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Host Immune Responses to Clostridioides difficile: Toxins and Beyond

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.

SUBMITTER: Nibbering B

PROVIDER: S-EPMC8724541 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Ebselen, a reactive organoselenium compound, was shown to inhibit toxins TcdA and TcdB by covalently binding to their cysteine protease domains. It was suggested that ebselen lacked antimicrobial activity against Clostridioides difficile. However, this perception conflicts with C. difficile having essential cysteine-containing enzymes that could be potential targets and the reported antimicrobial activity of ebselen against other species. Hence, we reevaluated the anti-C. difficile properties of ebselen. Susceptibility testing revealed that its activity was either slightly reduced by pyruvate found in Wilkins-Chalgren agar or obliterated by blood in brucella agar. In brain heart infusion (BHI) agar, ebselen inhibited most C. difficile strains (MICs of 2 to 8 μg/ml), except for ribotype 078 that was intrinsically resistant (MIC = 32 to 128 μg/ml). Against C. difficile R20291, at concentrations below its minimal bactericidal concentration (MBC), 16 μg/ml, ebselen inhibited production of toxins and spores. Transcriptome analysis revealed that ebselen altered redox-associated processes and cysteine metabolism and enhanced expression of Stickland proline metabolism, likely to regenerate NAD+ from NADH. In cellular assays, ebselen induced uptake of cysteine, depleted nonprotein thiols, and disrupted the NAD+/NADH ratio. Taken together, killing of C. difficile cells by ebselen occurs by a multitarget action that includes disrupting intracellular redox, which is consistent with ebselen being a reactive molecule. However, the physiological relevance of these antimicrobial actions in treating acute C. difficile infection (CDI) is likely to be undermined by host factors, such as blood, which protect C. difficile from killing by ebselen. IMPORTANCE We show that ebselen kills pathogenic C. difficile by disrupting its redox homeostasis, changing the normal concentrations of NAD+ and NADH, which are critical for various metabolic functions in cells. However, this antimicrobial action is hampered by host components, namely, blood. Future discovery of ebselen analogues, or mechanistically similar compounds, that remain active in blood could be drug leads for CDI or probes to study C. difficile redox biology in vivo.

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Host Immune Responses to Clostridioides difficile: Toxins and Beyond

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