Influenza and SARS-Coronavirus Activating Proteases TMPRSS2 and HAT Are Expressed at Multiple Sites in Human Respiratory and Gastrointestinal Tracts

Abstract

The type II transmembrane serine proteases TMPRSS2 and HAT activate influenza viruses and the SARS-coronavirus (TMPRSS2) in cell culture and may play an important role in viral spread and pathogenesis in the infected host. However, it is at present largely unclear to what extent these proteases are expressed in viral target cells in human tissues. Here, we show that both HAT and TMPRSS2 are coexpressed with 2,6-linked sialic acids, the major receptor determinant of human influenza viruses, throughout the human respiratory tract. Similarly, coexpression of ACE2, the SARS-coronavirus receptor, and TMPRSS2 was frequently found in the upper and lower aerodigestive tract, with the exception of the vocal folds, epiglottis and trachea. Finally, activation of influenza virus was conserved between human, avian and porcine TMPRSS2, suggesting that this protease might activate influenza virus in reservoir-, intermediate- and human hosts. In sum, our results show that TMPRSS2 and HAT are expressed by important influenza and SARS-coronavirus target cells and could thus support viral spread in the human host.

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

“…The same can be expected for SARS-CoV-2, although affinity of SARS-S and SARS-2-S for ACE2 remains to be compared. It has been suggested that the modest ACE2 expression in the upper respiratory tract (Bertram et al, 2012;Hamming et al, 2004) might limit SARS-CoV transmissibility. In light of the potentially increased transmissibility of SARS-CoV-2 relative to SARS-CoV, one may speculate that the new virus might exploit cellular attachment-promoting factors with higher efficiency than SARS-CoV to ensure robust infection of ACE2 + cells in the upper respiratory tract.…”

TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections

“…A non-catalytic TMPRSS2 (S441A) significantly abrogated the entry of MERS-CoV compared to normal TMPRSS2 [62]. Although other host proteases such as HAT, MSPL and DESC1 have been suggested to be involved in the priming of MERS-CoV, their expression levels in lung tissue are considerably lower than that of TMPRSS2, indicating a limited role of these proteases in viral propagation in host lung tissue [63,64]. These observations demonstrate that MERS-CoV infection is largely dependent on the activity of endogenous TMPRSS2.…”

TMPRSS2 and MSPL Facilitate Trypsin-Independent Porcine Epidemic Diarrhea Virus Replication in Vero Cells

“…As previously described, transmembrane protease serine 2 (TMPRSS2) and human airway trypsin-like protease (HAT) can facilitate the spread of human influenza viruses [22,23,24,25]. TMPRSS2 and TMPRSS4 play important roles in influenza virus replication, supporting the spread of influenza virus in the absence of trypsin [26].…”