Associate professor Affiliated Hospital of Youjiang Medical University for Nationalities Brigham and Women's Hospital Baise, Guangxi, China (People's Republic)
Background: Transmembrane protease serine type 2 (TMPRSS2) activates the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). TMPRSS2 is known to be expressed in several cell types in normal lungs and inhibition of TMPRSS2 blocks SARS-CoV-2 entry to cells in cell culture models, thus suggesting that TMPRSS2 is a potential therapeutic target in COVID-19. However, the effect of COVID-19 pneumonia on TMPRSS2 protein expression is not known.
Objective: To characterizeTMPRSS2 expression in non-human primate (NHP) and human lungs with and without SARS-CoV-2 infection.
Design/Methods: TMPRSS2 protein expression was examined in preterm, full-term, and adult NHP (Papio papio)lung homogenates and paraffin-embedded lung sections by immunoblotting and immunohistochemistry, respectively. Double immunofluorescence (IF) analysis for pro-surfactant C (pro-SPC) and TMPRSS2 was performed on paraffin-embedded autopsy lung specimens from COVID-19 patients (n=4).
Results: TMPRSS2 expression was significantly lower in preterm NHP lungs compared to full-term and adult NHP lungs, whereas there was no difference in TMPRSS2 levels between full-term and adult lungs. Immunohistochemistry demonstrated robust TMPRSS2 expression in bronchial epithelial cells, type 1 (AT1) and type 2 alveolar epithelial cells (AT2), alveolar macrophages and some vascular endothelial cells in control adult NHP and human lung sections. Double IF analysis with antibodies against pro-SPC, a marker of AT2s and club cells revealed TMPRSS2 expression in all pro-SPC-positive cells. In autopsy lung specimens from patients with COVID-19 pneumonia (Table 1), there was markedly reduced immunoreactivity for both proteins, but especially TMPRSS2. Notably, while some pro-SPC was detected in desquamated cells in alveolar spaces, these cells no longer expressed TMPRSS2. In contrast TMPRSS2 expression was maintained in intact AT1s in alveolar walls as well as alveolar macrophages. Conclusion(s): TMPRSS2 expression is significantly downregulated in AT2s, but not AT1s in COVID-19 pneumonia. These observations suggest that SARS-CoV-2, similar to SARS-CoV, preferentially infects AT2s. They also suggest that TMPRSS2 cooperates with other viral entry factors harbored in AT2s, but not present in AT1s, to facilitate entry of SARS-CoV-2 into host cells.
Authors/Institutions: Yujie Jiang, Brigham and Women's Hospital, Boston, Massachusetts, United States; Sourabh Soni, Brigham and Women's Hospital, Boston, Massachusetts, United States; Yohannes Tesfaigzi, Brigham and Women's Hospital, Boston, Massachusetts, United States; Jason L. Hornick, Brigham and Women's Hospital, Boston, Massachusetts, United States; Sule Cataltepe, Brigham and Women's Hospital, Boston, Massachusetts, United States