Delayed Antiviral Immune Responses in Severe Acute Respiratory Syndrome Coronavirus Infected Pregnant Mice.

Guohua Zhu,Gaowei Hu,Di Qu,Dajin Li,Qiliang Cai,Shujuan Du,Lu Liu,Meirong Du,Xin Lu,Yuyan Wang,Xixi Huang,Yizhun Zhu

doi:10.3389/fmicb.2021.806902

Abstract

Sex differences in immune responses had been reported to correlate with different symptoms and mortality in the disease course of coronavirus disease 2019 (COVID-19). However, whether severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection interferes with females’ fertility and causes different symptoms among pregnant and non-pregnant females remains unknown. Here, we examined the differences in viral loads, SARS-CoV-2-specific antibody titers, proinflammatory cytokines, and levels of T cell activation after SARS-CoV-2 sub-lethal infection between pregnant and non-pregnant human Angiotensin-Converting Enzyme II (ACE2) transgenic mouse models. Both mice showed elevated levels of viral loads in the lung at 4 days post-infection (dpi). However, viral loads in the pregnant group remained elevated at 7 dpi while decreased in the non-pregnant group. Consistent with viral loads, increased production of proinflammatory cytokines was detected from the pregnant group, and the IgM or SARS-CoV-2-specific IgG antibody in serum of pregnant mice featured delayed elevation compared with non-pregnant mice. Moreover, by accessing kinetics of activation marker expression of peripheral T cells after infection, a lower level of CD8+ T cell activation was observed in pregnant mice, further demonstrating the difference of immune-response between pregnant and non-pregnant mice. Although vertical transmission did not occur as SARS-CoV-2 RNA was absent in the uterus and fetus from the infected pregnant mice, a lower pregnancy rate was observed when the mice were infected before embryo implantation after mating, indicating that SARS-CoV-2 infection may interfere with mice’s fertility at a specific time window. In summary, pregnant mice bear a weaker ability to eliminate the SARS-CoV-2 virus than non-pregnant mice, which was correlated with lower levels of antibody production and T cell activation.

Highlights

Epidemiologic investigations indicate that pregnancy is associated with a higher risk of disease severeness and mortality after viral infections, such as influenza, Ebola, and Lassa fever (Silasi et al, 2015)
The results indicated that both pregnant and non-pregnant mice were susceptible to SARS-CoV-2 infection, while the pregnant mice displayed weaker virus removal ability
Some COVID-19 disease cases were reported for evidence of mother-to-fetal transmission at a terminal gestational stage, it is difficult to assess whether SARS-CoV-2 infection would interfere with gestation and whether the pregnancy would affect vulnerability and the immune response to SARSCoV-2 infection

Summary

Introduction

Epidemiologic investigations indicate that pregnancy is associated with a higher risk of disease severeness and mortality after viral infections, such as influenza, Ebola, and Lassa fever (Silasi et al, 2015). Investigating the potential risks of viral infections during pregnancy is essential for taking appropriate clinical interventions. It has been 2 years since the global Coronavirus disease 2019 (COVID-19) pandemic outbreak. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the COVID-19 (Ren et al, 2020; Harvey et al, 2021). Most pathogens that cause infections in pregnant mothers cannot reach the fetus, largely due to the potent protective mechanisms provided by placental cells, including syncytiotrophoblasts (Parry et al, 1997; Koi et al, 2002; Arora et al, 2017). Building upon single-cell RNA-sequencing data, researchers found that human placental cells express mRNA for SARSCoV-2 receptors throughout pregnancy (Ashary et al, 2020)

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