From first contact to challenge: Lung immune modulation by single-sex Schistosoma mansoni infections

Schistosomiasis is a chronic parasitic disease caused by blood flukes of the genus Schistosoma and remains a major public health concern in endemic regions. Following skin penetration, schistosomula migrate through multiple host tissues before maturing into adult worm within the mesenteric vasculature. Immunological priming critically influences host responses during secondary infections, yet the importance of prior single-sex Schistosoma mansoni infection on pulmonary recall immunity remains largely unknown. Since the lungs serve as an important immunological checkpoint during schistosomula migration, we herein investigated how single-sex and bisexual priming influence the pulmonary immune landscape upon reinfection.

Using a murine reinfection model, mice were infected with male, female or mixed-sex S. mansoni cercariae and subsequently challenged with a bisexual infection. Pulmonary immune responses were analyzed by expression of key-regulatory genes, high-dimensional flow cytometry, tSNE/FlowSOM clustering and immune cell phenotyping.

Single-sex priming resulted in distinct immune responses compared to bisexual infection. Male priming was associated with reduced pulmonary worm burden and a preferential enrichment of circulating CD4+ central and effector memory T cells, whereas female priming promoted the accumulation of CD4+ resident memory T cells together with broader alterations in pulmonary myeloid cell populations. Our findings demonstrate that the sex of primary Schistosoma mansoni infection differently programs pulmonary immune recall responses, particularly through distinct organization of the CD4+ memory T cell compartment. The association between male priming, enrichment of circulating memory T cell subsets and reduced pulmonary worm burden identifies pulmonary memory T cell organization as a potential correlate of protection during reinfection.