Pathogenesis of viral infections during pregnancy

Abstract

SUMMARYViral infections during pregnancy are associated with significant adverse perinatal and fetal outcomes. Pregnancy is a unique immunologic and physiologic state, which can influence control of virus replication, severity of disease, and vertical transmission. The placenta is the organ of the maternal-fetal interface and provides defense against microbial infection while supporting the semi-allogeneic fetus via tolerogenic immune responses. Some viruses, such as cytomegalovirus, Zika virus, and rubella virus, can breach these defenses, directly infecting the fetus and having long-lasting consequences. Even without direct placental infection, other viruses, including respiratory viruses like influenza viruses and severe acute respiratory syndrome coronavirus 2, still cause placental damage and inflammation. Concentrations of progesterone and estrogens rise during pregnancy and contribute to immunological adaptations, placentation, and placental development and play a pivotal role in creating a tolerogenic environment at the maternal-fetal interface. Animal models, including mice, nonhuman primates, rabbits, and guinea pigs, are instrumental for mechanistic insights into the pathogenesis of viral infections during pregnancy and identification of targetable treatments to improve health outcomes of pregnant individuals and offspring.

Keywords: HIV; IL-1β; SARS-CoV-2; Zika virus; estrogen; herpes; influenza; progesterone; type I IFN.

Fig 1

Research and public interest in viral infections during pregnancy peak during epidemics and pandemics. On 20 October 2023, using the search terms “virus infection and pregnancy” in PubMed (A) or “virus and pregnancy” in Google (B), numbers of peer-reviewed publications and public interest scores, respectively, peaked during the 2009 H1N1 influenza A virus pandemic, 2016 Zika virus epidemic, and the COVID-19 pandemic (in blue). The Google interest score of each month (0–100 score of relative search interest reported by Google Trends) was summed to get a cumulative interest score for that year.

Fig 2

Physiologic, immunologic, and hormonal shifts during pregnancy. Pregnancy is not a static state. Early in gestation, helper T cell type 1 (Th1) and proinflammatory immune cells and pathways activate the proinflammatory processes of implantation and placentation. As pregnancy progresses, Th1 immunity and inflammatory phenotypes are reduced and Th2 immunity and regulatory phenotypes are increased. As gestation progresses, the cardiac and pulmonary systems must adjust to account for the growing fetus. Hormones including progesterone, estrogens, and cortisol increase during pregnancy to support these physiologic and immunologic changes. Figure generated with BioRender.com.

Fig 3

Comparison of human and mouse pregnancies. With mice being the most common model of disease pathogenesis during pregnancy, identification of distinctions and similarities with humans is needed. Both mice and humans have hemochorial placentas and increased circulating progesterone, estrogens, and cortisol/corticosterone during pregnancy. Both mice and humans experience similar immunologic shifts during pregnancy. Mice have shorter gestations and large litters, while humans undergo a shift of progesterone and estrogen production from the corpus luteum to the placenta. Figure generated with BioRender.com.

Fig 4

The impact of Zika virus at the maternal-fetal interface. Zika virus is a flavivirus with a single-stranded RNA genome, transmitted primarily by Aedes spp. mosquitos. Following infection and maternal viremia, Zika virus can infect the placenta and the fetus. Animal models of Zika virus infection during pregnancy have indicated that placental immune responses, including the production of type 1 IFN and IL-1β and activity of proinflammatory macrophages and CD4+ T cells, contribute to pathology. Immune responses at the maternal-fetal interface are associated with tissue damage, placental dysfunction, and adverse fetal outcomes, including intrauterine growth restriction and microcephaly (49, 50, 83, 187, 188). Figure generated with BioRender.com.