Iron Is Critical for Mucosal-Associated Invariant T Cell Metabolism and Effector Functions.

Mucosal-Associated Invariant T (MAIT) cells are a population of innate T cells that play a critical role in host protection against bacterial and viral pathogens. Upon activation, MAIT cells can rapidly respond via both TCR-dependent and -independent mechanisms, resulting in robust cytokine production. The metabolic and nutritional requirements for optimal MAIT cell effector responses are still emerging. Iron is an important micronutrient and is essential for cellular fitness, in particular cellular metabolism. Iron is also critical for many pathogenic microbes, including those that activate MAIT cells. However, iron has not been investigated with respect to MAIT cell metabolic or functional responses. In this study, we show that human MAIT cells require exogenous iron, transported via CD71 for optimal metabolic activity in MAIT cells, including their production of ATP. We demonstrate that restricting iron availability by either chelating environmental iron or blocking CD71 on MAIT cells results in impaired cytokine production and proliferation. These data collectively highlight the importance of a CD71-iron axis for human MAIT cell metabolism and functionality, an axis that may have implications in conditions where iron availability is limited.

Population-Based Serologic Survey of Vibrio cholerae Antibody Titers before Cholera Outbreak, Haiti, 2022.

A Vibrio cholerae O1 outbreak emerged in Haiti in October 2022 after years of cholera absence. In samples from a 2021 serosurvey, we found lower circulating antibodies against V. cholerae lipopolysaccharide in children <5 years of age and no vibriocidal antibodies, suggesting high susceptibility to cholera, especially among young children.

A population-based serological survey of Vibrio cholerae antibody titers in Ouest Department, Haiti in the year prior to the 2022 cholera outbreak.

After three years with no confirmed cholera cases in Haiti, an outbreak of Vibrio cholerae O1 emerged in October 2022. Levels of pre-existing antibodies provide an estimate of prior immunologic exposure, reveal potentially relevant immune responses, and set a baseline for future serosurveillance. We analyzed dried blood spots collected in 2021 from a population-weighted representative cross-sectional serosurvey in two communes in the Ouest Department of Haiti. We found lower levels of circulating IgG and IgA antibodies against V. cholerae lipopolysaccharide (LPS, IgG and IgA p<0.0001) in those below 5 years of age compared to those five years and older. Among a subset of patients with higher titers of antibodies, we were unable to detect any functional (vibriocidal) antibodies. In conclusion, the lack of detectable functional antibodies, and age-discordant levels of V. cholerae LPS IgG, suggest that populations in Haiti may be highly susceptible to cholera disease, especially among young children.

Decreased NHE3 expression in colon cancer is associated with DNA damage, increased inflammation and tumor growth.

Dysregulation of intra- and extracellular pH in cancer contributes to extracellular matrix remodeling, favors cell migration, proliferation, and metastasis. Although the primary attention has been focused on the role of the ubiquitous Na+/H+ exchanger isoform NHE1, the role of NHE3, the predominant apical isoform in colonic surface epithelium in the pathogenesis of colon cancer has not been investigated. Here, we show that NHE3 mRNA expression is significantly reduced in colorectal cancer patients and that low NHE3 expression is associated with poorer survival. Deletion of NHE3 in ApcMin mice evaluated at 15 weeks of age (significant mortality was observed beyond this time) led to lower body weights, increased mucosal inflammation, increased colonic tumor numbers, evidence of enhanced DNA damage in tumor surface epithelium, and to significant alteration in the gut microbiota. In the absence of the inflammatory and microbial pressors, ca. 70% knockdown of NHE3 expression in SK-CO15 cells led to reduced intracellular pH, elevated apical pH, dramatic differences in their transcriptomic profile, increased susceptibility to DNA damage, increased proliferation, decreased apoptosis and reduced adhesion to extracellular matrix proteins. Our findings suggest that loss of NHE3 in the surface epithelium of colonic tumors has profound consequences for cancer progression and behavior.