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1.
Cell ; 183(5): 1312-1324.e10, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33212011

RESUMO

Interferon (IFN)-Is are crucial mediators of antiviral immunity and homeostatic immune system regulation. However, the source of IFN-I signaling under homeostatic conditions is unclear. We discovered that commensal microbes regulate the IFN-I response through induction of IFN-ß by colonic DCs. Moreover, the mechanism by which a specific commensal microbe induces IFN-ß was identified. Outer membrane (OM)-associated glycolipids of gut commensal microbes belonging to the Bacteroidetes phylum induce expression of IFN-ß. Using Bacteroides fragilis and its OM-associated polysaccharide A, we determined that IFN-ß expression was induced via TLR4-TRIF signaling. Antiviral activity of this purified microbial molecule against infection with either vesicular stomatitis virus (VSV) or influenza was demonstrated to be dependent on the induction of IFN-ß. In a murine VSV infection model, commensal-induced IFN-ß regulated natural resistance to virus infection. Due to the physiological importance of IFN-Is, discovery of an IFN-ß-inducing microbial molecule represents a potential approach for the treatment of some human diseases.


Assuntos
Imunidade Inata , Microbiota , Viroses/microbiologia , Animais , Bacteroides fragilis/fisiologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Colo/patologia , Colo/virologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glicolipídeos/metabolismo , Imunidade Inata/efeitos dos fármacos , Interferon beta/sangue , Interferon beta/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Microbiota/efeitos dos fármacos , Polissacarídeos Bacterianos/farmacologia , Receptor 4 Toll-Like/metabolismo , Vesiculovirus/fisiologia , Viroses/genética
2.
PLoS One ; 12(11): e0188600, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29190678

RESUMO

Type I interferons (IFNα, IFNß) are key regulators of innate and adaptive immunity, modulating the severity of both viral and bacterial infections. While type I IFN signaling leads to improved outcomes in viral infections, its role in bacterial infections is more contextual and depends on the specific pathogen and route of infection. Given the limited evidence on whether type I IFN signaling affects enteric bacterial pathogens, we investigated the role of this signaling pathway in Salmonella enterica serovar Typhimurium (S. typhimurium)-induced colitis. Comparing mice deficient in IFNAR1- the common receptor for IFNα and IFNß- with wild-type mice, we found that type I IFN signaling leads to more rapid death, more severe colonic inflammation, higher serum levels of pro-inflammatory cytokines, and greater bacterial dissemination. Specific ablation of plasmacytoid dendritic cells (pDCs), which are prominent producers of type I IFNs in antiviral responses, did not alter survival after infection. This result established that pDCs do not play a major role in the pathogenesis of S. typhimurium colitis. Flow cytometric analysis of macrophages and conventional dendritic cells (cDCs) during active colitis demonstrated an increase in CD11c- macrophages and CD103+ cDCs in the colon of Ifnar1-/- animals. Interestingly, cells expressing the anti-inflammatory cytokine receptor IL-10R are more abundant within these subsets in Ifnar1-/- than in wild-type mice. Moreover, blockade of IL-10R in Ifnar1-/- mice increased their susceptibility to S. typhimurium colitis, suggesting that altered numbers of these immunoregulatory cells may underlie the difference in disease severity. This cross-talk between type I IFN and IL-10R signaling pathways may represent a key host cellular mechanism to investigate further in order to unravel the balance between pathogenic inflammation and homeostasis of the colon. Taken together, our data clearly demonstrate that type I IFN signaling is pathogenic in S. typhimurium colitis.


Assuntos
Colite/patologia , Células Dendríticas/metabolismo , Interferon Tipo I/metabolismo , Mucosa Intestinal/metabolismo , Macrófagos/metabolismo , Receptores de Interleucina-10/metabolismo , Infecções por Salmonella/metabolismo , Transdução de Sinais , Animais , Colite/metabolismo , Colite/microbiologia , Citocinas/metabolismo , Mucosa Intestinal/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infecções por Salmonella/microbiologia , Salmonella typhimurium/metabolismo , Índice de Gravidade de Doença
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