Regulation of humoral immunity in a mouse model of hookworm infection

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Estimated 700 million people are affected by hookworm infections world-wide leading to major socioeconomic problems and a pronounced health impact caused by anemia, malnutrition and growth retardation of children. While medications can reduce worm burden they are often of low efficiency due to reinfections and may lead to the emergence of drug resistance. Vaccines are not yet available for human hookworm infections. The helminth Nippostrongylus brasiliensis (Nb) is a frequently used laboratory model to study the mechanisms of hookworm infections including pathways of protective immunity in mice. Nb infections elicit a strong type 2 immune response in the lung and small intestine with pronounced eosinophilia, high IgE levels and accumulation of Th2 cells and ILC2s. The focus of this proposal is the analysis of the humoral immune response to Nb especially after secondary infection or immunization with a single Nb-derived protein. We could previously show that during Nb infection the IL-4/IL-13-induced transcription factor STAT6 is required in B cells for germinal center (GC) formation in addition to its known function for class switch recombination to IgE. We further identified STAT6-regulated genes in B cells that we will now functionally characterize as part of this proposal to uncover how these genes may be involved in the GC response, plasma cell (PC) differentiation and formation of memory B cells. Using a fate-mapping approach, we will determine the differentiation and persistence of memory B cells and PCs after primary and secondary Nb infection. We will also analyze the B cell receptor (BCR) repertoire of fate-mapped cells and determine the linked BCR/transcriptome profile in single cells to identify expanded clones from which BCRs can be cloned and used to identify Nb-derived antigens or generate BCR-transgenic mice. Recently, we identified a new Nb-derived antigen that provides protective immunity against a Nb challenge infection. The protective effect occurs in the skin and is lost in basophil-deficient mice suggesting that it requires antibody-mediated activation of basophils. Further characterization of the humoral immune response to this antigen could lead to development of new vaccination strategies against helminths in the future.