Composition of the gut microbiota influences infection severity and pregnancy outcome in Plasmodium chabaudi-infected pregnant mice

Abstract

Abstract Placental malaria, a severe clinical manifestation of Plasmodium falciparum infection, is a major cause of pregnancy loss, neonatal mortality, and severe maternal illness. We have developed a novel mouse model for pregnancy maintenance during maternal malaria infection utilizing outbred Swiss Webster mice. When infected with Plasmodium chabaudi in early gestation, several inbred mouse strains will abort their pregnancies at midgestation. However, outbred Swiss Webster mice infected with P. chabaudi in early gestation carry their pregnancies to term, allowing us to explore the immunological balance between parasite clearance and pregnancy success. The composition of the gut microbiota may alter this balance. As described by Villarino et al., C57BL/6 mice sourced from different vendors display microbiota-dependent differences in Plasmodium infection severity resulting in a susceptible or resistant phenotype. Similarly, pregnant Swiss Webster mice with susceptible gut microbes develop higher parasite burdens than mice with resistant gut microbes, although both cohorts produce live pups at term. Despite the lower parasite burdens observed in resistant mice, these dams tend to produce fewer viable pups per litter, suggesting a trade-off between accelerated parasite clearance and pregnancy success. We hypothesize that the difference in litter size between susceptible and resistant dams is a result of the elevated levels of pro-inflammatory cytokines observed in resistant dams. The levels of systemic TNF and IFN-γ, which have previously been associated with the clearance of blood-stage malaria infection and pregnancy loss in P. chabaudi-infected pregnant C57BL/6 mice, are expected to be higher in resistant mice.