Sequelae of Fetal Infection in a Non-human Primate Model of Listeriosis

Listeria monocytogenes (Lm) is a common environmental bacterium that thrives on vegetation and soil matter, but can infect humans if contaminated food products are ingested, resulting in severe disease in immunosuppressed populations, including pregnant women and newborns. To better understand how the unique immunological milieu of pregnancy increases susceptibility to infection, we study listeriosis in cynomolgus macaques, a non-human primate that closely resembles humans in placentation and in the physiology, and immunology of pregnancy. Non-human primates are naturally susceptible to Lm infection, and spontaneous abortions due to listeriosis are known to occur in outdoor macaque colonies, making them ideal models to understand the disease pathogenesis and host-pathogen relationship of listeriosis. We have previously shown that Lm infection in the first trimester has a high rate of miscarriage. This study expands on our previous findings by assessing how the quantity of Lm as well as stage of pregnancy at the time of exposure may influence disease susceptibility. In the current study we inoculated a cohort of macaques with a lower dose of Lm than our previous study and although this did not result in fetal demise, there was evidence of in utero inflammation and fetal distress. Animals that were reinfected with an equivalent or higher dose of the same strain of Lm resulted in approximately half of cases continuing to term and half ending in fetal demise. These cases had inconsistent bacterial colonization of the fetal compartment, suggesting that Lm does not need to directly infect the placenta to cause adverse pregnancy outcomes. Timed surgical collection of tissues following inoculation demonstrated that transmission from mother to fetus can occur as soon as 5 days post-inoculation. Lastly, third trimester inoculation resulted in pregnancy loss in 3 out of 4 macaques, accompanied by characteristic pathology and Lm colonization. Collectively, our studies demonstrate that common laboratory culture tests may not always recover Lm despite known maternal ingestion. Notably, we also find it is possible for maternal infection to resolve in some cases with no discernible adverse outcome; however, such cases had evidence of a sterile intrauterine inflammatory response, with unknown consequences for fetal development.