Epithelium‐specific MyD88 signaling, but not DCs or macrophages, control acute intestinal infection with <i>Clostridium difficile</i>

Mamareli, Panagiota; Kruse, Friederike; Friedrich, Chr.; Smit, Nathiana; Strowig, Till; Sparwasser, Tim; Lochner, Matthias

doi:10.1002/eji.201848022

Cited by 5 publications

(5 citation statements)

References 51 publications

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“…There is an increased appreciation that different types of epithelial cells provide signals that help to coordinate the enteric nervous system, gut physiology and mucosal immunity in order to maintain tolerance. For extracellular pathogens, enterocytes promote clearance of the helminth Trichuris muris ( 74 ) and the bacteria Clostridium difficile ( 75 ) and Citrobacter rodentium ( 57 ). Less is known about how enterocytes respond to intracellular infections, although inflammasome-mediated extrusion of Salmonella -infected enterocytes limits bacterial spread ( 76 ).…”

Section: Discussionmentioning

confidence: 99%

Enterocyte–innate lymphoid cell crosstalk drives early IFN-γ-mediated control of Cryptosporidium

et al. 2022

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SUMMARY The intestinal parasite, Cryptosporidium , is a major contributor to global child mortality and causes opportunistic infection in immune deficient individuals. Innate resistance to Cryptosporidium , which specifically invades enterocytes, is dependent on the production of IFN-γ, yet whether enterocytes contribute to parasite control is poorly understood. In this study, utilizing a mouse-adapted strain of C. parvum , we show that epithelial-derived IL-18 synergized with IL-12 to stimulate innate lymphoid cell (ILC) production of IFN-γ required for early parasite control. The loss of IFN-γ-mediated STAT1 signaling in enterocytes, but not dendritic cells or macrophages, antagonized early parasite control. Transcriptional profiling of enterocytes from infected mice identified an IFN-γ signature and enrichment of the anti-microbial effectors IDO, GBP and IRG. Deletion experiments identified a role for Irgm1/m3 in parasite control. Thus, enterocytes promote ILC production of IFN-γ that acts on enterocytes to restrict the growth of Cryptosporidium .

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Section: Discussionmentioning

confidence: 99%

Enterocyte–innate lymphoid cell crosstalk drives early IFN-γ-mediated control of Cryptosporidium

et al. 2022

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“…However, this raises the question as to why animals infected with FM2.5, that show high and equivalent levels of tissue colonisation by 48 hpi and which are producing high amounts of toxin, do not show equivalent levels of weight loss and tissue inflammation at this and subsequent time points. Several studies have shown that the S-layer is essential in immune activation [ 39 , 40 ] driving the production of proinflammatory cytokines via TLR4/MyD88 dependent pathways and enhancing the toxin-activated inflammasome [ 32 , 41 , 42 ]. Together, this implies that the timing or spatial localisation of toxins and the S-layer relative to the epithelial barrier could be crucial to immune activation.…”

Section: Discussionmentioning

confidence: 99%

An intact S-layer is advantageous to Clostridioides difficile within the host

et al. 2023

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Clostridioides difficile is responsible for substantial morbidity and mortality in antibiotically-treated, hospitalised, elderly patients, in which toxin production correlates with diarrhoeal disease. While the function of these toxins has been studied in detail, the contribution of other factors, including the paracrystalline surface layer (S-layer), to disease is less well understood. Here, we highlight the essentiality of the S-layer in vivo by reporting the recovery of S-layer variants, following infection with the S-layer-null strain, FM2.5. These variants carry either correction of the original point mutation, or sequence modifications which restored the reading frame, and translation of slpA. Selection of these variant clones was rapid in vivo, and independent of toxin production, with up to 90% of the recovered C. difficile population encoding modified slpA sequence within 24 h post infection. Two variants, subsequently named FM2.5varA and FM2.5varB, were selected for study in greater detail. Structural determination of SlpA from FM2.5varB indicated an alteration in the orientation of protein domains, resulting in a reorganisation of the lattice assembly, and changes in interacting interfaces, which might alter function. Interestingly, variant FM2.5varB displayed an attenuated, FM2.5-like phenotype in vivo compared to FM2.5varA, which caused disease severity more comparable to that of R20291. Comparative RNA sequencing (RNA-Seq) analysis of in vitro grown isolates revealed large changes in gene expression between R20291 and FM2.5. Downregulation of tcdA/tcdB and several genes associated with sporulation and cell wall integrity may account for the reported attenuated phenotype of FM2.5 in vivo. RNA-seq data correlated well with disease severity with the more virulent variant, FM2.5varA, showing s similar profile of gene expression to R20291 in vitro, while the attenuated FM2.5varB showed downregulation of many of the same virulence associated traits as FM2.5. Cumulatively, these data add to a growing body of evidence that the S-layer contributes to C. difficile pathogenesis and disease severity.

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“…However, this raises the question as to why animals infected with FM2.5, that show high and equivalent levels of tissue colonisation by 48 hpi, do not show equivalent levels of weight loss and tissue inflammation as R20291 infected animals. Several studies have shown that the S-layer is essential in immune activation (Jarchum et al 2012; Mamareli et al 2019), driving the production of proinflammatory cytokines via TLR4/MyD88 dependent pathways and enhancing the toxin-activated inflammasome (Ryan et al, 2011; Cowardin et al, 2015; McDermott et al, 2016). Together, this implies that the timing or spatial localisation of toxins and the S-layer relative to the epithelial barrier could be crucial to immune activation.…”

Section: Discussionmentioning

confidence: 99%

An intact S-layer is advantageous toClostridioides difficilewithin the host

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et al. 2022

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Clostridioides difficile is responsible for substantial morbidity and mortality in antibiotically-treated, hospitalised, elderly patients, in which toxin production correlates with diarrhoeal disease. While the function of these toxins has been studied in detail, the contribution of other factors, including the paracrystalline surface layer (S-layer), to disease is less well known. Here, we highlight the essentiality of the S-layer in vivo by reporting the recovery of S-layer revertants, following infection with the S-layer-null strain, FM2.5. Sequencing of the slpA gene revealed either correction of the original point mutation or modification of the sequence upstream of the mutation, which restored the reading frame, and translation of slpA. Selection of these strains was rapid, with up to 90% of isolates identified as revertants 24 h post infection. Two revertant isolates, RvA and RvB, showed modification of 3 and 13 amino acids respectively, compared to wild type sequence. Structural determination of SlpA from RvB revealed a different orientation of its domains, resulting in a reorganisation of the lattice assembly and changes in interacting interfaces which might result in functional differences. These revertants showed differing patterns of disease in vivo; RvA causing equivalent severity to R20291 and RvB an attenuated FM2.5-like phenotype. Comparative RNA sequencing (RNA-Seq) analysis of in vitro grown isolates showed large changes in differentially expressed genes (DEGs) between R20291 and FM2.5 namely in TcdA/TcdB expression, in transcripts associated with sporulation and those linked to cell wall integrity, which may account for attenuation observed in vivo. In comparison, smaller differences were observed between RvA/R20291, and RvB/FM2.5 respectively, which correlated with observed disease severity in vivo. Cumulatively, these data highlight that the S-layer plays a role in C. difficile disease.

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Epithelium‐specific MyD88 signaling, but not DCs or macrophages, control acute intestinal infection with Clostridium difficile

Cited by 5 publications

References 51 publications

Enterocyte–innate lymphoid cell crosstalk drives early IFN-γ-mediated control of Cryptosporidium

Enterocyte–innate lymphoid cell crosstalk drives early IFN-γ-mediated control of Cryptosporidium

An intact S-layer is advantageous to Clostridioides difficile within the host

An intact S-layer is advantageous toClostridioides difficilewithin the host

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