From mice to women: the conundrum of immunity to infection during pregnancy

Abstract

Resistance to infection is the ability of the host to evoke a strong immune response sufficient to eliminate the infectious agent. In contrast, maternal tolerance to the fetus necessitates careful regulation of immune responses. Successful pregnancy requires the maternal host to effectively balance the opposing processes of maternal immune reactivity and tolerance to the fetus. However, this balance can be perturbed by infections which are recognized as the major cause of adverse pregnancy outcome including pre-term labor. Select pathogens also pose a serious threat of severe maternal illness. These include intracellular and chronic pathogens that have evolved immune evasive strategies. Murine models of intracellular bacteria and parasites that mimic pathogenesis of infection in humans have been developed. While human epidemiological studies provide insight into maternal immunity to infection, experimental infection in pregnant mice is a vital tool to unravel the complex molecular mechanisms of placental infection, congenital transmission and maternal illness. We will provide a comprehensive review of the pathogenesis of several infection models in pregnant mice and their clinical relevance. These models have revealed the immunological function of the placenta in responding to, and resisting infection. Murine feto-placental infection provides an effective way to evaluate new intervention strategies for managing infections during pregnancy, adverse fetal outcome and long-term effects on the offspring and mother.

Fig. 1

Schematic diagram of mouse and human placenta. Top panel is a cartoon image of the human and mouse placenta respectively indicating orientation of the maternal decidua, spiral artery and trophoblast layers. A transverse section of the area indicated by the inset box in each image is shown in the bottom panel to highlight the cellular details. (a) List of cells and structures that are similar between human and mouse placenta. (b) Cells and structures distinctive to the human placenta. (c) Comparative cells and structures seen in the mouse placenta.

Fig. 2

Modulation of immunity to infection in pregnancy. A schematic diagram showing the different ways in which infectious agents may interact with the feto-maternal interface cells and trophoblast. The left panel shows that parasites such as T. gondii are controlled by a strong Th1 and cytotoxic CD8 T cell response. The Th1 cytokines in an infected host may inflict damage to the trophoblast leading to fetal loss. The trophoblast inturn produces IL-10 and anti-inflammatory cytokines that inhibit the Th1 response against the parasite. Macrophages and dendritic cells infected with the parasite may reach the feto-maternal interface leading to trophoblast infection and congenital transmission. Prior antibody immunity in chronically infected mothers can prevent congenital transmission. The middle panel shows that viruses such as influenza require a strong type I interferon response for clearance. However, this response may be dampened in the pregnant host due to enhanced T regulatory cell numbers and Th2 cytokine bias. High viral titers in peripheral tissue and severe maternal illness can occur despite lack of placental infection. The right panel shows that facultative intracellular bacteria such as Salmonella can reach the feto-maternal interface by escaping the maternal blood or may be carried by infected macrophages and dendritic cells. Once in the feto-placental milieu they efficiently infect trophoblast cells and profound pathogen proliferation ensues. This evokes massive inflammation and loss of placental tissue integrity. The inflammatory cytokines evoked by placental infection may convert resident T regulatory cells into Th17 cells, culminating in fetal loss and severe maternal illness.