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Investigating Sex Differences in COVID-19 Immune Response

Utilizing large-scale patient data and samples from the Cleveland Clinic COVID-19 registry, Dr. Cheng’s team identified clinical characteristics and immune-related mechanisms associated with sex differences in COVID-19 outcomes.


A new Cleveland Clinic study has uncovered novel immunological insights into sex differences in COVID-19 susceptibility and severity that may help explain the elevated risk for severe illness and death observed in male COVID-19 patients. Published in Signal Transduction and Targeted Therapy, the findings could pave the way toward sex-specific prevention and treatment strategies for COVID-19.

“Previous studies have demonstrated that males tend to have weaker immune responses to infections compared to females, and clinical observations indicate that these findings may hold true for COVID-19,” said the study’s lead author Feixiong Cheng, PhD, Genomic Medicine. “Because sex differences in immune responses may have a direct impact on the efficacy of vaccines and immune-related treatments, there is a pressing need to better understand the sex differences in COVID-19 outcomes.”

In this study, the researchers analyzed large-scale patient data and samples from the Cleveland Clinic COVID-19 registry to investigate clinical characteristics and immune-related mechanisms underlying sex differences in COVID-19.

Sex-specific inflammatory responses may explain male vulnerabilty to COVID-19 

Looking at the patient registry data, they found that males were more likely than females to have a positive COVID-19 laboratory test, be admitted to the hospital or intensive care unit (ICU), have a longer hospital or ICU stay and require mechanical ventilation. Hospitalized male patients also had increased levels of several inflammatory markers (C-reactive protein, procalcitonin and the neutrophil-lymphocyte ratio) compared to females.

“Our observations suggest that men have an elevated likelihood of COVID-19 infection and severe outcomes, which potentially could be explained by sex-specific inflammatory responses,” said Dr. Cheng.

The researchers then analyzed patient samples to uncover potential underlying mechanisms for the sex differences in immune responses. They identified different abundances of epithelial and immune cells in males compared to females and found that interactions between some of the cells were stronger in male patients, indicating the cells’ potential roles in the increased COVID-19 severity seen in males.

For example, male patients displayed elevated abundances of epithelial squamous cells and monocytes (a type of white blood cell involved in the immune response), and both cell types had higher levels of pro-inflammatory factors. The squamous cells also had increased expression of the entry factors that enable SARS-CoV-2 (the virus that causes COVID-19) to infect human cells while monocytes had elevated expression of the male-biased (upregulated in males) inflammation-associated genes TLR7 and BTK.

“Importantly, we determined that monocyte-elevated expression of TLR7 and BTK was associated with severe outcomes in males with COVID-19, which suggests that predisposition to a pro-inflammatory state contributes to COVID-19 vulnerability,” said Dr. Cheng. “Altogether, our study provides the basis to decipher immune responses underlying sex differences in COVID-19 and develop precision medicine approaches to prevent and treat COVID-19 in males and females.”

Yuan Hou, PhD, a postdoctoral fellow in Dr. Cheng’s lab, is first author on the study, which was supported by the National Institute on Aging, the National Heart, Lung, and Blood Institute (both part of the National Institutes of Health) and Cleveland Clinic’s VeloSano Pilot Program.

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