Abstract
Epidemiological studies have identified a correlation between maternal helminth infections and reduced immunity to some early childhood vaccinations, but the cellular basis for this is poorly understood. Here, we investigated the effects of maternal Schistosoma mansoni infection on steady-state offspring immunity, as well as immunity induced by a commercial tetanus/diphtheria vaccine using a dual IL-4 reporter mouse model of maternal schistosomiasis. We demonstrate that offspring born to S. mansoni infected mothers have reduced circulating plasma cells and peripheral lymph node follicular dendritic cells at steady state. These reductions correlate with reduced production of IL-4 by iNKT cells, the cellular source of IL-4 in the peripheral lymph node during early life. These defects in follicular dendritic cells and IL-4 production were maintained long-term with reduced secretion of IL-4 in the germinal center and reduced generation of TFH, memory B, and memory T cells in response to immunization with tetanus/diphtheria. Using single-cell RNASeq following tetanus/diphtheria immunization of offspring, we identified a defect in cell-cycle and cell-proliferation pathways in addition to a reduction in Ebf-1, a key B-cell transcription factor, in the majority of follicular B cells. These reductions are dependent on the presence of egg antigens in the mother, as offspring born to single-sex infected mothers do not have these transcriptional defects. These data indicate that maternal schistosomiasis leads to long-term defects in antigen-induced cellular immunity, and for the first time provide key mechanistic insight into the factors regulating reduced immunity in offspring born to S. mansoni infected mothers.
Highlights
Schistosomiasis is an infectious disease caused by trematode parasites of the genus Schistosoma, with S. mansoni, S. haematobium, and S. japonicum causing the most human morbidity [1]
We demonstrate that offspring born to S. mansoni infected mothers have reduced circulating plasma cells and peripheral lymph node follicular dendritic cells at steady state
We establish a model of maternal Schistosoma mansoni infection in dual IL-4 reporter mice
Summary
Schistosomiasis is an infectious disease caused by trematode parasites of the genus Schistosoma, with S. mansoni, S. haematobium, and S. japonicum causing the most human morbidity [1]. This disease affects an estimated 779 million people who are at risk, and 207 million people infected annually [2], with the highest prevalence in adolescents and young adults (10 to 24 years of age) [3]. Children born to mothers infected with S. mansoni presented lower anti-measles antibody levels [7] at 2 years of age These data suggest that populations where schistosomiasis is endemic, are vulnerable to vaccine failure, and susceptible to deaths due to preventable infectious diseases. Endemic regions may require an adjusted immunization regimen in order to ensure optimal protection against diseases, but mechanistic studies are needed to examine this
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