A systematic review of ETEC epidemiology focusing on colonization factor and toxin expression.

Background Despite recent progress in understanding the molecular basis of Vibrio cholerae pathogenesis, there is relatively little knowledge of the factors that determine the variability in human susceptibility to V. cholerae infection. Methods and findings We performed an observational study of a cohort of household contacts of cholera patients in Bangladesh, and compared the baseline characteristics of household members who went on to develop culture-positive V. cholerae infection with individuals who did not develop infection. Although the vibriocidal antibody is the only previously described immunologic marker associated with protection from V. cholerae infection, we found that levels of serum IgA specific to three V. cholerae antigens-the B subunit of cholera toxin, lipopolysaccharide, and TcpA, the major component of the toxin-co-regulated pilus-also predicted protection in household contacts of patients infected with V. cholerae O1, the current predominant cause of cholera. Circulating IgA antibodies to TcpA were also associated with protection from V. cholerae O139 infection. In contrast, there was no association between serum IgG antibodies specific to these three antigens and protection from infection with either serogroup. We also found evidence that host genetic characteristics and serum retinol levels modify susceptibility to V. cholerae infection. Conclusions Our observation that levels of serum IgA (but not serum IgG) directed at certain V. cholerae antigens are associated with protection from infection underscores the need to better understand anti-V. cholerae immunity at the mucosal surface. Furthermore, our data suggest that susceptibility to V. cholerae infection is determined by a combination of immunologic, nutritional, and genetic characteristics; additional factors that influence susceptibility to cholera remain unidentified.

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Susceptibility to Vibrio cholerae Infection in a Cohort of Household Contacts of Patients with Cholera in Bangladesh

Individuals with blood group O are more susceptible than other individuals to severe cholera, although the mechanism underlying this association is unknown. To assess the respective roles of both intrinsic host factors and adaptive immune responses that might influence susceptibility to infection with Vibrio cholerae, we prospectively followed a cohort of household contacts of patients with cholera in Bangladesh. In this study, we made the novel observation that persons with blood group O were less likely than those with other blood groups to become infected with V. cholerae O1 (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.53 to 0.85; P = 0.008). Consistent with prior studies, however, household contacts with blood group O were more likely to develop severe illness if infected with V. cholerae O1 (OR, 2.3; 95% CI, 0.98 to 5.59; P = 0.05). While blood group O protected significantly against infection with V. cholerae O1, there was no evidence of protection against V. cholerae O139. A multivariate analysis demonstrated that the association between blood group O and protection from infection with V. cholerae O1 was independent of age, gender, and baseline anti-cholera toxin and vibriocidal antibody titers. Based on this epidemiologic evidence, we propose a hypothesis for understanding the association between blood group O and the risk of infection with V. cholerae O1 and O139 as well as the risk of developing severe symptoms once infected.

https://iai.asm.org/content/iai/73/11/7422.full.pdf

Blood Group, Immunity, and Risk of Infection with Vibrio cholerae in an Area of Endemicity

The environmental reservoirs for Vibrio cholerae are natural aquatic habitats, where it colonizes the chitinous exoskeletons of copepod molts. Growth of V. cholerae on a chitin surface induces competence for natural transformation, a mechanism for intra-species gene exchange. The antigenically diverse O-serogroup determinants of V. cholerae are encoded by a genetically variable biosynthetic cluster of genes that is flanked on either side by chromosomal regions that are conserved between different serogroups. To determine whether this genomic motif and chitin-induced natural transformation might enable the exchange of serogroup-specific gene clusters between different O serogroups of V. cholerae, a strain of V. cholerae O1 El Tor was co-cultured with a strain of V. cholerae O139 Bengal within a biofilm on the same chitin surface immersed in seawater, and O1-to-O139 transformants were obtained. Serogroup conversion of the O1 recipient by the O139 donor was demonstrated by comparative genomic hybridization, biochemical and serological characterization of the O-antigenic determinant, and resistance of O1-to-O139 transformants to bacteriolysis by a virulent O1-specific phage. Serogroup conversion was shown to have occurred as a single-step exchange of large fragments of DNA. Crossovers were localized to regions of homology common to other V. cholerae serogroups that flank serogroup-specific encoding sequences. This result and the successful serogroup conversion of an O1 strain by O37 genomic DNA indicate that chitin-induced natural transformation might be a common mechanism for serogroup conversion in aquatic habitats and for the emergence of V. cholerae variants that are better adapted for survival in environmental niches or more pathogenic for humans.

Serogroup Conversion of Vibrio cholerae in Aquatic Reservoirs

Background. Multiple Vibrio cholerae infections in the same household are common. The objective of this study was to examine the incidence of V. cholerae infection and associated clinical symptoms in household contacts of patients with cholera and to identify risk factors for development of severe dehydration in this cohort. Methods. Household contacts of hospitalized patients with cholera were observed with frequent clinical assessments and collection of serum and rectal swab samples for culture for a period of 21 days after presentation of the index case. Results. One-half (460 of 944) of all contacts reported diarrhea during the study period, and symptoms most frequently began 2 days after presentation of the index case. Antibiotics were used by 199 (43%) of 460 contacts with diarrhea. Results of rectal swab cultures for V. cholerae were positive for 202 (21%) of 944 contacts, and 148 (73%) infected contacts experienced diarrhea. Significant dehydration developed in 26 contacts; predictors of dehydration included vomiting, each additional day of diarrhea, and blood group O status. Conclusions. In urban Bangladesh, the burden of diarrheal illness among household contacts of patients with cholera is higher than was previously estimated, and prophylactic intervention is feasible, because the majority of symptomatic cases of V. cholerae infection in contacts begin soon after presentation of the index case. Re-evaluation of targeted chemoprophylaxis for household contacts of patients with cholera may be warranted.

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Clinical Outcomes in Household Contacts of Patients with Cholera in Bangladesh

Vibrio cholerae O139 has recently emerged as the second etiologic agent of cholera in Asia. A study was carried out to evaluate the induction of specific immune responses to the organism in V. cholerae O139-infected patients. The immune responses to V. cholerae O139 Bengal were studied in patients by measuring antibody-secreting cells (ASC), as well as vibriocidal and antitoxic antibodies in the circulation. These responses were compared with those in patients with V. cholerae O1 disease. Strong immunoglobulin A (IgA) and IgM ASC responses were seen against the homologous lipopolysaccharide or serogroup of V. cholerae. The magnitude and isotype of the responses were similar in O139- and O1-infected patients. Vibriocidal antibody responses were seen against bacteria of the homologous but not heterologous serogroup, and these responses reflect the lack of cross-protection between the infections caused by the two serogroups. The two groups of patients showed comparable cholera toxin-specific ASC responses, with the IgG isotype dominating over the IgA isotype, as well as comparable antitoxic immune responses in plasma. These results suggest that despite having a polysaccharide capsule, V. cholerae O139 induces systemic and intestine-derived ASC responses in peripheral blood comparable to those seen in patients with V. cholerae O1 disease.

Comparison of immune responses in patients infected with Vibrio cholerae O139 and O1.

Vibrio cholerae serogroup O139, now considered to be the second organism capable of causing epidemic severe dehydrating cholera, contains a capsular polysaccharide which makes it difficult for it to be used in the conventional vibriocidal antibody assay optimized for V. cholerae O1. After modification of the procedure, which involved the use of specific bacterial strains, a lower bacterial inoculum, and increased amounts of complement, the vibriocidal antibody responses to V. cholerae O139 were measured in acute- and convalescent-phase sera from 33 V. cholerae O139-infected and 18 V. cholerae O1-infected patients and in single serum samples from 20 healthy control subjects. The responses in these individuals to V. cholerae O1 strains were also determined. Significant elevations in the homologous antibody response were found only in the convalescent-phase sera from both groups of patients with cholera. These findings may explain the basis for the lack of heterologous protection between the two serogroups of V. cholerae. Healthy controls had higher background levels of vibriocidal antibody to V. cholerae O1 than to V. cholerae O139.

https://cvi.asm.org/content/cdli/2/6/685.full.pdf

Comparison of the vibriocidal antibody response in cholera due to Vibrio cholerae O139 Bengal with the response in cholera due to Vibrio cholerae O1.

Cholera toxin (CT)-specific antibody responses of the immunoglobulin E (IgE) isotype in the sera of adult patients suffering from infection with either Vibrio cholerae O1, V. cholerae O139, or enterotoxigenic Escherichia coli (ETEC) were analyzed and compared with those in the sera of volunteers immunized with a bivalent B subunit O1/O139 whole-cell cholera vaccine. A significant IgE response to CT was observed in 90% of the patients with V. cholerae O1 infection (18 of 20; P = <0.001) and 95% of the patients with V. cholerae O139 infection (19 of 20; P = <0.001). Similarly, the majority of the patients with ETEC diarrhea (83%; 13 of 15) showed a positive IgE response to CT. Eight of 10 North American volunteers (80%) orally challenged with V. cholerae O1 showed CT-specific IgE responses (P = 0.004). In contrast, Swedish volunteers immunized with the oral cholera vaccine showed no IgE responses to CT (P value not significant). During the study period, total IgE levels in the sera of the diarrheal patients, the North American volunteers, and the Swedish cholera vaccinees alike remained unchanged. However, the total IgE levels in the sera of patients and healthy Bangladeshi controls were on average 89-fold higher than those in the sera of the healthy Swedish volunteers and 34-fold higher than those in the sera of the North American volunteers.

Enterotoxin-specific immunoglobulin E responses in humans after infection or vaccination with diarrhea-causing enteropathogens.

Vibrio cholerae serogroup O139, now considered to be the second organism capable of causing epidemic severe dehydrating cholera, contains a capsular polysaccharide which makes it difficult for it to be used in the conventional vibriocidal antibody assay optimized for V. cholerae O1. After modification of the procedure, which involved the use of specific bacterial strains, a lower bacterial inoculum, and increased amounts of complement, the vibriocidal antibody responses toV. choleraeO139 were measured in acute- and convalescentphase sera from 33 V. cholerae O139-infected and 18 V. cholerae O1-infected patients and in single serum samplesfrom20healthycontrolsubjects.TheresponsesintheseindividualstoV.choleraeO1strainswerealso determined. Significant elevations in the homologous antibody response were found only in the convalescentphase sera from both groups of patients with cholera. These findings may explain the basis for the lack of heterologous protection between the two serogroups of V. cholerae. Healthy controls had higher background levels of vibriocidal antibody toV. choleraeO1 than toV. choleraeO139.

Golam Mohi

Papers

Comparison of immune responses in patients infected with Vibrio cholerae O139 and O1.

Comparison of the vibriocidal antibody response in cholera due to Vibrio cholerae O139 Bengal with the response in cholera due to Vibrio cholerae O1.

Enterotoxin-specific immunoglobulin E responses in humans after infection or vaccination with diarrhea-causing enteropathogens.

Comparison of the Vibriocidal Antibody Response in Cholera due toVibrio choleraeO139 Bengal with the Response in Cholera due toVibrio choleraeO1