A novel framework for understanding susceptibility to hepatotropic infections in low resource settings

We present a novel 'systems' framework to explain increased susceptibility to hepatotrophic infections in low resource settings where host exposures to hepatotoxic agents of environmental and biological nature coexist. The JiVitA Research Project has prospectively followed the pregnancies of ~60,000 women since 2007 from Northern Bangladesh. A 1100 subsample was selected for biochemical analysis. Plasma at 1st trimester (TM), 3rd TM and 3 months post-partum (PP) of these women were tested for anti-Hepatitis E Virus (HEV) IgG using an NIH in-house immunoassay to the open reading frame-3 of HEV. 40 women were identified as seroconverters, with 39 seroconverting between the 3rd TM and 3 months PP. 40 age, parity and sector of residence-matched controls were selected from the non-seroconverters in the sub-study. A panel of micronutrients and cytokines were analyzed in the plasma from the 1st TM, 3rd TM and 3 months PP of these 80 women. Urinary metal concentrations, including arsenic, were also analyzed from the 1st and 3rd TM. The seroconverters were found to have lower circulating zinc (p=0.04) as well as a greater prevalence of anemia (p=0.045), as measured by circulating hemoglobin, and vitamin D deficiency (p=0.08) when compared to the controls at the 1st TM. Throughout pregnancy, seroconverters displayed higher concentrations of both pro- (IFN-(gamma), IL-1b, IL-2, IL-8, IL-12 and TNF-(alpha)) and anti-inflammatory (IL-4, IL-5, IL-10, IL-13) cytokines compared to the controls. Inorganic arsenic concentrations were similar in the 1st TM for seroconverters (65.6(mu)g/L) and controls (64.7(mu)g/L). The seroconverters maintained these concentrations through the 3rd TM (61.6(mu)g/L) while the concentration in the controls decreased (35.9(mu)g/L). The seroconverters displayed marked differences in their micronutrient, cytokine and arsenic profiles at early pregnancy, before seroconversion occurred. The opportunity to study host factors in seroconverters prior to infection is rare. This cohort represents a unique opportunity to examine susceptibility to hepatotropic infections across multiple, interconnected axes-nutrition, toxin exposure, immunocompetence and infection. We propose a novel conceptual framework of host-level risk factors for hepatotrophic pathogens such as HEV. Arsenic intake, from food and water, along with micronutrient deficiencies, from inadequate diet and a high infectious disease burden, may lead to dysregulated cytokine expression and immunologic compromise. This dysregulation in combination with hepatotoxicity from arsenic and heavy metal exposure lead to immunosuppression, increasing the risk of HEV and other hepatotrophic pathogen infection and illness.