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

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.

Effect of severe acute respiratory syndrome coronavirus 2 infection during pregnancy in K18-hACE2 transgenic mice

“…Infection with SARS-CoV-2 at the post-implantation stage did not induce a significant difference in pregnancy outcomes compared to the control group. This result is similar to previously published findings that state that embryo resorption did not occur in infected mice after E4.5 [ 26 ]. Viral RNA was not detected in the female reproductive tract, indicating that the virus cannot infect the reproductive tract or the fetus.…”

“…K18-hACE2 transgenic mice are the most sensitive to SARS-CoV-2 and can model non-severe and severe SARS-CoV-2 affected patients in many animal models [ 25 ]. Studies using K18-hACE2 transgenic mice revealed the expression of hACE2 mRNA in the lungs, brain, kidneys, and small intestine [ 25 , 26 ]. In addition, it has been discovered that the neuro-invasion of SARS-CoV-2 is dependent on hACE2 expression [ 27 ].…”

Maternal immunization with distinct influenza vaccine platforms elicits unique antibody profiles that impact the protection of offspring

“…Epidemiological data and studies in pregnant mice demonstrate pregnancy is a risk factor for severe COVID-19, and vaccination has been associated with improved outcomes. 48,49 In the search for a universal influenza vaccine, these findings highlight the functionality of maternal antibodies elicited via distinct vaccine delivery systems and are vital to refine vaccine development pipelines for this high-risk group. Our results are in alignment with recent advances such as Pfizer's maternal respiratory syncytial virus (RSV) vaccine.…”

Pregnancy-induced differential expression of SARS-CoV-2 and influenza a viral entry factors in the lower respiratory tract

“…This could be addressed with single cell RNA sequencing studies in the future. Fifth, despite upregulated innate immune surveillance, other facets of infection, such as viral clearance and activation of adaptive immunity could be adversely impacted with pregnancy as was recently shown in pregnant transgenic hACE2-chimera female mice [ 54 ], or by sex hormones per se [ 55 – 57 ]. More importantly, we only capture the baseline state of innate immune gene expression and, therefore, are unable to comment on whether such enhanced expression results in increased ability to respond to viral challenge.…”