ACE2 and TMPRSS2 distribution in the respiratory tract of different animal species and its correlation with SARS-CoV-2 tissue tropism

Abstract

A wide range of animal species show variable susceptibility to SARS-CoV-2; however, host factors associated with varied susceptibility remain to be defined. Here, we examined whether susceptibility to SARS-CoV-2 and virus tropism in different animal species are dependent on the expression and distribution of the virus receptor angiotensin-converting enzyme 2 ( ACE2 ) and the host cell factor transmembrane serine protease 2 ( TMPRSS2 ). We cataloged the upper and lower respiratory tract of multiple animal species and humans in a tissue-specific manner and quantitatively evaluated the distribution and abundance of ACE2 and TMPRSS2 mRNA in situ . Our results show that: (i) ACE2 and TMPRSS2 mRNA are abundant in the conduction portion of the respiratory tract, (ii) ACE2 mRNA occurs at a lower abundance compared to TMPRSS2 mRNA, (iii) co-expression of ACE2-TMPRSS2 mRNAs is highest in those species with the highest susceptibility to SARS-CoV-2 infection (i.e., cats, Syrian hamsters, and white-tailed deer), and (iv) expression of ACE2 and TMPRSS2 mRNA was not altered following SARS-CoV-2 infection. Our results demonstrate that while specific regions of the respiratory tract are enriched in ACE2 and TMPRSS2 mRNAs in different animal species, this is only a partial determinant of susceptibility to SARS-CoV-2 infection. IMPORTANCE SARS-CoV-2 infects a wide array of domestic and wild animals, raising concerns regarding its evolutionary dynamics in animals and potential for spillback transmission of emerging variants to humans. Hence, SARS-CoV-2 infection in animals has significant public health relevance. Host factors determining animal susceptibility to SARS-CoV-2 are vastly unknown, and their characterization is critical to further understand susceptibility and viral dynamics in animal populations and anticipate potential spillback transmission. Here, we quantitatively assessed the distribution and abundance of the two most important host factors, angiotensin-converting enzyme 2 and transmembrane serine protease 2, in the respiratory tract of various animal species and humans. Our results demonstrate that while specific regions of the respiratory tract are enriched in these two host factors, they are only partial determinants of susceptibility. Detailed analysis of additional host factors is critical for our understanding of the underlying mechanisms governing viral susceptibility and reservoir hosts.

Host Cell Proteases Involved in Human Respiratory Viral Infections and Their Inhibitors: A Review

“…Proteases from all three of these categories are co-opted by SARS-CoV-2, and their presence in the host has important implications for both transmission of the virus and pathology. The expression of ACE2 and TMPRSS2 that is highly homologous to human ACE2 and TMPRSS2 is known to be an important susceptibility factor in animal infection with SARS-CoV-2 [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. Additionally, many of the human proteases are polymorphic.…”

The Neurological Implications of COVID-19: A Comprehensive Narrative Review

“…The S protein must undergo cleavage by proteases at the appropriate position to accomplish its fusion function [20]; it is cleaved by proprotein convertases such as the transmembrane protease serine 2 (TMPRSS2) and furin in the virus-producer cells. Recent studies have demonstrated that several other cellular proteases besides TMPRSS2 and furin can induce proteolytic cleavage of the S protein, such as TMPRSS4, trypsin-like proteases, and cathepsin L [21]. A hypothesis about a novel concept states that the cleavage of the S protein S1 subunit by furin results in a higher number of free S protein molecules, even with higher affinity than the original one, that can bind other ACE2 and other receptors in various tissues.…”

“…As with other members of the coronavirus family, it is known that angiotensin-converting enzyme 2 (ACE2) has a high affinity for the S protein from SARS-CoV-2 [22][23][24][25]. Differences in host susceptibility arise from the interaction between the receptor-binding domain and ACE2, while discrepancies in viral tropism and tissue distribution are likely determined by the distribution and abundance of ACE2 and TMPRSS2 and possibly other cellular proteases that are still under investigation [21]. To date, there are several studies focusing entirely on ACE2 as the major SARS-CoV-2 entry host receptor field [4], but research also shows ACE2 is expressed at very low levels in brain tissue, raising the question about other cofactors implicated in virus-host cell interactions in cells with low ACE2 expression [26].…”