Defining serologic correlates of human hookworm infection

点击翻译按钮获取中文摘要

PROJECT SUMMARY Hookworm infection is a leading cause of anemia, malnutrition and growth delay in poor countries, especially in sub-Saharan Africa, where millions of people are infected. Current strategies to control hookworm rely on Mass Drug Administration of anthelminthic drugs, although evidence calls into question the long-term effectiveness of this approach to sustainably control or eliminate hookworm in populations at risk. Since 2007, Yale University and the Noguchi Memorial Institute for Medical Research at the University of Ghana have collaborated to characterize the epidemiology of hookworm in endemic communities. These studies have identified factors associated with hookworm infection status and response to deworming treatment. Preliminary data using human samples from Kintampo North, Ghana, suggests that host antibody (IgG) levels directed at hookworm adult worm excretory/secretory (ES) proteins are closely correlated with active infection. However, to date little is known about the targets of these antibody responses to hookworm antigens, which is a major gap in understanding of host-parasite interactions and pathogenesis. We hypothesize that host antibodies to specific hookworm proteins are predictive of infection status, and that a particular class of proteins, namely allergens, are the drivers of this response. Studies in Specific Aim 1 will validate the correlation between IgG antibody levels and infection status using 1,002 human serum samples and demographic data collected between 2007-2020 in Ghana field studies. Antibody levels will be measured by ELISA and analyzed for associations with hookworm infection status as determined by fecal microscopy. Data from human studies will be compared to results from controlled infection and treatment studies using the hamster model of Necator americanus. Studies in Aim 2 will focus on identifying the specific protein targets of host antibody responses using recombinant protein expression and Label Free Quantitative proteomics. Candidate hookworm allergen proteins will be expressed and purified, followed by screening for immunoreactivity using the human and hamster serum samples described in Aim 1. In addition, N. americanus adult worm ES proteins will be immunoprecipitated using highly reactive serum pools, followed by LC-MS/MS isolation and peptide mapping against hookworm/helminth genome sequence databases. These experiments will test the hypothesis that hookworm allergens are antigenic drivers of the host immune response that is associated with active infection. The overarching goals of the proposed research are to (1) correlate antibody responses with infection status and (2) characterize the role of hookworm allergens and novel antigenic proteins in host immune responses. These studies leverage a longstanding, productive collaboration between the University of Ghana and Yale that led to generation of novel preliminary data and adaptation of the first African hookworm strain in a laboratory model. These studies will enhance our understanding of hookworm pathogenesis and inform development of innovative tools to monitor deworming programs in endemic communities.