Sex differences in SARS-CoV-2 infection rates and the potential link to prostate cancer

Abstract

The recent outbreak of infections and the pandemic caused by SARS-CoV-2 represent one of the most severe threats to human health in more than a century. Emerging data from the United States and elsewhere suggest that the disease is more severe in men. Knowledge gained, and lessons learned, from studies of the biological interactions and molecular links that may explain the reasons for the greater severity of disease in men, and specifically in the age group at risk for prostate cancer, will lead to better management of COVID-19 in prostate cancer patients. Such information will be indispensable in the current and post-pandemic scenarios.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1. Molecular drivers of SARS-CoV-2 productive infection.

ACE2 and TMPRSS2 are co-expressed on ciliated bronchial epithelial cells and type II pneumocytes and the epithelia of small intestine thus making these potential organ sites and routes for SARS-CoV-2 infection. The virus utilizes the Spike glycoprotein (S) to attach to the host cell and trigger fusion events between the virus and host lipid bilayers. Host ACE2 and TMPRSS2 are critical mediators of this process. The virus is then internalized through receptor-mediated endocytosis, or via clathrin-mediated pathways or through lipid rafts at the plasma membrane. Once inside the host cytoplasm, the viruses release their genomes to allow replication of their genetic material. Encapsulated viral-like particles with RNA genomes arise in the ERGIC complex before they erupt as mature virus.

Fig. 2. Comparison of Risk factors between COVID-19 and prostate cancer.

Men are at a higher risk of SARS-CoV-2 infection than women. Shared risk factors involved in COVID-19 mortality, prostate cancer risk, and conceptual rationale for aggressive clinical management of COVID-19 in prostate cancer patients in the post-pandemic era or if the infection reoccurs.

Fig. 3. Graphical representation of the theoretical risks and potential routes of dissemination of SARS-CoV-2 to the prostate.

This is based on tissue level expression of a TMPRSS2 and ACE2; and b the presence of virus in body fluids such as urine, semen, and feces. Systemic or tissue derived inflammation, during COVID-19, has the potential to accelerate pre-existing prostate cancer resulting in an aggressive phenotype and therefore represents a potential risk factor for prostate cancer patients.

Fig. 4. Sex differences in COVID-19.

Illustration highlights potential biological (hormone signaling, immunological) and behavioral differences between males and females that contribute to sex divergence in response to SARS-CoV-2. Estrogens have protective functions that contribute to stronger innate immune response in females resulting in faster clearance of virus loads. Androgens and AR regulate tissue level expression of TMPRSS2; serine protease involved in SARS-CoV-2 infection combined with immunosuppressive effects and comorbidities can contribute to the severity of disease in males. Inflammation, an outcome of COVID-19 associated with severe infection, is a potential risk factor for prostate cancer and can augment progression of active disease.

Fig. 5. Major drugs and vaccines for COVID-19.

Illustration summarizes potential drugs and vaccines for COVID-19 that target either host receptors, viral replication, virus assembly, or host immune response. Drugs that have been implicated in prostate cancer management (Degalerix, Anti-androgens, Glucocorticoid receptor antagonists, metformin, and rapamycin) appear in the blue lines. # Nasal Poly-ICLC (Hiltonol®), Oncovir Inc, is being investigated as a new therapeutic agent at Mount Sinai.