Host recognition of Clostridium difficile and the innate immune response

Abstract

Clostridium difficile is a Gram-positive, spore forming bacillus and the most common cause of antibiotic-associated diarrhea in the United States. Clinical outcomes of C. difficile infection (CDI) range from asymptomatic colonization to pseudomembranous colitis, sepsis and death. Disease is primarily mediated by the action of the Rho-glucosylating toxins A and B, which induce potent pro-inflammatory signaling within the host. The role of this inflammatory response during infection is just beginning to be appreciated, with recent data suggesting inflammatory markers correlate closely with disease severity. In addition to the toxins, multiple innate immune signaling pathways have been implicated in establishing an inflammatory response during infection. In intoxication-based models of disease, inflammation typically enhances pathogenesis, while protection from infection seems to require some level of inflammatory response. Thus, the host immune response plays a key role in shaping the course of infection and a balanced inflammatory response which eradicates infection without damaging host tissues is likely required for successful resolution of disease.

Microbiota-Regulated IL-25 Increases Eosinophil Number to Provide Protection during Clostridium difficile Infection

“…Neutrophils are considered the hallmark innate effector cell of human C. difficile infection, but IL-25 signaling is primarily associated with eosinophilia (Cowardin and Petri Jr., 2014; Fort et al, 2001). Therefore, we sought to identify the ability of IL-25 to modulate neutrophils, eosinophils, and monocytes in lamina propria of the colon on day 3 of CDI.…”

“…First, eosinophils may protect the host by regulating immune responses to promote a balanced inflammatory environment that effectively combats the pathogen but prevents off-target host tissue destruction. This is plausible, as the immune response has a multifaceted role during disease and different immune mediators play a protective or pathogenic roles during CDI (Cowardin and Petri Jr., 2014). Eosinophils have previously been demonstrated to promote a beneficial immune response in the colon.…”

“…Following colonization, the release of chief virulence factors, toxins A and B, causes epithelial cell rounding and death compromising the integrity of the intestinal barrier. Therapy involves treatment with antibiotics such as vancomycin, fidaxomicin, or metronidazole (Cowardin and Petri Jr., 2014). In addition to effectively targeting C. difficile, these antibiotics can inhibit the reestablishment of beneficial endogenous flora, which may in part explain the high numbers of relapses and deaths associated with this disease.…”

Clostridium difficile infection

“…Cell–cell signalling contributes to both colonization and virulence factor expression 59,60 . Host recognition of C. difficile is mediated via pattern recognition receptors and myeloid differentiation primary response 88 (MYD88)- and nucleotide-binding oligomerization domain-containing protein 1 (NOD1)-dependent pathways 61,62 (FIG. 3).…”

The role of gut microbiota in atopic asthma and allergy, implications in the understanding of disease pathogenesis

“…For example, colonization of the gut by C difficile may induce a cascade of inflammatory responses which results in mucosal inflammation and the disruption of the epithelial barrier. This state of inflammatory process involves TLR5 binding and the activation of NFκB which is the key transcription factor controlling the expression of inflammatory genes . A dysbiotic environment within the gut may also result in the degradation of IgA and increased levels of IgE which is linked to the pathogenesis of asthma as well as the other allergies …”