Why do men perform worse than women because of COVID-19? A new study suggests it’s not something wrong with men, it’s something right with women. Specifically, the innate immune system of women.
A team of researchers from Princeton University, the Simons Foundation’s Flatiron Institute, the Icahn School of Medicine at Mount Sinai and the Naval Medical Research Center had begun studying a group of nearly 3,000 US Marine Corps personnel. before a COVID-19 outbreak during their training in 2020, and continued to follow them through infections and after. The results of their study appear in the current issue of the journal Cell Systems.
Using RNA sequencing and analysis of clinical measures, the research team found that although infected women had higher rates of symptoms, their average viral load was 2.6 times lower than that of infected women. men. They also identified molecular signatures that indicated a sex-specific genetic basis for the difference. “Sex-specific responses to COVID-19 are notoriously difficult to study, due to the many confounding variables, including comorbidities, differences in environment, physical fitness, etc.,” said Olga Troyanskaya, Professor of Computer Science and the Lewis-Sigler Institute for Integrative Genomics (LSI) and Director of Princeton Precision Health at Princeton University, Associate Director of Genomics at the Simons Foundation Flatiron Institute and one of two co-lead authors of the study.
“This study has created an unprecedented opportunity,” she said. “This group of Marines training and living together on base makes for a very large, well-controlled cohort. They’re all about the same age, live in almost identical conditions, eat similar foods. They’re about at the same fitness level. All had similar disease severity – asymptomatic or mild COVID. The other critical point was that this study included longitudinal PCR testing, blood collection and symptom reporting – leading to data before, during and after their COVID cases.
“Through a well-controlled longitudinal study of young Marine recruits, we were able to identify sex differences across many parameters, including symptoms, viral load, blood transcriptome, RNA splicing, and proteomic signatures,” said Stuart Sealfon, MD, the Sara B and Seth M. Glickenhaus professor of neurology at Icahn Mount Sinai and the study’s other co-lead author. “We found that women have higher expression of the antiviral interferon-stimulated gene (ISG) before infection, a wide range of genes that typically function to inhibit viral replication. Our results indicate that these ISG differences might influence sex differences in response to viral infection.
Identifying these ISG differences won’t immediately lead to a treatment plan, the researchers warn, but it does open a clear path for biomedical research.
“Identifying unique gender signatures will help inform the design of future medical countermeasures that can prevent and treat SARS-CoV-2 infections not only among military recruits, but also improve global public health” said Commander Andrew Letizia, Physician Assistant. director of the Naval Medical Research Center’s Infectious Diseases Branch and principal investigator and study author.
The authors note some limitations to their study, including that the cohort was mostly healthy young adults and did not include any cases of severe COVID-19, which limited their ability to draw firm conclusions about the appropriateness of these results for older or less healthy people. individuals or the development of more severe COVID-19.
Leverage Big Data
Troyanskaya is a computational biologist, using advanced analytical techniques to sift through huge datasets. This allowed the research team to sift through the many existing hypotheses about sex differences and find a causal explanation for the differences in results: the sex-specific molecular signatures that are present prior to infection.
“Women have a more active immune system, even before they get sick,” explained Natalie Sauerwald, one of the co-first authors, a researcher at the Flatiron Institute and a visiting research associate at Princeton University. The other co-first author, Zijun “Frank” Zhang, was also a postdoctoral researcher with Troyanskaya at Princeton and Flatiron before joining the research faculty of the Division of Artificial Intelligence in Medicine at Cedars-Sinai Medical Center.
“Our analysis indicates that women’s innate immunity is more activated before and during infection, helping to fight the virus more effectively,” Sauerwald said.
Immune warfare is grueling, which is also why women show more severe symptoms during COVID infections: higher fevers, more intense fatigue and more intense coughs.
“Remember that the symptoms are partly due to your immune system fighting the infection,” Troyanskaya said.
The result is that women feel sicker when fighting the disease, but they have lower viral loads and better outcomes than men with the same exposure.
It was already known that men had worse COVID outcomes, but what made this study unique was that the computer scientists had enough data — and, importantly, pre-infection blood tests — to create a model. causal linking sex-specific pre-infection innate immune states. response to infection and outcomes.
“There are many biological differences between males and females,” Sauerwald said. “Men have a higher incidence of cardiovascular disease and other comorbidities. There are hormonal differences and many other factors that could potentially explain this male-female difference in COVID. But with our data and modeling, we were able for the first time to show a significant link between differences in immune level before infection between the sexes and the outcomes we observed during infection.
For the COVID-19 Health Action Response for Marines (CHARM) study to investigate the basis of COVID sex differences, researchers collected and analyzed data from Marine recruits at the start of their training. A total of 2,641 men and 244 women who were initially seronegative for SARS-CoV-2 were followed for 12 weeks with regular screening for symptoms, PCR tests and blood sampling.
During those three months, which included two weeks of supervised quarantine and 10 weeks of marine 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, before the vaccines or treatments were released, and none of the participants were enrolled in any other clinical trials at the time.
“Pre-infection antiviral innate immunity contributes to sex differences in SARS-CoV-2 infection», by Natalie Sauerwald, Zijun Zhang, Irene Ramos, Venugopalan D. Nair, Alessandra Soares-Schanoski, Yongchao Ge, Weiguang Mao, Hala Alshammary, Ana S. Gonzalez-Reiche, Adriana van de Guchte, Carl W. Goforth, Rhonda A Lizewski, Stephen E. Lizewski, Mary Anne S. Amper, Mital Vasoya, Nitish Seenarine, Kristy Guevara, Nada Marjanovic, Clare M. Miller, German Nudelman, Megan A. Schilling, Rachel SG Sealfon, Michael S. Termini, Sindhu Vangeti, Dawn L. Weir, Elena Zaslavsky, Maria Chikina, Ying Nian Wu, Harm Van Bakel, Andrew G. Letizia, Stuart C. Sealfon, and Olga G. Troyanskaya, appears in the current issue of Cell Systems (DOI: 10.1016/j.cels.2022.10.005). This work was supported by the Defense Health Agency through the Naval Medical Research Center and the Defense Advanced Research Projects Agency as a member of Epigenetic characterization and observation (ECHO) program.
Elizabeth Dowling of Icahn Mount Sinai contributed to this article.