Influence of Host Interleukin-10 Polymorphisms on Development of Traveler's Diarrhea Due to Heat-Labile Enterotoxin-ProducingEscherichia coliin Travelers from the United States Who Are Visiting Mexico

Abstract

Up to 60% of U.S. visitors to Mexico develop traveler's diarrhea (TD), mostly due to enterotoxigenicEscherichia coli (ETEC) strains that produce heat-labile (LT) and/or heat-stable (ST) enterotoxins. Distinct single-nucleotide polymorphisms (SNPs) within the interleukin-10 (IL-10) promoter have been associated with high, intermediate, or low production of IL-10. We conducted a prospective study to investigate the association of SNPs in the IL-10 promoter and the occurrence of TD in ETEC LT-exposed travelers. Sera from U.S. travelers to Mexico collected on arrival and departure were studied for ETEC LT seroconversion by using cholera toxin as the antigen. Pyrosequencing was performed to genotype IL-10 SNPs. Stools from subjects who developed diarrhea were also studied for other enteropathogens. One hundred twenty-one of 569 (21.3%) travelers seroconverted to ETEC LT, and among them 75 (62%) developed diarrhea. Symptomatic seroconversion was more commonly seen in subjects who carried a genotype producing high levels of IL-10; it was seen in 83% of subjects with the GG genotype versus 54% of subjects with the AA genotype at IL-10 gene position ؊1082 (P, 0.02), in 71% of those with the CC genotype versus 33% of those with the TT genotype at position ؊819 (P, 0.005), and in 71% of those with the CC genotype versus 38% of those with the AA genotype at position ؊592 (P, 0.02). Travelers with the GCC haplotype were more likely to have symptomatic seroconversion than those with the ATA haplotype (71% versus 38%; P, 0.002). Travelers genetically predisposed to produce high levels of IL-10 were more likely to experience symptomatic ETEC TD.Traveler's diarrhea (TD) affects up to 60% of short-term U.S. visitors to developing countries (23). Although TD is a self-limited disease with few acute complications, it can result in significant transient discomfort, cause changes in travel plans, and produce temporary incapacitation (25). TD has also been associated with long-term complications, such as postinfectious reactive arthritis, (27) Guillain-Barré neuropathy (22), and postinfectious irritable bowel syndrome (17).Up to 85% of TD cases are bacterial in origin. In Mexico, enterotoxigenic Escherichia coli (ETEC) is the single mostcommonly identified agent in the stools of travelers with diarrhea, ranging from 19% to 40% of cases (3). ETEC isolates from travelers can produce heat-labile toxin (LT), heat-stable toxin (ST), or both toxins simultaneously (LT/ST). Approximately 43% to 68% of strains isolated from subjects with TD in Mexico produce LT alone or in combination with ST (1,11,13). Contact with ETEC LT, as a result of vaccination or after natural infection, is associated with the production of LTspecific antibodies (8, 15) and may serve as an indicator of ETEC LT exposure.Previous studies carried out in Bangladesh have demonstrated that after adjusting for confounding variables, such as age and prior exposure, ETEC LT can be identified with similar frequencies in the stools of children with diarrhea and healthy controls (...

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

“…High levels of IL-10 in our study appear to be inadequate in resolving ETEC infections. This result is consistent with findings that LT-ETEC-infected individuals with IL-10 alleles associated with high IL-10 produc- tion had a limited ability to rapidly clear infection (12). These findings suggest that the antiinflammatory effects of high levels of IL-10 inhibit the clearance of ETEC infections.…”

“…Recent research has reported that distinct cytokine pathways are involved in the host responses to each of these enteropathogens (12,21). These findings suggest that a specific cytokine response adequate for resolving one pathogen infection may be inappropriate against a different pathogen and so lead to prolonged infection and pathogenesis.…”

Association of Diarrheagenic Escherichia coli Pathotypes with Infection and Diarrhea among Mexican Children and Association of Atypical Enteropathogenic E. coli with Acute Diarrhea

“…In line with this, recent studies have shown that both genetic predisposition (9,14) and nutritional status (17,18,30) increase the probability of a DEP diarrhea episode.…”

Toxin-Mediated Effects on the Innate Mucosal Defenses: Implications for Enteric Vaccines

“…Incomplete protection against ETEC is also seen in the face of preexisting, low-level anti-LT immu-VOL. 77,2009 MINIREVIEW 5211 on May 9, 2018 by guest http://iai.asm.org/ nity in travelers, who must also have naturally induced anti-LT antibodies (22). Toxin and other ETEC antigen antibody responses derived from natural protection and vaccines wane over time (10,90), data reinforced by the cholera-like ETEC disease seen in Bangladeshi adults (73).…”