# Influenza B virus suppression of Chromosome Y-linked genes increases pulmonary virus replication and disease severity in male mice

## TL;DR

Influenza B virus causes more severe disease in male mice due to suppression of protective genes on the Y chromosome, which can be reduced with oseltamivir treatment.

## Contribution

The study identifies Y chromosome genes as key mediators of male-biased influenza B virus susceptibility in mice.

## Key findings

- Male mice with a Y chromosome had higher virus titers and disease severity compared to females.
- Oseltamivir treatment reduced virus levels and disease severity in males to levels seen in females.
- Influenza B virus suppressed Y-linked genes Uty and Ddx3y, which oseltamivir reversed.

## Abstract

Influenza B viruses (IBV) are transmitted among humans, with disease being worse in men than women. C57BL/6 male and female mice were inoculated with Victoria lineage B/Brisbane/60/2008 containing a PB2 F406Y mutation. Juvenile, adult, and aged males exhibited greater virus titers, morbidity, and pulmonary inflammation than age-matched females. Oseltamivir treatment reduced virus titers in males thereby reducing morbidity and pulmonary cytokine responses to female-equivalent levels. Infection of transgenic and mutant mice that allowed for separation of sex chromosome dosage from gonadal sex effects revealed that the presence of a Y chromosome (ChrY) was the major contributing factor for male-biased susceptibility to IBV. IBV infection suppressed pulmonary Uty and Ddx3y expression in ChrY-bearing mice, which was reversed by oseltamivir treatment, suggesting that virus replication inhibits protective ChrY gene expression, causing male-biased IBV pathogenesis.