Adverse outcomes in SARS-CoV-2–infected pregnant mice are gestational age–dependent and resolve with antiviral treatment
Patrick S. Creisher, … , Andrew Pekosz, Sabra L. Klein
Patrick S. Creisher, … , Andrew Pekosz, Sabra L. Klein
Published August 15, 2023
Citation Information: J Clin Invest. 2023;133(20):e170687. https://doi.org/10.1172/JCI170687.
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Research Article Reproductive biology Article has an altmetric score of 16

Adverse outcomes in SARS-CoV-2–infected pregnant mice are gestational age–dependent and resolve with antiviral treatment

Abstract

SARS-CoV-2 infection during pregnancy is associated with severe COVID-19 and adverse fetal outcomes, but the underlying mechanisms remain poorly understood. Moreover, clinical studies assessing therapeutics against SARS-CoV-2 in pregnancy are limited. To address these gaps, we developed a mouse model of SARS-CoV-2 infection during pregnancy. Outbred CD1 mice were infected at E6, E10, or E16 with a mouse-adapted SARS-CoV-2 (maSCV2) virus. Outcomes were gestational age–dependent, with greater morbidity, reduced antiviral immunity, greater viral titers, and impaired fetal growth and neurodevelopment occurring with infection at E16 (third trimester equivalent) than with infection at either E6 (first trimester equivalent) or E10 (second trimester equivalent). To assess the efficacy of ritonavir-boosted nirmatrelvir, which is recommended for individuals who are pregnant with COVID-19, we treated E16-infected dams with mouse-equivalent doses of nirmatrelvir and ritonavir. Treatment reduced pulmonary viral titers, decreased maternal morbidity, and prevented offspring growth restriction and neurodevelopmental impairments. Our results highlight that severe COVID-19 during pregnancy and fetal growth restriction is associated with heightened virus replication in maternal lungs. Ritonavir-boosted nirmatrelvir mitigated maternal morbidity along with fetal growth and neurodevelopment restriction after SARS-CoV-2 infection. These findings prompt the need for further consideration of pregnancy in preclinical and clinical studies of therapeutics against viral infections.

Authors

Patrick S. Creisher, Jamie L. Perry, Weizhi Zhong, Jun Lei, Kathleen R. Mulka, W. Hurley Ryan III, Ruifeng Zhou, Elgin H. Akin, Anguo Liu, Wayne Mitzner, Irina Burd, Andrew Pekosz, Sabra L. Klein

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Figure 6

Ritonavir-boosted nirmatrelvir mitigates maternal morbidity and reduced viral titers in the lungs of pregnant dams.

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Ritonavir-boosted nirmatrelvir mitigates maternal morbidity and reduced ...
Uninfected adult nonpregnant and pregnant (E16) females were euthanized, liver tissue collected, and Western blots performed to quantify the amount of overall CYP3A expression (A, n = 4–5/group). At E16, pregnant dams or age-matched nonpregnant females were intranasally infected with 1 × 105 TCID50 of maSCV2 or mock inoculated with media. Starting at 4 hours after infection and continuing twice daily for 5 days or until tissue collection, mice were treated with 1.7 mg nirmatrelvir and 0.6 mg ritonavir per dose or vehicle and were monitored for changes in body mass for 14 days (B, n = 6/group from 2 independent replicates). A subset of dams were euthanized at 3 DPI, nasal turbinate and lung tissue were collected, and viral titers were measured by TCID50 assay (C and D, n = 5–11/group). RNA was extracted from lung homogenate, reverse transcribed using ProtoScript II First Strand cDNA Synthesis Kit, the Mpro region amplified, and Oxford Nanopore sequenced by Plasmidaurus. Consensus sequences were imported and aligned to Mpro using ClustalO v1.2.3 in Geneious Prime v2023.0.4. Alignments were imported into R v4.1.1., visualized, and annotated using seqvisR v0.2.5 (E, n = 4/group). Bars represent the mean ± SEM from 2 independent replications with individual mice indicated by shapes (A, C, and D). Statistical significance was determined by 2 tailed unpaired t test (A), 2-way ANOVA with Bonferroni posthoc test of AUCs (B), or 2-way ANOVA with Bonferroni posthoc test (C and D). Sequence graphic built using Biorender.com. LOD, limit of detection. *P < 0.05.