Intestinal Microbiota of Mice Influences Resistance to Staphylococcus aureus Pneumonia

Abstract

c Th17 immunity in the gastrointestinal tract is regulated by the intestinal microbiota composition, particularly the presence of segmented filamentous bacteria (sfb), but the role of the intestinal microbiota in pulmonary host defense is not well explored. We tested whether altering the gut microbiota by acquiring sfb influences the susceptibility to staphylococcal pneumonia via induction of type 17 immunity. Groups of C57BL/6 mice which differed in their intestinal colonization with sfb were challenged with methicillin-resistant Staphylococcus aureus in an acute lung infection model. Bacterial burdens, bronchoalveolar lavage fluid (BALF) cell counts, cell types, and cytokine levels were compared between mice from different vendors, mice from both vendors after cohousing, mice given sfb orally prior to infection, and mice with and without exogenous interleukin-22 (IL-22) or anti-IL-22 antibodies. Mice lacking sfb developed more severe S. aureus pneumonia than mice colonized with sfb, as indicated by higher bacterial burdens in the lungs, lung inflammation, and mortality. This difference was reduced when sfb-negative mice acquired sfb in their gut microbiota through cohousing with sfb-positive mice or when given sfb orally. Levels of type 17 immune effectors in the lung were higher after infection in sfb-positive mice and increased in sfb-negative mice after acquisition of sfb, as demonstrated by higher levels of IL-22 and larger numbers of IL-22؉ TCR␤ ؉ cells and neutrophils in BALF. Exogenous IL-22 protected mice from S. aureus pneumonia. The murine gut microbiota, particularly the presence of sfb, promotes pulmonary type 17 immunity and resistance to S. aureus pneumonia, and IL-22 protects against severe pulmonary staphylococcal infection.

The regulation of host defences to infection by the microbiota

“…This hypothesis is supported by a study showing that mice with segmented filamentous bacteria (SFB) in the gastrointestinal tract survive Staphylococcus aureus pneumonia better than those without 61. SFB are known to regulate T‐cell differentiation in the murine intestine, which protects against intestinal infection,47 but this new work demonstrates that SFB also play a wider role in enhancing extra‐intestinal host defences.…”

“…SFB are known to regulate T‐cell differentiation in the murine intestine, which protects against intestinal infection,47 but this new work demonstrates that SFB also play a wider role in enhancing extra‐intestinal host defences. After intranasal infection with methicillin‐resistant Staphylococcus aureus , SFB‐negative mice had higher bacterial burdens in the lung and spleen, compared with SFB‐positive mice 61. Mice colonized with SFB had increased numbers of IL‐22‐producing cells in the lung, a cytokine known to enhance epithelial barrier integrity and drive the production of antimicrobial peptides crucial for mucosal defences 64.…”

“…The importance of this cytokine was demonstrated by experiments showing that addition of recombinant IL‐22 to SFB‐negative mice rescued defects in lung immunity caused by the absence of SFB, and neutralization of IL‐22 in SFB‐positive mice abrogated any differences between SFB‐positive and SFB‐negative animals. If SFB‐negative mice were made SFB‐positive by co‐housing with SFB‐positive mice, or by oral gavage with SFB‐positive faeces, their defences against staphylococcal pneumonia were enhanced 61. Hence, differing microbiota compositions can have a significant impact on the host's resistance to extra‐intestinal infection.…”

Розвиток Імунної Відповіді При Стафілококовій Пневмонії (Частина 3)

“…В то время как все IFN I типа взаимодействуют с общим гетеродимерным рецептором -IFNAR (IFNAR1 и IFNAR2), IFN-λ связываются с IFNLR, который представляет собой уникальный гетеродимерный рецептор, состоящий из двух субъединиц: общей с рецепторным семей-ством IL-10R субъединицы IL10Rβ, и специфиче-ской для IFN-λ субъединицы IFNLR1 или IL28Rα [58]. Интерфероны III типа, взаимодействуя со сво-им рецептором, активируют факторы транскрипции IRF-1, IRF-3, IRF-7 и NF-κB, которые изменяют экспрессию таргетных генов [33].…”

Microbiote intestinal et développement du système immunitaire

“…La colonisation par SFB est en particulier indispensable pour reproduire la stimulation de la réponse TH17 induite par un microbiote complexe [22,23,32]. De façon intéressante, les effets de la SFB sur la maturation des réponses immunes intestinales murines s'accompagnent d'un effet de barrière vis-à-vis de la colonisation par des bactéries pathogènes, non seulement dans l'intestin [30] mais aussi dans les poumons [33]. Cet effet protecteur a été attribué à l'induction de la réponse TH17 mais aussi, de façon plus indirecte, profondément réduites lors d'un traitement antibiotique.…”