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

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

doi:10.3389/fmicb.2021.806902

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

Front Microbiol. 2022 Jan 21:12:806902. doi: 10.3389/fmicb.2021.806902. eCollection 2021.

Authors

Guohua Zhu¹, Shujuan Du², Yuyan Wang², Xixi Huang^{1

3}, Gaowei Hu², Xin Lu¹, Dajin Li^{1

3}, Yizhun Zhu^{3

4}, Di Qu², Qiliang Cai², Lu Liu^{1

3}, Meirong Du^{1

3

5}

Affiliations

¹ Laboratory for Reproductive Immunology, NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Hospital of Obstetrics and Gynecology, Shanghai Medical College, Fudan University, Shanghai, China.
² MOE & NHC & CAMS Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology and Parasitology, Shanghai Institute of Infectious Diseases and Biosecurity, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai, China.
³ Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
⁴ State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Taipa, Macau SAR, China.
⁵ Department of Obstetrics and Gynecology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.

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.

Keywords: SARS-CoV-2; T cell activation; fertility; immune responses; pregnancy.