The functional prediction of transmembrane serine protease 2 (TMPRSS2) in priming S-protein of SARS-CoV-2 among vertebrates
Tianming Lan1, 3*, Han Lei1, 5*, Le Zhang1, 5*, Haimeng Li4, Sunil Kumar Sahu1, 6, Yixin Zhu4, Huan Liu7, Yan Hua2#
  1. BGI-Shenzhen, Shenzhen 518083, China
  2. Guangdong Provincial Key Laboratory of Silviculture, Protection and Utilization, Guangdong Academy of Forestry, Guangzhou 510520, China
  3. Department of Biology, University of Copenhagen, DK-2100 Copenhagen, Denmark
  4. School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049, China
  5. College of Wildlife And Protected Area, Northeast Forestry University. Harbin 150040, China Guangdong Provincial Academician Workstation of BGI Synthetic Genomics,BGI-Shenzhen, Shenzhen, 518120,China
  6. State Key Laboratory of Agricultural Genomics, BGI-Shenzhen, Shenzhen 518083, China
  7. Guangdong Provincial Key Laboratory of Genome Read and Write, BGI-Shenzhen 518083, Shenzhen, China
*These authors contributed equally
# Correspondence should be addressed to: Yan Hua (wildlife530@hotmail.com)
Abstract
The coronavirus disease 19 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the outbreak has rapidly spread worldwide causing a global severe pneumonia pandemic. Several animals have been proven to be affected by the SARS-CoV-2, posing an enormous threat to humans. However, to confirm the intermediate hosts in the epidemic regions, it is unrealistic to detect its presence in each and every animal one by one. An active transmembrane serine protease 2 (TMPRSS2) which functions in priming of S-protein of SARS-CoV-2 is one of the most important prerequisites for an animal to be an intermediate host, but the utilizing capability of TMPRSS2 for non-human animals is largely unknown. Here, we systematically predicted the ability of TMPRSS2 to prime S-protein of SARS-CoV-2 in 164 vertebrates by analyzing the phylogenetic clustering and possible functional changes induced by amino acid variation in TMPRSS2. Mammals were predicted to be the most likely animals to effectively use the TMPRSS2 for priming S-protein of SARS-CoV-2. Especially, we predicted the possible effective utilizing ability of TMPRSS2 in rats and pigs, which are reported non-susceptible to SARS-CoV-2. Given the wide distribution and the close relationships among human, pig and rat, a periodic and careful monitoring is required for pigs and rats to prevent the possible SARS-CoV-2 transmission to human.
Introduction
The COVID-19 has been rapidly spreading worldwide since its outbreak during late 2019[1]. Now it has become a global pandemic with 7,039,918 cases and 404,396 deaths globally as of 9 June 2020[2]. The COVID-19 usually causes severe respiratory illness and transmitted human-to-human, like severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS), which has been proved to be caused by SARS-CoV-2[3]. At present, no effective vaccines and drugs have been developed to prevent or cure the infection of SARS-CoV-2.
A 96.2% whole genome sequence identity between the human SARS-CoV-2 and the bat (Rhinolophus affinis ) coronavirus Bat-CoV-RaTG13 indicated the probable bat origin of the SARS-CoV-2[4]. However, the SARS-CoV-2 is less likely to transfer to humans from bats because of the lack of direct contact between humans and bats. Similar to SARS-CoV, the intermediate hosts are also expected to serve as bridges for transmission of SARS-CoV2 between humans and animals. To date, several animals have been found to be potential intermediate hosts, including pangolins, dogs, cats, ferrets and hamsters[5,6,7,8,9,10,11]. A metallopeptidase, angiotensin converting enzyme II (ACE2) has been proven to be the cell entry receptor of SARS-CoV[12]. Similarly, SARS-CoV-2 also uses the ACE2 as a cognate receptor to enter into target cells[4]. The initial interaction between the S-protein of SARS-CoV-2 and ACE2 help SARS-CoV-2 attach to target cells. In addition, cell entry requires S-protein priming by cellular proteases, the TMPRSS2, which can activate and cleave the S-protein and facilitate the membrane fusion of virus and cell[13]. ACE2 and TMPRSS2 are supposed to be indispensable for SARS-CoV-2 infection.
Identifying possible intermediate hosts can directly contribute to the prevention and control for the transmission of SARS-CoV-2. As COVID-19 is a worldwide pandemic now, it is difficult to detect SARS-CoV-2 in animals which are distributed all across the world to determine the hosts. Phylogenetic analysis and critical site comparison of ACE2 has been used for predicting the intermediate hosts of SARS-CoV-2, showing that mammals,pangolins and cats are supposed to be more susceptible to SARS-CoV-2 than birds[14]. However, it is to be noted that the SARS-CoV-2 cannot enter into target cells without S-protein priming mediated by TMPRSS2. In this study, we combined sequence alignment, phylogenetic analysis and potential damaging effects on amino acid changes in TMPRSS2 to systematically predict the most likely intermediate hosts by screening 164 species from the perspective of TMPRSS2’s function on S-protein priming of SARS-CoV-2.
2 Material and Methods