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#
- BGI-Shenzhen, Shenzhen 518083, China
- Guangdong Provincial Key Laboratory of Silviculture, Protection and
Utilization, Guangdong Academy of Forestry, Guangzhou 510520, China
- Department of Biology, University of Copenhagen, DK-2100 Copenhagen,
Denmark
- School of Future Technology, University of Chinese Academy of
Sciences, Beijing 100049, China
- 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
- State Key Laboratory of Agricultural Genomics, BGI-Shenzhen, Shenzhen
518083, China
- 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