Paternal SARS-CoV-2 infection impacts sperm small noncoding RNAs and increases anxiety in offspring in a sex-dependent manner
- Elizabeth A. Kleeman
- Carolina Gubert
- Sonali N. Reisinger
- Kathryn C. Davidson
- Da Lu
- Merle Dayton
- Liana Mackiewicz
- Bethany A. Masson
- Pranav Adithya
- Alexandra L. Garnham
- Gemma Stathatos
- Moira K. O’Bryan
- Rikeish R. Muralitharan
- Francine Z. Marques
- Shanshan Li
- Huan Liao
- Shae McLaughlin
- Emmet T. Keough
- Michelle Y. Wheeler
- Pamudika Kiridena
- Marcel Doerflinger
- Marc Pellegrini
- Anthony J. Hannan
2025-10-11
Given that the SARS-CoV-2 virus, and the COVID-19 pandemic, constitutes a major environmental challenge faced by billions of people worldwide, we investigated whether paternal pre-conceptual SARS-CoV-2 infection has impacts on sperm RNA content, and intergenerational (F1) and transgenerational (F2) effects on offspring phenotypes. Using an established mouse-adapted SARS-CoV-2 (P21) preclinical model, we infected adult male mice with the virus, or performed a mock control infection, and bred them with naïve female mice four weeks later, when males were no longer infectious. Here we show that offspring of infected sires display increased anxiety-like behaviors. Additionally, the F1 offspring have significant transcriptomic changes in their hippocampus. Various sperm small noncoding RNAs, including PIWI-interacting RNAs, transfer-derived RNAs and microRNAs, are differentially altered by prior paternal SARS-CoV-2 infection. Microinjection of RNA from the sperm of SARS-CoV-2 infected males into fertilized oocytes leads to a phenotype resembling that of the naturally born F1 offspring, supporting the interpretation that sperm RNAs are contributing to the outcomes of our paternal SARS-CoV-2 model. Therefore, this study provides evidence that paternal SARS-CoV-2 infection impacts sperm and affects offspring phenotypes. These findings have public-health implications and inform further research in males affected by COVID-19, and their offspring.