediated suppression of CAMP did not correlate with reduced transcriptional expression of key vitamin D signaling components, such as CYP27B1 or vitamin D receptor, suggesting a vitamin D-independent mechanism. Blocking interferon-signaling pathways did not reverse hMVP-mediated suppression of CAMP, indicating that the suppressive effect is largely interferon-independent. Instead, we identified C/EBPα as the key modulator of hMPV-mediated suppression of CAMP. hMPV infection strongly repressed the expression of C/EBPα, and a knockdown study confirmed that C/EBPα is critical for CAMP expression in human macrophages. Such modulation of CAMP (and C/EBPα) could be reproduced by TLR1/2 ligand treatment in human macrophages, suggesting a common mechanism underlying pathogen-mediated downregulation of CAMP through C/EBPα. This study opens up a new understanding of altered human antimicrobial responses following infections.
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Li, Youxian; Lund, Cecilie; Nervik, Ida; Loevenich, Simon; Døllner, Henrik & Anthonsen, Marit Walbye
[Show all 7 contributors for this article]
(2018).
Characterization of signaling pathways regulating the expression of pro-inflammatory long form thymic stromal lymphopoietin upon human metapneumovirus infection.
Scientific Reports.
8,
p. 1–11.
doi:
10.1038/s41598-018-19225-0.
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Thymic stromal lymphopoietin (TSLP) is associated with several allergic diseases including asthma. Two isoforms of TSLP exist in humans, a long form (lfTSLP) and a short form (sfTSLP), displaying distinct immunological functions. Recently, TSLP was found to be upregulated in human airway cells upon human metapneumovirus (hMPV) infection, yet it remains unclear if the two isoforms are regulated differently during hMPV infection. Importantly, the molecular mechanisms underlying hMPV-mediated TSLP induction remain undescribed. In this study, we characterized the expression and regulation of TSLP in hMPV-infected human airway cells. We demonstrated that hMPV strongly induced the expression of pro-inflammatory lfTSLP in human airway epithelial cells and lung fibroblasts. Further, knockdown of pattern recognition receptors retinoic acid-inducible gene I (RIG-I) or Toll-like receptor 3 (TLR3), as well as downstream signal transducers, abrogated hMPV-mediated lfTSLP induction. Importantly, silencing of TANK-binding kinase 1 (TBK1) also impaired hMPV-mediated lfTSLP induction, which could be attributed to compromised NF-κB activation. Overall, these results suggest that TBK1 may be instrumental for hMPV-mediated activation of NF-κB downstream RIG-I and TLR3, leading to a specific induction of lfTSLP in hMPV-infected human airway cells.
View all works in NVA
Published
Oct. 24, 2023 11:51 AM
- Last modified
Oct. 26, 2023 2:00 PM
