PubMed Journals: J Virol
Source: PMID: 21325420
⇦ ⇨ J Virol. 2011 May;85(9):4122-34. doi:
⇩ 10.1128/JVI.02232-10. Epub 2011 Feb 16.
Evidence that TMPRSS2 activates the
severe acute respiratory syndrome coronavirus
spike protein for membrane fusion and reduces
viral control by the humoral immune response.
Glowacka I(1), Bertram S, Müller MA, Allen
P, Soilleux E, Pfefferle S, Steffen I, Tsegaye
TS, He Y, Gnirss K, Niemeyer D, Schneider
H, Drosten C, Pöhlmann S.
(1) Institute of Virology, Hannover Medical School,
30625 Hannover, Germany.
The spike (S) protein of the
severe acute respiratory syndrome coronavirus (SARS-CoV) can
be proteolytically activated by cathepsins
B and L upon viral uptake into target cell
endosomes. In contrast, it is largely unknown
whether host cell proteases located in the
secretory pathway of infected cells and/or
on the surface of target cells can cleave
SARS S. We along with others could previously
show that the type II transmembrane protease
TMPRSS2 activates the influenza virus hemagglutinin
and the human metapneumovirus F protein
by cleavage. Here, we assessed whether SARS
S is proteolytically processed by TMPRSS2.
Western blot analysis revealed that SARS
S was cleaved into several fragments upon
coexpression of TMPRSS2 (cis-cleavage) and
upon contact between SARS S-expressing cells
and TMPRSS2-positive cells (trans-cleavage).
cis-cleavage resulted in release of SARS
S fragments into the cellular supernatant
and in inhibition of antibody-mediated
neutralization, most likely because SARS
S fragments function as antibody decoys.
trans-cleavage activated SARS S on effector
cells for fusion with target cells and allowed
efficient SARS S-driven viral entry into
targets treated with a lysosomotropic agent
or a cathepsin inhibitor. Finally, ACE2,
the cellular receptor for SARS-CoV, and
TMPRSS2 were found to be coexpressed by
type II pneumocytes, which represent important
viral target cells, suggesting that SARS
S is cleaved by TMPRSS2 in the lung of
SARS-CoV-infected individuals. In summary,
we show that TMPRSS2 might promote viral
spread and pathogenesis by diminishing viral
recognition by neutralizing antibodies and
by activating SARS S for cell-cell and virus-cell
DOI: 10.1128/JVI.02232-10 PMCID: PMC3126222
PMID: 21325420 [Indexed for MEDLINE]