Viral immunity during human pregnancy [electronic resource] : lessons from influenza and Zika viruses

Pregnancy is a unique state of human development and immunological tolerance. Pregnant women are at increased risk of severe disease from a number of viruses including influenza, cytomegalovirus, and Zika virus. Here, we present several vignettes that explore maternal immunity and viral pathogenesis. We first examine the adaptive antibody-based immune response to influenza vaccination in pregnant women. Inactivated influenza vaccine (IIV) is recommended during pregnancy to prevent influenza infection and its complications in pregnant women and their infants. However, the extent to which pregnancy modifies the antibody response to vaccination remains unclear, and prior studies have focused primarily on hemagglutinin inhibition (HI) titers. A more comprehensive understanding of how pregnancy modifies the humoral immune response to influenza vaccination will aid in maximizing vaccine efficacy. Healthy pregnant women and control women were studied prior to, 7 days after and 28 days after vaccination with IIV. HI titers, microneutralization (MN) titers and the frequency of circulating plasmablasts were evaluated in pregnant vs. control women. Pregnant women and control women mount similarly robust serologic immune responses to IIV, with no significant differences for any influenza strain in post-vaccination geometric mean HI or MN titers. HI and MN titers correlate, though MN titers demonstrate more robust changes pre- vs. post-vaccination. The induction of circulating plasmablasts is increased in pregnant women compared to control. From our study, we see that pregnant women do not have impaired humoral immune responses to IIV and may have increased circulating plasmablast production compared to control women. Then, we characterize the innate cellular response to IIV in a similar cohort. We characterized the immune response of monocytes and plasmacytoid dendritic cells (pDCs) to IAV infection in pregnant (n=21) and non-pregnant (n=21) women. In pregnant women, monocytes and pDCs exhibit an exaggerated pro-inflammatory immune response to two strains of IAV compared to non-pregnant women, characterized by increased expression of MHC class II (~2.0-fold), CD69 (~2.2-fold), interferon gamma induced protein 10 (IP-10, ~2.0-fold) and macrophage inflammatory protein-1beta (MIP-1b- ~1.5-fold). This enhanced innate inflammatory response during pregnancy could contribute to pulmonary inflammation following IAV infection. Finally, we turn to Zika virus, which caused a major epidemic in Latin American countries from 2015-2016. Zika virus (ZIKV) infection during pregnancy is linked to microcephaly attributed to infection of developing brain structures. ZIKV infects neural progenitor cells in vitro, though its effects on other developmentally relevant stem cell populations, including cranial neural crest cells (CNCCs), have not been assessed. CNCCs give rise to most cranial bones and exert paracrine effects on the developing brain. Here, we report that CNCCs are productively infected by ZIKV, but not by the related dengue virus. ZIKV-infected CNCCs undergo limited apoptosis but secrete cytokines that promote death and drive aberrant differentiation of neural progenitor cultures. Addition of two such cytokines, LIF or VEGF, at levels comparable to those secreted by ZIKV-infected CNCCs is sufficient to recapitulate premature neuronal differentiation and apoptotic death of neural progenitors. Thus, our results suggest that CNCC infection by ZIKV may contribute to associated embryopathies through signaling cross-talk between developing face and brain structures. To conclude, we consider some of the unanswered questions raised by these studies. We also propose several new lines of inquiry into influenza and Zika virus pathogenesis and immunity to further explore the topics presented here.

Keywords: Immunology.
Advisor: Blish Catherine
Davis Mark advisor. Thesis advisor
Idoyaga Juliana
Kirkegaard Karla advisor. Thesis advisor