Associations between Mucosal Innate and Adaptive Immune Responses and Resolution of Diarrheal Pathogen Infections

Abstract

The identification of immune response mechanisms that contribute to the control of diarrheal disease in developing countries remains an important priority. We addressed the role of fecal chemokines and cytokines in the resolution of diarrheal Escherichia coli and Giardia lamblia infections. Stools collected from 127 Mexican children 5 to 15 months of age enrolled in a randomized, double-blind, placebo-controlled, vitamin A supplementation trial were screened for enteropathogenic Escherichia coli (EPEC), enterotoxigenic E. coli (ETEC), and Giardia lamblia. Fecal concentrations of tumor necrosis factor alpha (TNF-␣), monocyte chemoattractant protein-1 (MCP-1), interleukin-4 (IL-4), IL-5, IL-6, IL-8, IL-10, and interferon-␥ (IFN-␥) were determined. Hazard models incorporating cytokine variables were fit to durations of asymptomatic and symptomatic pathogen infections, controlling for treatment group. Increased levels of TNF-␣ and IL-6 were associated with decreased durations of EPEC infection and increased ETEC durations. Increased IL-4 and IFN-␥ levels were associated with decreased and increased durations, respectively, of both EPEC and ETEC infections. Increased IL-10 levels were associated with increased and decreased durations of asymptomatic and symptomatic EPEC infections, respectively, and increased durations of both asymptomatic and symptomatic ETEC infections. Increased levels of MCP-1, IFN-␥, IL-4, and IL-5 were associated with increased G. lamblia infection duration, while increased IL-8 levels were associated with decreased durations. Differences in proinflammatory and Treg cytokine levels are associated with differences in the resolution of inflammatory and noninflammatory pathogen infections.Pediatric diarrheal disease continues to be an important health problem in developing countries, with the disabilityadjusted life year (DALY) for this disease estimated to be approximately 100 million, Ͼ95% of which is due to mortality (36). A broad range of gastrointestinal pathogens cause diarrhea among young children in these settings. Diarrheagenic Escherichia coli pathotypes (DEPs) represent a leading bacterial cause of diarrhea, with enteropathogenic E. coli (EPEC) and enterotoxigenic E. coli (ETEC) representing the most important pathogens of this group (7, 41). The disease burden due to such gastrointestinal parasites as Giardia lamblia also continues to be an important health problem in countries such as Mexico (31).We have addressed the efficacy of vitamin A supplementation in reducing the burden of pathogen-specific diarrhea by carrying out a randomized, placebo-controlled, double-blind trial among children living in peri-urban areas of Mexico City. Supplementation in this trial was associated with pathogenspecific effects on the fecal innate and adaptive cytokine responses and with divergent pathogen-specific clinical outcomes (30, 32). We now want to understand how the effect of vitamin A on these cytokine responses is associated with pathogenspecific outcomes.Recent research has reported that distin...

Persistent G. lamblia impairs growth in a murine malnutrition model

“…The immune response at these time points is characterized by a predominance of B220 + cells in the lamina propria, elevated Il4 and Il5 mRNA, and intraepithelial eosinophils, consistent with a Th2-biased response. Similarly, markers of Th2 responses have been documented in human infections, including eosinophilic infiltrates in approximately one-third of jejunal biopsies from children (40), elevated IL-4 and IL-5 in stools of children who fail to clear Giardia (41), and elevated serum IL-13 following acute infection in adults (45). The mechanisms driving this response are poorly understood, and the clinical studies did not exclude the presence of coinfecting helminths, which is associated with both mucosal eosinophils and susceptibility to G. lamblia (46).…”

“…In longitudinal studies of children in Mexico, stool cytokine analysis showed that children who failed to clear Giaridia had increased IL-4, IL-5, MCP1, and IFN-γ, and decreased IL-8 (41). Observing that eosinophils were increased, we proceeded to investigate mRNA cytokine profiles in matched mouse duodenal tissues ( Figure 5, A-I).…”

Household and personal factors are sources of heterogenity in intestinal parasite clearance among Mexican children 6–15 months of age supplemented with vitamin A and zinc

“…Zinc may delay the development of a protective Th2 response during this critical period. Elevated fecal Th2 cytokine concentrations among vitamin A supplemented children in this same community are associated with reduced lengths of G. intestinalis infection (Long KZ et al, 2010;Long KZ et al, 2011).…”

Giardia: both a harmless commensal and a devastating pathogen

“…In severe cases of giardiasis, during infection Giardia trophozoites attach to the epithelium of the proximal small bowel aided by their ventral adhesive discs, evade host defenses possibly by undergoing genetic variation (12), and produce local alterations of villus structure and cellular apoptosis. The most devastating effects of Giardia infection are related to damage of the absorptive small bowel mucosa, together with abnormal intestinal immunity that favors chronic infection (13,14). While there is little evidence that preexistent malnutrition in young children makes them more susceptible to Giardia infection, once they are infected, persistent symptoms and health consequences are more likely to develop (15).…”