Why men are at higher risk from COVID-19
Researchers from Osaka University provide cellular evidence for the observed differences
between the response to COVID-19 infection in males and females
Osaka, Japan – COVID-19 has had a huge global impact since the initial outbreak in 2019.
Men and women show different responses to this disease, with men having a higher risk frominfection. The underlying cellular basis for this difference is not fully understood, but now a
research group from Osaka University have uncovered sex-specific differences in a type ofimmune cell called regulatory T cells, or “Treg cells”, and in the production of proteins called
antibodies, as part of the response to COVID-19 infection.
The immune system is responsible for clearing viral infections, as well as producing many of
the acute symptoms of COVID-19, and so it is critical to understand the changes that occur
to the immune system of infected patients. The “humeral response”, the production ofantibodies, is dysregulated in COVID-19. Cells called “Treg cells” were suspected to beresponsible for this, as their role in the immune system is to regulate other immune cells andsuppress their activities to control the strength of the immune response.
Of particular relevance are “Tfr cells”, a subset of the Treg cell population responsible forcontrol of antibody production. The team observed that male patients lose circulating Tfr cells
at a faster rate than female patients, and identified sex-specific differences to a wholenetwork of different cell types that are associated with the production of antibodies.
Many COVID patients begin to produce “autoantibodies” as part of their response to the virus.
These antibodies are aimed at proteins produced by the human body instead of targeting thevirus and can neutralize protective host factors, and the production of these may play a criticalrole in how the infection progresses. “Regulation of the immune system by Treg cells may
therefore be key in understanding susceptibility to, and recovery from, COVID-19,” explains
first author Jonas Nørskov Søndergaard.
The team used an approach known as single-cell proteomics by mass spectrometry, allowing
individual immune cells to be identified and analyzed. This showed that patients with COVID19 have changes to the ratio between circulating Tfr cells and a network of other cells
associated with the production of antibodies, which in turn is strongly correlated with theantibody levels. A sex bias was seen in this response, with females having more circulating
Tfr cells while males had higher antibody levels. “This provides significant cellular evidenceof dysregulated antibody responses in COVID-19 patients,” explains senior author JamesBadger Wing. “The reduction of cTfr observed in all COVID-19 patients, but particularly inmales, may underlie this dysregulated antibody production.”
The identification of this cellular basis for the known sex-specific differences will be key inprotecting everyone, especially those most at risk, from COVID-19 infection.
###The article, “A sex-biased imbalance between Tfr, Tph, and atypical B cells determines
antibodyresponses

in COVID-19patients”, was published

inPNASat DOI:

10.1073/pnas.2217902120.
Summary: Researchers from Osaka University have shown sex-specific differences in theimmune response to COVID-19 infection. By identifying and analyzing the immune cell
population in COVID-19 patients, they showed that infection results in a reduced ratio ofcirculating follicular T regulatory (cTfr) cells to a network of antibody-producing proteins,correlated with dysregulated antibody production. This cTfr cell reduction is more significant
in males, providing cellular evidence for the observed association between increased risk
and male sex.
Tweet: Underlying reasons revealed for why men are at higher risk from COVID-19
Primary Keyword: Health and medicine
Additional Keywords: Autoantibodies, COVID 19, Immune response, Humoral immunity,
Mass spectrometry, Neutralizing antibodies, Regulatory T cells, Single cell profiling, Viral
infections

Fig. 1Sex skewed disruption between T-follicular regulatory cells (Tfr), T-peripheral helper cells(Tph) and antibody producing B-cells and plasmablasts during acute COVID-19.

Title: A sex-biased imbalance between Tfr, Tph, and atypical B cells determines
antibody responses in COVID-19 patients
Journal: Proceedings of the National Academy of Sciences
Authors: Jonas Nørskov Søndergaard, Janyerkye Tulyeu, Ryuya Edahiro, Yuya Shirai,
Yuta Yamaguchi, Teruaki Murakami, Takayoshi Morita, Yasuhiro Kato, Haruhiko Hirata,
Yoshito Takeda, Daisuke Okuzaki, Shimon Sakaguchi, Atsushi Kumanogoh, Yukinori
Okada, and James Badger Wing
DOI: 10.1073/pnas.2217902120

Funded by:
Japan Society for the Promotion of Science
Japan Agency for Medical Research and Development
Moonshot Research & Development Program
Takeda Science Foundation
Nippon Foundation

Leading Advanced Projects for medical innovation
Bioinformatics Initiative of Graduate School of Medicine, Osaka University
Immunology Frontier Research Center, Osaka University