Host Immune Responses to Clostridioides difficile: Toxins and Beyond

Britt Nibbering, Dale N Gerding, Ed J Kuijper, Romy D Zwittink, Wiep Klaas Smits, Britt Nibbering, Dale N Gerding, Ed J Kuijper, Romy D Zwittink, Wiep Klaas Smits

Abstract

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.

Keywords: Clostridioides difficile; NTCD; immune response; non-toxigenic C. difficile; non-toxin proteins; toxins.

Conflict of interest statement

DG holds technology for the use of non-toxigenic C. difficile for the prevention and treatment of CDI licensed to Destiny Pharma plc, Brighton, United Kingdom. EK has received an unrestricted research grant from Vedanta Bioscience, Boston, United States. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Nibbering, Gerding, Kuijper, Zwittink and Smits.

Figures

FIGURE 1
FIGURE 1
Comparison of the immune responses to toxigenic Clostridioides difficile (C. difficile) and non-toxin proteins. (A) Responses to toxigenic C. difficile and its toxins. Toxins damage colonocytes which results in the loss of epithelial barrier integrity and the production of antimicrobial peptides (AMPs), such as LL-37, interleukins (ILs), IL-25 and IL-33, and reactive oxygen species (ROS) and nitrogen oxygen species (NOS). Subepithelial enteric glial cells add to a pro-inflammatory environment by the production of S100B and IL-6 and the toxin affected epithelial cells attract plasminogen which in turn contributes to the production IL-10, IL-12, and other cytokines. The resident microbiome also contributes by producing AMPs and pro-inflammatory cytokines and as the barrier function of the colon is decreased translocation of the intestinal microbiome contributes to further enhances inflammation. Subsequently, resident colonic epithelial cells produce chemokines to attract immune cells to the site of infection, such as IL-8 and CXCL-1. Neutrophils arrive at the site of infection and provide support by tackling the vegetative cells and secreting pro-inflammatory cytokines, including interferon γ (IFN-γ) and aid in the production of other pro-inflammatory molecules, such as ROS. IFN-γ performs several actions, namely stimulation of phagocytosis by macrophages and the repair mechanisms of colonocytes. Eosinophils are drawn to the site of infection by IL-25 and produce pro-inflammatory cytokines, including IL-4, that both results in a Th2 response and a dampening of the immune response and tissue repair. During C. difficile infection (CDI), macrophages phagocytose vegetative cells and potentially spores and secrete pro-inflammatory cytokines, such as IL-1β and IL-6. Innate lymphoid cells are attracted by IL-33, IL-23 and IL-1β and ILC3s produce pro-inflammatory cytokines, including IL-17a, IFN- γ, and tumor necrosis factor (TNF) and in that way stimulate a Th17 response. ILCs also produce IL-22 that stimulates phagocytosis by macrophages, the killing of commensals by neutrophils, and AMP production by epithelial cells. ILC2 cells secrete IL-13 and IL-5 of which the latter attracts eosinophils. Dendritic cells (DCs) produce TNF-α in response to damaged epithelium and phagocytose these cells. Finally, plasma cells produce antibodies targeting toxins and vegetative cells. (B) Responses to non-toxin proteins and non-toxigenic C. difficile. SLPs can induce the production of IL-10 and directly stimulate phagocytosis by macrophages and SLPA has also been shown to trigger a pro-inflammatory immune response through IL-6, TNF-α, and IL-12p40 production by activated macrophages. Furthermore, SLPs activate DCs which in turn skew the adaptive immune response towards Th1 and Th17. FliC is recognized by toll like receptor 5 on colonocytes which produce IL-8 and CCL20 which attracts neutrophils, DCs, and lymphocytes. Finally, plasma cells produce antibodies against a variety of non-toxin proteins. Created with BioRender.com.
FIGURE 2
FIGURE 2
Clostridioides difficile cell envelope. A vegetative C. difficile cell expresses many proteins on its outer surface that the immune system can recognize. Additionally, C. difficile toxins are highly immunogenic. The flagella consists of FliD and FliC proteins. Cell wall proteins (Cwps), such as Cwp22 and Surface layer proteins (SLPs). TcdA, TcdB, and CDT. SLPs and other Cwps consist of a high molecular weight domain (HMW) in dark purple and a low molecular weight (LMW) protein in light purple. The LMW domain is exposed to the environment and can be recognized by the immune system. The bars represent putative lipid-containing polymers (Fagan et al., 2009). Created with BioRender.com.

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Source: PubMed

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