Sex differences in the effects of SARS-CoV-2 in young adults

A collaborative study of nearly 3,000 young, healthy members of the U.
S.
Marine Corps showed that significant immune differences between young men and women can modulate sex differences
in response to the virus that causes COVID-19.
The study, conducted by researchers at Princeton's Mount Sinai Icahn School of Medicine and the Naval Center for Medical Research, was published Nov.
7 in
the journal Cell Systems.

"Through a well-controlled longitudinal study of young Navy recruits, we were able to identify gender differences on a number of metrics, including symptoms, viral load, blood transcriptome, RNA splicing, and proteome signature," said Stuart Sealfon, MD, the Sara B.
and Seth M.
Glickenhaus Professor of Sinai Neurology at Mount Icaon and co-senior author
of the study 。 "We found that women with higher expression of preinfectious antiviral interferon-stimulating genes (ISGs), a broad set of genes that normally play a role
in inhibiting viral replication.
Our results suggest that these ISG differences may mediate sex differences
in response to viral infection.
”

COVID-19 has caused more than 6.
5 million deaths worldwide, and on average, the outcome is worse for
men.
Men and women have different
innate and adaptive immune responses to SARS-CoV-2 infection, the virus that causes COVID-19.
Differences in these responses and outcomes may be influenced by pre-existing factors that either exacerbate the disease in men (such as the prevalence of androgen effects or comorbidities) or improve outcomes in women (such as the effectiveness of the immune system).

Andrew Letizia, MD, deputy director of the Infectious Diseases Bureau at the Naval Medical Research Center, said: "The identification of unique characteristics between genders will help inform the design of future medical countermeasures that will not only prevent and treat SARS-CoV-2 infections among recruits, but also improve global public health
.
"

To understand the basis of these gender differences, the research team analyzed data
collected from a group of Marine recruits who were just beginning military training.
Through the prospective Marine Corps COVID-19 Health Action Response (CHARM) study, a total of 2641 men and 244 women who were initially SARS-CoV-2 seronegative were followed longitudinally, including symptom screening, SARS-CoV-2 series cotton swab PCR testing, and blood sampling for molecular analysis
.
Within 12 weeks of study start, including two weeks of supervised isolation and 10 weeks of recruit training, a total of 1,033 men and 137 women tested positive
for SARS-CoV-2.
The study was conducted between May and September 2020, when no participants participated in other clinical trials
until the release of a vaccine and treatment specifically for SARS-CoV-2.
The collaboration of academic and military scientists with the Marine Corps allows the identification and analysis of pre-existing immune system differences and their significance in the molecular
and clinical sex differences observed during SARS-CoV-2 infection.

Using RNA sequencing and clinical measurements, the team found that infected women had a higher incidence of symptoms, but their average viral load was 2.
6 times
lower than that of men.
They also identified sex-specific molecular signatures
for gene expression, selective splicing, and immunoproteomics, the study of large numbers of proteins involved in immune responses.
Specifically, differential splicing of 594 loci was found only during male infection, while 376 genes and 270 loci were regulated
only in females.
Many of these immune response genes are sex-biased or sex-specific, and there are more
genes in women than men in a rich immune response.
This suggests that in women, the transcriptional and post-transcriptional immune response to acute SARS-CoV-2 infection is generally stronger
.

"Gender-specific response studies to Covid-19 are challenging because there are many confounding variables, including comorbidities, environmental differences, health conditions, and more
.
CHARM's unique, well-controlled longitudinal sampling cohort combined with computational analysis enabled the identification of relevant, sex-specific molecular signatures that existed prior to infection," said Olga Troyanskaya, professor of computer science at Princeton University and associate director of genomics at the Simons Foundation's Flatiron Institute, who is also a co-senior author
of the study.

The authors note that their study had some limitations, including that the cohort was predominantly young healthy adults and did not include any serious cases of COVID-19, which allowed them to tightly control baseline health, but limited their ability to draw definitive conclusions about the relevance of these findings to
older or less healthy people or the development of more severe COVID-19 。 The large, relatively homogeneous cohort of young Navy recruits exposed to the virus under similar recruit training conditions minimized the effects of confounding factors such as age, comorbidities, race, ethnicity, and environmental exposures, making it possible
to determine the causative contribution of baseline immune sex differences to molecular responses and symptoms caused by SARS-CoV-2 infection.

Pre-infection antiviral innate immunity contributes to sex differences in SARS-CoV-2 infection