Developmental Exposures to Arsenic: Pneumonia, Immunity, and Microbiomes (DEAPIM)

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ABSTRACT Exposure of human populations to arsenic via drinking water, air, and food is associated with significant morbidity and mortality. Along with impairments in immune function, an increased susceptibility to pneumonia has been observed in children exposed to high levels of arsenic. Pneumonia is a major global health concern accounting for 70% of pediatric hospitalizations in the US alone. Epidemiological studies indicate a decrease in the efficacy of respiratory vaccines in arsenic-exposed children. While vaccine efficacy is largely dependent on host immune function, recent evidence indicates that the gut microbiome may also play a role. However, the interrelationship of immune function and the microbiome on vaccine response in arsenic-exposed children has not been studied. It is likely that early exposures to arsenic compromise vaccines protecting against Streptococcus pneumoniae, the most common bacterial cause of pneumonia. The Scientific Premise is that Early life and in utero arsenic exposure in children leads to alterations in adaptive immunity via dysregulation of lymphocyte development and function. The impairment in these immune cells is responsible for decreases in protection from upper airway infections (such as S. pneumoniae) due to decreased vaccine PCV10 efficacy, as measured by S. pneumoniae nasopharyngeal (NP) carriage and anti-PCV circulating antibody titers. We also posit that arsenic disrupts the gut microbiome which may alter vaccine efficacy, due to altered adaptive T cell development. In Aim 1, we test the hypothesis that arsenic exposure in utero and during early life in children (1-2 year) leads to (a) impaired PCV10 antibody responses following a booster dose of PCV10, and (b) influences the NP microbiota diversity and the S. pneumoniae carriage. We will measure PCV10 titers and NP carriage using qRT-PCR and full length 16s rRNA sequencing. In Aim 2, we test the hypothesis that alterations in immune function and development are associated with early life arsenic exposure, leading to compromised host immunity. These measures include PBMC immune biomarkers and functional immune assays including: a) cell surface markers (CSM = T, B, NK, monocyte/dendritic cells, memory effector T cells) and the Th cell subsets (Th1, Th2, Th4, Th17, Treg) using 11-color flow cytometry; b) T cell proliferation; c) ex vivo cytokine production. In Aim 3 we test the hypothesis that differences in functional gut microbial composition are influenced by immune development and immune function. We will assess the gut bacterial microbiome by shotgun metagenomics and correlations with; a) PCV10 titers and the pneumococcal carriage (Aim1) and b) changes in immune markers/function (Aim 2). The study will be conducted among 400 children in Bangladesh ages between 1 and 2 years. Mothers of the participating children are part of a birth cohort and are followed throughout their pregnancy, and children are extremely well characterized for arsenic exposure in utero. These studies will provide new evidence on altered PCV vaccine response and the importance of the gut microbiome in adverse health outcomes associated with arsenic.