Delayed clearance of SARS-CoV2 in male compared to female patients: High ACE2 expression in testes suggests possible existence of gender-specific viral reservoirs

Aditi Shastri; Justin Wheat; Sachee Agrawal; Nirjhar Chaterjee; Kith Pradhan; Mendel Goldfinger; Noah Kornblum; Ulrich Steidl; Amit Verma; Jayanthi Shastri

Testes express high levels of ACE2 receptor: SARS-CoV2 enters cells via a complex, multiple-step process which begins with interaction of the viral surface spike protein with ACE2. 9,10 ACE2 is a plasma membrane bound monocarboxypeptidase that converts angiotensin II to angiotensin 1-7 (Ang 1-7), which antagonizes the hypertensive effects of Angiotensin I via stimulation of the MAS receptor. 11 We evaluated ACE2 expression at the mRNA and protein levels using tissue specific databases. We observed that ACE2 is expressed at high levels in the lungs, GI tract, myocardium, testes, and brush border cells of the renal proximal tubule at the mRNA levels (Fig 2A) . Interestingly, the testes was one of the sites with highest ACE2 expression in 3 independent RNA expression databases (Human Protein Atlas, FAMTOM5 and GETx) (Fig 2B) , consistent with prior reports. [12] [13] [14] ACE2 was also determined to be highly expressed in testicular cells at the protein levels (Fig 2D, E) . Interestingly, very little expression was seen in ovarian tissue (Fig 2C,F) . These data raise the possibility that SARS-CoV2 may bind to testicular ACE2 and the testes may serve as a male specific viral reservoir. Consistent with this hypothesis, a very recent study demonstrated testicular gonadal loss-of-function in SARS-CoV2 patients, suggesting possible damage to testicular cells during infection. 15 Taken together, these observations demonstrate that male subjects have delayed viral clearance. High expression of ACE2 RNA and protein in testes leads to the hypothesis that testicular viral reservoirs may exist and play a role in viral persistence, and should be further investigated by larger clinical studies. This hypothesis may have important implications for understanding the transmission and persistence of SARS-CoV2 virus in humans, and in a gender-specific manner.