Novel murine models of post-implantation and midgestional malaria-induced preterm birth

Despite major advances made in malaria treatment and control over recent decades, the development of new models for studying disease pathogenesis remains a vital part of malaria research efforts. The study of malaria infection during pregnancy is particularly reliant on mouse models, as a means of circumventing many challenges and costs associated with pregnancy studies in endemic human populations. Here, we introduce three novel murine models that will further our understanding of how post-implantation and midgestional malaria infection affects pregnancy outcomes. When C57BL/6J (B6) mice are infected with Plasmodium chabaudi chabaudi AS on either embryonic day (E) 6.5, 8.5, or 10.5, preterm birth occurs in all animals by E16.5, E17.5, or E18.5 respectively, with no evidence of intrauterine growth restriction. We found that the time to delivery, placental inflammatory and antioxidant transcript upregulation, and the relationships between parasitemia and transcript expression prior to preterm birth are different based on the embryonic day of infection. On the day before preterm delivery, E6.5 infected mice did not experience significant upregulation of the inflammatory or antioxidant gene transcripts examined; however, parasitemia correlated positively with Il1{beta}, Cox1, and Hmox1 placental transcript abundance. E8.5 infected mice had elevated transcripts for Ifn{gamma}, Tnf, Il10, Cox1, Cox2, Sod1, Sod2, Cat, and Nrf2, while Sod3 was the only transcript that correlated with parasitemia. Finally, E10.5 infected mice had elevated transcripts for Ifn{gamma} only, with a tendency for Tnf transcripts to correlate with parasitemia. Tumor necrosis factor deficient (TNF-/-) and TNF receptor 1 deficient (TNFR1-/-) mice infected on E8.5 experienced preterm birth at the same time as B6 controls. Further characterization of these models is necessary to discover new and/or existing mechanism(s) or trigger(s) responsible for malaria-driven preterm birth that is determined by gestational age upon maternal infection, parasite-host dynamics, or both.