Host immune responses to Listeria monocytogenes infection in the pregnant mouse

Abstract

The success of viviparity, or live births of the young, in mammalian species depends on strict regulation of the maternal immune system during pregnancy to induce and maintain tolerance of the fetus that also expresses paternal alloantigens. The paradox of how the mother provides protection from microbial infections without rejecting the allogeneic fetus has intrigued scientists for decades. The association between extreme prematurity births and intrauterine infection emphasizes the importance of understanding the host immune responses against uterine invading microbes during pregnancy to the prevention of preterm births.;This thesis describes two separate projects that study the host immunity against infections during pregnancy, using Listeria monocytogenes as a probe. First, using mice carrying the recessive null mutation in the Colony Stimulating Factor-1 (CSF-1) gene, we show that CSF-1-dependent macrophage functions are required for the maternal decidual immune responses against Listeria infections during early gestation The increased susceptibility of CSF-1-deficient mice to uterine infection by Listeria was due to their inability to control the expansion of colonized bacteria in the pregnant uterus, causing decidual cell death, tissue disintegration, and resorption of the developing embryo, despite successful decidual production of both TH1 cytokines and neutrophil chemotractants, and recruitment of neutrophils. Depletion of macrophages in hormonally induced pseudopregnant mice resulted in higher uterine bacterial levels after Listeria infection. These data suggest that the anti-Listeria responses in the maternal decidual tissue are dependent on CSF-1-regulated macrophages.;Second, using mice carrying a targeted inactivation of the indoleamine-2,3-dioxygenase (IDO) gene, we show that this enzyme is required for the placental, but not systemic, anti-Listeria response. Without IDO, pregnant mice were more susceptible to Listeria infection in the placenta, which was rescued by genetic crosses that generate heterozygous placentae. Moreover, fetally-derived IDO protects against Listeria infection in the pregnant mother.;Our understanding of the immune system during pregnancy and will provide the molecular basis for designing treatments against infections to minimize fetal morbidity and mortality, and also shed light on the mechanisms underlying immune tolerance to allow fine tuning and control of the immune system to help prevent and cure diseases.