Circulating Mucosal Associated Invariant T Cells Are Activated in Vibrio cholerae O1 Infection and Associated with Lipopolysaccharide Antibody Responses

Background: Mucosal Associated Invariant T (MAIT) cells are innate-like T cells found in abundance in the intestinal mucosa, and are thought to play a role in bridging the innate-adaptive interface. Methods: We measured MAIT cell frequencies and antibody responses in blood from patients presenting with culture-confirmed severe cholera to a hospital in Dhaka, Bangladesh at days 2, 7, 30, and 90 of illness. Results: We found that MAIT (CD3+CD4−CD161hiVα7.2+) cells were maximally activated at day 7 after onset of cholera. In adult patients, MAIT frequencies did not change over time, whereas in child patients, MAITs were significantly decreased at day 7, and this decrease persisted to day 90. Fold changes in MAIT frequency correlated with increases in LPS IgA and IgG, but not LPS IgM nor antibody responses to cholera toxin B subunit. Conclusions: In the acute phase of cholera, MAIT cells are activated, depleted from the periphery, and as part of the innate response against V. cholerae infection, are possibly involved in mechanisms underlying class switching of antibody responses to T cell-independent antigens

Biomarkers of Environmental Enteropathy are Positively Associated with Immune Responses to an Oral Cholera Vaccine in Bangladeshi Children

<div><p>Environmental enteropathy (EE) is a poorly understood condition that refers to chronic alterations in intestinal permeability, absorption, and inflammation, which mainly affects young children in resource-limited settings. Recently, EE has been linked to suboptimal oral vaccine responses in children, although immunological mechanisms are poorly defined. The objective of this study was to determine host factors associated with immune responses to an oral cholera vaccine (OCV). We measured antibody and memory T cell immune responses to cholera antigens, micronutrient markers in blood, and EE markers in blood and stool from 40 Bangladeshi children aged 3–14 years who received two doses of OCV given 14 days apart. EE markers included stool myeloperoxidase (MPO) and alpha anti-trypsin (AAT), and plasma endotoxin core antibody (EndoCab), intestinal fatty acid binding protein (i-FABP), and soluble CD14 (sCD14). We used multiple linear regression analysis with LASSO regularization to identify host factors, including EE markers, micronutrient (nutritional) status, age, and HAZ score, predictive for each response of interest. We found stool MPO to be positively associated with IgG antibody responses to the B subunit of cholera toxin (P = 0.03) and IgA responses to LPS (P = 0.02); plasma sCD14 to be positively associated with LPS IgG responses (P = 0.07); plasma i-FABP to be positively associated with LPS IgG responses (P = 0.01) and with memory T cell responses specific to cholera toxin (P = 0.01); stool AAT to be negatively associated with IL-10 (regulatory) T cell responses specific to cholera toxin (P = 0.02), and plasma EndoCab to be negatively associated with cholera toxin-specific memory T cell responses (P = 0.02). In summary, in a cohort of children 3–14 years old, we demonstrated that the majority of biomarkers of environmental enteropathy were positively associated with immune responses after vaccination with an OCV.</p></div

CD38⁺CD161^loVα7.2⁺ cells are inversely associated with age and changes in MAIT cells.

<p>A) Spearman correlation of day 2 to day 7 fold changes in %MAIT cells with fold changes across the same days in i) CD161^loVα7.2⁺, and ii) CD38⁺CD161^loVα7.2⁺ cells. B) Spearman correlation of CD38⁺CD161^loVα7.2⁺ cells with age for i) healthy controls and ii) cholera patients on day 7 after presentation.</p

Host characteristics of 40 children who received 2 doses of an oral cholera vaccine.

<p>Host characteristics of 40 children who received 2 doses of an oral cholera vaccine.</p

Comparison of enteropathy markers by age group.

<p>MPO = stool myeloperoxidase (ng/mL); AAT = stool alpha anti-trypsin (ug/mL); EndoCab = plasma endotoxin core antibody (GMU/mL); i-FABP = plasma intestinal fatty acid binding protein (pg/mL); sCD14 = plasma soluble CD14 (pg/mL).</p

Class-switched antibody responses against LPS are correlated with MAIT cell responses.

<p>Antibody responses against A) LPS, and B) CtxB, of cholera patients at days 2, 7, and 30 after hospitalization, displayed as mean with standard errors. Compared with day 2, * P<0.05; ** P<0.01; *** P<0.001. Correlation of fold changes in %MAIT cells and fold changes in antibody response against C) LPS, and D) CtxB, of cholera patients.</p

Host factors associated with immune responses to oral cholera vaccine in Bangladeshi children, determined by multivariate linear regression analysis with LASSO regularization.

<p>Host factors associated with immune responses to oral cholera vaccine in Bangladeshi children, determined by multivariate linear regression analysis with LASSO regularization.</p

Time line for vaccination, blood draws and immunological assays.

<p>Ab = antibody measurements; FASCIA = flow cytometric assay of specific cell-mediated immune responses in activated whole blood; RBP = Retinol binding protein; VitD = 25-OH vitamin D; EE markers = biomarkers of environmental enteropathy.</p