Acute dehydrating disease caused by Vibrio cholerae serogroups O1 and O139 induce increases in innate cells and inflammatory mediators at the mucosal surface of the gut

Abstract

Background and aims:The general concept is that as Vibrio cholerae is not invasive, it mediates a noninflammatory type of infection. This is being re-evaluated based on available data that natural cholera infection or cholera toxin induces a Th2-type of immune profile and stimulates the humoral immune response, innate cells, and mediators in the host. Methods: To perform a comprehensive analyses of the inflammatory components, we studied mucosal biopsies from patients, both adults and children with acute watery diarrhoea caused by V cholerae O1 and O139. Patients with cholera, adults (n = 30) and children (n = 18), as well as healthy controls (n = 24) were studied. Histochemical, immunohistochemical, and ultrastructural studies were carried out to elucidate the contribution of the different factors using paraffin and frozen duodenal and/or rectal sections as appropriate. Samples were collected during the acute stage and during early and/or late convalescence. Results: Following natural cholera infection, patients responded with increases in neutrophil polymorphs during the acute stage (p,0.001) compared with healthy controls whereas mucosal mast cells (MMC) (p = 0.008) and eosinophils (p = 0.034) increased in the gut during convalescence. Electron microscopic analyses of duodenal biopsies from adult patients showed increased piecemeal degranulation in both MMC and eosinophils and accumulation of lipid bodies in MMC. Duodenal biopsies from V cholerae O1 infected patients showed upregulation of myeloperoxidase, lactoferrin, PGHS-1, SCF, tryptase, tumour necrosis factor a, a-defensin, and eotaxin during the acute stage and chymase, interleukin 3 and major basic protein during convalescence. Conclusion: We have shown that innate cells and their mediators are upregulated in acute watery diarrhoea. These cells and factors of the innate arm may be important in the host's defence against cholera. Such effects may need to be simulated in a vaccine to achieve long lasting protection from cholera.

Neutrophils Are Essential for Containment of Vibrio cholerae to the Intestine during the Proinflammatory Phase of Infection

“…This equivalent colonization is observed despite a reduction of proinflammatory markers in the absence of flagella, which should correlate to decreased recruitment of neutrophils. Further, while infections in a mouse pneumonia model (13), rabbits (47), humans (43), and now adult mice (Fig. 3) show increased expression of regulatory and chemotactic markers IL-6, IL-10, and MIP-2 in the local tissue, there is no difference in these markers when neutrophils are depleted.…”

“…Increased numbers of circulating neutrophils, as well as increased concentration of neutrophil products, Lf and MPO, indicate a specific neutrophil response to V. cholerae early during natural human infection (12,43,44). Further, biopsies of acutely ill cholera patients demonstrate infiltration of neutrophils into the lamina propria, accompanied by congestion of the vasculature and endothelial damage (32).…”

“…However, histological studies demonstrated a low abundance of neutrophils in a patient pool from Vellore, India, with moderate-to-severe cholera disease, suggesting that they may not have a significant impact on V. cholerae infection (32). In contrast, other reports do indicate a neutrophil response during the acute phase of V. cholerae infection (12,43,44). In the present study, we use mice depleted of neutrophils to determine whether and how neutrophils contribute to cholera disease during the proinflammatory phase of infection.…”

“…Recent studies in humans of the immune response to natural V. cholerae El Tor O1 infection reveal that persons who naturally acquire cholera transition through an early proinflammatory phase characterized by an increase in markers of inflammation as demonstrated by gut biopsy, stool sample, and peripheral blood analysis. Patients show increased levels of C-reactive protein, total white blood cells, neutrophils, and bactericidal proteins lactoferrin (Lf) and myeloperoxidase (MPO) (12,43,44). This proinflammatory phase persists during acute, symptomatic illness and is then followed by a noninflammatory convalescent phase, during which expression of inflammatory markers are suppressed (44).…”

Rethinking cholera pathogenesis- No longer all in the same “camp”

“…In fact, it is increasingly being recognized that Ctx can cause epithelial barrier dysfunction in vivo and in vitro, and that human cholera patients do in fact present with evidence of epithelial damage and activation of an innate immune response during the acute phase of the disease. [15][16][17] Thus, particularly in the setting of infection with El Tor variants of V. cholerae, which in fact have become predominant causes of modern epidemics, we must entertain a more nuanced understanding of the mechanisms that result in life-threatening disease. 7,18,19 These more complex mechanisms, moreover, may be overlaid on host-specific factors, such as variations in innate immune reactivity and perhaps also the influence of the highly variable resident microbiota, which is known to modulate epithelial function.…”