Surface layer proteins from virulent Clostridium difficile ribotypes exhibit signatures of positive selection with consequences for innate immune response

Lynch, Mark; Walsh, Thomas A.; Marszalowska, Izabela; Webb, Andrew E.; MacAogain, Micheál; Rogers, Thomas R.; Windle, Henry J.; Kelleher, Dermot; O’Connell, Mary J.; Loscher, Christine E.

doi:10.1186/s12862-017-0937-8

Cited by 19 publications

(9 citation statements)

References 59 publications

(77 reference statements)

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“…It has been reported that SLPs of Lactobacillus helveticus induce inflammatory mediator production in human and mouse macrophages 91. Cytokine expression was also observed when mouse bone marrow–derived immature DCs were exposed to SLP from C. difficile 92,93. We therefore analyzed whether SlpA from B. thuringiensis induced the expression of inflammatory mediators from human retinal Muller cells.…”

Section: Resultsmentioning

confidence: 99%

S-layer Impacts the Virulence ofBacillusin Endophthalmitis

Mursalin

Coburn

Livingston

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Purpose Bacillus causes a sight-threating infection of the posterior segment of the eye. The robust intraocular inflammatory response in this disease is likely activated via host innate receptor interactions with components of the Bacillus cell envelope. S-layer proteins (SLPs) of some Gram-positive pathogens contribute to the pathogenesis of certain infections. The potential contributions of SLPs in eye infection pathogenesis have not been considered. Here, we explored the role of a Bacillus SLP (SlpA) in endophthalmitis pathogenesis. Methods The phenotypes and infectivity of wild-type (WT) and S-layer deficient (Δ slpA ) Bacillus thuringiensis were compared. Experimental endophthalmitis was induced in C57BL/6J mice by intravitreally injecting 100-CFU WT or Δ slpA B. thuringiensis . Infected eyes were analyzed by bacterial counts, retinal function analysis, histology, and inflammatory cell influx. SLP-induced inflammation was also analyzed in vitro. Muller cells (MIO-M1) were treated with purified SLP. Nuclear factor-κB (NF-κB) DNA binding was measured by ELISA and expression of proinflammatory mediators from Muller cells was measured by RT-qPCR. Results Tested phenotypes of WT and Δ slpA B. thuringiensis were similar, with the exception of absence of the S-layer in the Δ slpA mutant. Intraocular growth of WT and Δ slpA B. thuringiensis was also similar. However, eyes infected with the Δ slpA mutant had significantly reduced inflammatory cell influx, less inflammatory damage to the eyes, and significant retention of retinal function compared with WT-infected eyes. SLP was also a potent stimulator of the NF-κB pathway and induced the expression of proinflammatory mediators (IL6, TNFα, CCL2, and CXCL-1) in human retinal Muller cells. Conclusions Taken together, our results suggest that SlpA contributes to the pathogenesis of Bacillus endophthalmitis, potentially by triggering innate inflammatory pathways in the retina.

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Section: Resultsmentioning

confidence: 99%

S-layer Impacts the Virulence ofBacillusin Endophthalmitis

Mursalin

Coburn

Livingston

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…Mutations in the flic gene in C. difficile have directly or indirectly been associated with increased mortality of flic mutant in a gnotobiotic mouse models and the mutant strains are nonmotile (Barketi-Klai et al, 2014) and in other flagellated species the flagella also plays a role in adherence and regulation of other genes not directly involved in motility. C. difficile flagellae, as well as SLPs (that are discussed later), exhibit immune stimulating properties through binding to TLRs and pattern recognition receptors expressed on the basolateral side of intestinal epithelial cells (Ryan et al, 2011;Batah et al, 2016;Lynch et al, 2017). Purified C. difficile FliC specifically acts on TLR5 -through which it induces the NF-κB and P38 activation, and to a lesser degree ERK1/2 and JNK MAPKs activation, to stimulate the production and secretion of IL-8 and CCL20 (Yoshino et al, 2012;Batah et al, 2016).…”

Section: Innate and Adaptive Immune Responses To Non-toxin Proteins Of Clostridioides Difficilementioning

confidence: 99%

“…TNFα, IL-12p40, IL-6, and IL-10 are produced, as exemplified by the upregulation of CD40, CD80, and MHCII on DCs and macrophages. Further, the SLPs can stimulate bacterial clearance the by macrophages (Ryan et al, 2011;Collins et al, 2014;Lynch et al, 2017). SLPs have been shown to activate DCs, bridging between innate and adaptive response, which in turn skews the T cell response toward a Th1 and Th17 response (Ausiello et al, 2006).…”

Section: Innate and Adaptive Immune Responses To Non-toxin Proteins Of Clostridioides Difficilementioning

confidence: 99%

“…SLPs have been shown to activate DCs, bridging between innate and adaptive response, which in turn skews the T cell response toward a Th1 and Th17 response (Ausiello et al, 2006). A difference in the immune responses to SLPs isolated from a variety of C. difficile stains has been demonstrated (Lynch et al, 2017). SLPs isolated from epidemic strains appear to stimulate a higher secretion of IL-12p40, IL-10, and IL-6 by macrophages and a higher expression of CD40 on macrophages.…”

Section: Innate and Adaptive Immune Responses To Non-toxin Proteins Of Clostridioides Difficilementioning

confidence: 99%

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Host Immune Responses to Clostridioides difficile: Toxins and Beyond

et al. 2021

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Clostridioides difficile is often resistant to the actions of antibiotics to treat other bacterial infections and the resulting C. difficile infection (CDI) is among the leading causes of nosocomial infectious diarrhea worldwide. The primary virulence mechanism contributing to CDI is the production of toxins. Treatment failures and recurrence of CDI have urged the medical community to search for novel treatment options. Strains that do not produce toxins, so called non-toxigenic C. difficile, have been known to colonize the colon and protect the host against CDI. In this review, a comprehensive description and comparison of the immune responses to toxigenic C. difficile and non-toxigenic adherence, and colonization factors, here called non-toxin proteins, is provided. This revealed a number of similarities between the host immune responses to toxigenic C. difficile and non-toxin proteins, such as the influx of granulocytes and the type of T-cell response. Differences may reflect genuine variation between the responses to toxigenic or non-toxigenic C. difficile or gaps in the current knowledge with respect to the immune response toward non-toxigenic C. difficile. Toxin-based and non-toxin-based immunization studies have been evaluated to further explore the role of B cells and reveal that plasma cells are important in protection against CDI. Since the success of toxin-based interventions in humans to date is limited, it is vital that future research will focus on the immune responses to non-toxin proteins and in particular non-toxigenic strains.

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“…Following germination, C. difficile strains producing toxins can cause disease by damaging colonic epithelial cells, disrupting tight junctions, and activating both innate and adaptive immune response. While it is critical to appreciate the diverse virulence factors employed by C. difficile , such as surface layer proteins that modulate host-pathogen interaction and disease severity, 58 we will focus the following sections on the role of C. difficile toxins in disease outcome.…”

Section: Microbiologic Factors Associated With CDI Outcomesmentioning

confidence: 99%

Defining the black box: a narrative review of factors associated with adverse outcomes from severe Clostridioides difficile infection

Ressler

Wang

Rao

2021

Therap Adv Gastroenterol

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In the United States, Clostridioides difficile infection (CDI) is the leading cause of healthcare-associated infection, affecting nearly half a million people and resulting in more than 20,000 in-hospital deaths every year. It is therefore imperative to better characterize the intricate interplay between C. difficile microbial factors, host immunologic signatures, and clinical features that are associated with adverse outcomes of severe CDI. In this narrative review, we discuss the implications of C. difficile genetics and virulence factors in the molecular epidemiology of CDI, and the utility of early biomarkers in predicting the clinical trajectory of patients at risk of developing severe CDI. Furthermore, we identify associations between host immune factors and CDI outcomes in both animal models and human studies. Next, we highlight clinical factors including renal dysfunction, aging, blood biomarkers, level of care, and chronic illnesses that can affect severe CDI diagnosis and outcome. Finally, we present our perspectives on two specific treatments pertinent to patient outcomes: metronidazole administration and surgery. Together, this review explores the various venues of CDI research and highlights the importance of integrating microbial, host, and clinical data to help clinicians make optimal treatment decisions based on accurate prediction of disease progression.

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Surface layer proteins from virulent Clostridium difficile ribotypes exhibit signatures of positive selection with consequences for innate immune response

Cited by 19 publications

References 59 publications

S-layer Impacts the Virulence ofBacillusin Endophthalmitis

S-layer Impacts the Virulence ofBacillusin Endophthalmitis

Host Immune Responses to Clostridioides difficile: Toxins and Beyond

Defining the black box: a narrative review of factors associated with adverse outcomes from severe Clostridioides difficile infection

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