Summary: A new study offers a possible explanation for why men infected with the novel coronavirus often experience more severe illness and face a higher risk of death than women. Investigators focused on ACE2 receptors—the entry point the virus uses to infect human cells—and report that the testes, along with the lungs and kidneys, show some of the highest ACE2 expression levels. ACE2 was not detected in ovarian tissue. These observations support prior evidence of impaired testicular function in some male COVID-19 patients and raise the possibility that testicular tissue could serve as a gender-specific reservoir for the virus, potentially contributing to slower viral clearance in men.
Source: Albert Einstein College of Medicine
Researchers from Montefiore Health System and Albert Einstein College of Medicine, working with the Kasturba Hospital for Infectious Diseases in Mumbai, India, examined gender differences in how quickly people clear SARS-CoV-2 from the body and explored a biological explanation for those differences. Their data suggest that men clear the virus more slowly than women and identify the testes as a potential male-specific site where the virus might persist.
The findings were shared in a preprint posted on MedRxiv, a repository that allows rapid dissemination of research results prior to formal peer review. During the COVID-19 pandemic, such platforms have been widely used to speed the sharing of scientific observations.
“Studies from many regions have consistently shown higher rates of serious illness and death from COVID-19 among men compared with women,” says Aditi Shastri, M.D., assistant professor of medicine at Einstein, clinical oncologist at the Montefiore Einstein Center for Cancer Care, and lead author of the study. “In our analysis, men took longer to clear the virus following infection, which may help explain their worse clinical outcomes.”
The investigation of viral clearance analyzed 68 symptomatic patients (48 men and 20 women) evaluated at Kasturba Hospital. All participants initially tested positive by nasopharyngeal or oropharyngeal swab and were then retested with serial swabs until results returned negative, indicating viral clearance. The median time to a negative test was significantly shorter for women—four days—compared with six days for men.
To strengthen their observation, the team also followed three families in which both male and female household members tested positive. In each family, female members cleared the virus earlier than their male relatives, consistent with the broader cohort results.
To investigate a biological mechanism for the delayed clearance observed in males, the authors examined the distribution of angiotensin-converting enzyme 2 (ACE2), the receptor SARS-CoV-2 uses to enter cells. Cells and tissues that express high levels of ACE2 are theoretically more susceptible to viral infection and possible sites for prolonged viral presence.
Using three independent RNA expression databases, the researchers found that the testes were among the tissues with the highest ACE2 expression, alongside the lungs and kidneys. At the same time, ovarian tissue showed little to no detectable ACE2 expression in these datasets.
Dr. Shastri cautions that direct proof of viral infection and replication within testicular tissue still needs confirmation through targeted studies, including pathology and clinical trials. Nonetheless, she notes that prior research from China reported altered sex hormone levels consistent with impaired testicular function in male COVID-19 patients, supporting the concern that the testes may be affected by the disease. If confirmed, such effects could have important clinical and public health implications.
The Montefiore-Einstein study lists senior authors including Amit Verma, M.B.B.S., professor of medicine and developmental & molecular biology at Einstein and director of hematologic malignancies at Montefiore; Ulrich Steidl, M.D., Ph.D., professor of cell biology and medicine and associate chair for translational research in oncology at Montefiore; and Jayanthi Shastri, M.D., a microbiologist and infectious disease specialist who directs the molecular diagnostic laboratory at Kasturba Hospital and led the serial monitoring efforts in Mumbai.
About this neuroscience research article
Source:
Albert Einstein College of Medicine
Media Contacts:
Elaine Iandoli – Albert Einstein College of Medicine
Image Source:
Image credited to Albert Einstein College of Medicine.
Original Research:
Title: “Delayed clearance of SARS-CoV2 in male compared to female patients: High ACE2 expression in testes suggests possible existence of gender-specific viral reservoirs” by Aditi Shastri, Justin Wheat, Sachee Agrawal, Nirjhar Chaterjee, Kith Pradhan, Mendel Goldfinger, Noah Kornblum, Ulrich Steidl, Amit Verma, and Jayanthi Shastri.
Published as a preprint on MedRxiv, DOI: 10.1101/2020.04.16.20060566.
Abstract (summary)
The novel coronavirus SARS-CoV-2 has been associated with higher incidence and greater disease severity in males across multiple cohorts. To evaluate whether viral clearance differs by sex, symptomatic patients in Mumbai were tested serially by RT-PCR. Among 68 subjects (median age 37 years; range 3–75), 48 were male and 20 were female. Females achieved viral clearance significantly earlier than males, with a median difference of two days (P = 0.038). In three family clusters where both sexes were infected, female members cleared the virus earlier in each household. Examination of tissue-specific ACE2 expression across independent repositories showed high ACE2 levels in the testes and lower expression in ovarian tissue. These findings indicate delayed SARS-CoV-2 clearance in males and raise the possibility that high ACE2 expression in testes could allow testicular viral reservoirs to contribute to prolonged viral persistence in men, a hypothesis that warrants further investigation.
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