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.

Maternal infection during pregnancy is known to alter the development and function of offspring’s immune system, leading to inappropriate immune responses to common childhood infections and immunizations. Although this is an expanding field, maternal parasitic infections remain understudied. Millions of women of reproductive age are currently at risk for parasitic infection, whereas many pregnant, chronically infected women are excluded from mass drug administration due partially to a lack of resources, as well as fear of unknown adverse fetal developmental outcomes. In areas endemic for multiple parasitic infections, such as sub-Saharan Africa, there are increased rates of morbidity and mortality for various infections during early childhood in comparison with nonendemic areas. Despite evidence supporting similar immunomodulatory effects between various parasite species, there is no clear mechanistic understanding of how maternal infection reprograms offspring immunity. This brief review will compare the effects of selected maternal parasitic infections on offspring immunity.

IL‐4 is critical for differentiation of Th2 cells and antibody isotype switching, but our work demonstrated that it is produced in the peripheral LN under both Type 2, and Type 1 conditions, raising the possibility of other functions. We found that IL‐4 is vital for proper positioning of hematopoietic and stromal cells in steady state, and the lack of IL‐4 or IL‐4Rα correlates with disarrangement of both follicular dendritic cells and CD31+ endothelial cells. We observed a marked disorganization of B cells in these mice, suggesting that the lymphocyte‐stromal cell axis is maintained by the IL‐4 signaling pathway. This study showed that absence of IL‐4 correlates with significant downregulation of Lymphotoxin alpha (LTα) and Lymphotoxin beta (LTβ), critical lymphokines for the development and maintenance of lymphoid organs. Moreover, immunization of IL‐4 deficient mice with Type 2 antigens failed to induce lymphotoxin production, LN reorganization, or germinal center formation, while this process is IL‐4 independent following Type 1 immunization. Additionally, we found that Type 1 antigen mediated LN reorganization is dependent on IFN‐γ in the absence of IL‐4. Our findings reveal a role of IL‐4 in the maintenance of peripheral lymphoid organ microenvironments during homeostasis and antigenic challenge.

Macrophages have a defined role in the pathogenesis of metabolic disease and cholesterol metabolism where alternative activation of macrophages is thought to be beneficial to both glucose and cholesterol metabolism during high fat diet induced disease. It is well established that helminth infection protects from metabolic disease, but the mechanisms underlying protection are not well understood. Here, we investigated the effects of Schistosoma mansoni infection and cytokine activation in the metabolic signatures of bone marrow derived macrophages using an approach that integrated transcriptomics, metabolomics, and lipidomics in a metabolic disease prone mouse model. We demonstrate that bone marrow derived macrophages (BMDM) from S. mansoni infected male ApoE-/- mice have dramatically increased mitochondrial respiration compared to those from uninfected mice. This change is associated with increased glucose and palmitate shuttling into TCA cycle intermediates, increased accumulation of free fatty acids, and decreased accumulation of cellular cholesterol esters, tri and diglycerides, and is dependent on mgll activity. Systemic injection of IL-4 complexes is unable to recapitulate either reductions in systemic glucose AUC or the re-programing of BMDM mitochondrial respiration seen in infected males. Importantly, the metabolic reprogramming of male myeloid cells is transferrable via bone marrow transplantation to an uninfected host, indicating maintenance of reprogramming in the absence of sustained antigen exposure. Finally, schistosome induced metabolic and bone marrow modulation is sex-dependent, with infection protecting male, but not female mice from glucose intolerance and obesity. Our findings identify a transferable, long-lasting sex-dependent reprograming of the metabolic signature of macrophages by helminth infection, providing key mechanistic insight into the factors regulating the beneficial roles of helminth infection in metabolic disease.

44 45 Despite strong evidence that helminth infections are protective against the development of 46 metabolic disease, a major gap exists in understanding the mechanism(s) underlying this. We 47 have previously found that Schistosoma mansoni induces profound alterations to the metabolic 48 transcriptome of hepatic macrophages and protects male ApoE -/on high fat diet from the 49 development of obesity, glucose intolerance, and atherosclerosis. Here we demonstrate that 50 macrophages derived from the bone marrow (BMDM) of S. mansoni infected male ApoE -/mice 51 have dramatically increased mitochondrial respiration and mitochondrial mass compared to those 52 from uninfected mice. This change is accompanied by increased glucose and palmitate shuttling 53 into TCA cycle intermediates and decreased accumulation of cellular cholesterol esters. The 54 systemic effects of metabolic modulation by schistosome infection are a function of biological 55 sex, where schistosome infection protects ApoE -/male mice from obesity, glucose intolerance, 56 and increased serum triglycerides, but not female mice. The sex-dependent effects of infection 57 extend to myeloid cells specifically, where metabolic reprogramming leads to opposite 58 cholesterol phenotypes in BMDM from infected females and males. Finally, we demonstrate that 59 the metabolic reprogramming of male myeloid cells is transferrable via bone marrow 60 transplantation to an uninfected host, indicating maintenance of reprogramming in the absence of 61 ongoing schistosome antigen exposure. This work provides strong evidence that S. 62 mansoni systemically reprograms the metabolism of the myeloid compartment in a sex-63 dependent manner. 64 65 Author Summary 66Globally helminth endemic regions have lower incidences of metabolic disease. Schistosomiasis 67 in particular has been shown to protect male mice from the development of atherosclerosis, 68 diabetes and obesity while altering the metabolism of liver macrophages. In this present study we 69 sought to understand if metabolic modulation occurs systemically, and if these effects occur in 70 females as well. We have found for the first time that macrophages generated from bone marrow 71 myeloid progenitors from infected male mice have long-lived increases in their basal metabolism 72 of lipids. We have also found that unlike male mice, female mice infected with Schistosoma 73 mansoni are not protected from the development of diabetes and obesity. S. mansoni infection 74 induces opposite changes to macrophage transcription and metabolism in males and females. 75Importantly we demonstrate that the changes to male macrophage metabolism can be transferred 76to an uninfected host. This suggests that metabolic reprogramming is long-lived without 77 exposure to active infection, and the development of a memory-like phenotype. 78 79 80 Introduction 81 82 Cardiovascular disease (CVD) is the leading worldwide cause of mortality [1, 2]. In the United 83States, 65% of adults diagnosed with diabetes have elevated LDL cholestero...