Persistent replication of severe acute respiratory syndrome coronavirus in human tubular kidney cells selects for adaptive mutations in the membrane protein.

Filippo Pacciarini

Thursday, 30 Oct 2008 17:55 UTC

Pacciarini F, Ghezzi S, Canducci F, Sims A, Sampaolo M, Ferioli E, Clementi M, Poli G, Conaldi PG, Baric R, Vicenzi E.
J Virol. 2008 Jun;82(11):5137-44

The Severe Acute Respiratory Syndrome (SARS) emerged in China and spread to several countries worldwide in a few months resulting in the infection of 8,096 people and 774 deaths from 2002 to 2003. A novel human coronavirus (SARS-CoV) was independently isolated from SARS patients in 3 different continents.
SARS is a systemic disease characterized by both lung pathology and
widespread extra-pulmonary virus dissemination causing multiple organ injuries.
In this regard, renal dysfunction is an ominous sign in patients with SARS and the involvement of the kidney in SARS cases has been associated with a high (91.7%) mortality rate.
In order to investigate the potential SARS-CoV kidney tropism, we have evaluated the susceptibility of human renal cells of tubular and glomerular origin to in vitro SARS-CoV infection.
Immortalized cultures of differentiated proximal tubular epithelial cells (PTEC), glomerular mesangial (MC) and glomerular epithelial cells (podocytes) were found to express the SARS-CoV receptor angiotensin converting enzyme-2 (ACE2) on their surface. Productive infection, however, occurred only in PTEC cells and a transient infection with poor virus production was observed in MC cells. SARS-CoV did not cause overt cytopathic effects in PTEC or MC. Of interest, PTEC, but not MC, maintained stable levels of SARS-CoV production in serial subcultures suggesting a state of persistent state of infection. In this regard, a SARS-CoV variant with increased replication capacity in PTEC was selected. This SARS-CoV variant acquired a single nonconservative amino acid change in the viral membrane protein. The point mutation was sufficient for enhanced SARS-CoV replication and persistence in PTEC when introduced in a SARS-CoV recombinant infectious clone. These findings indicate that human PTEC may represent a site of SARS-CoV productive and persistent replication favoring the emergence of viral variants with increased replication capacity at least in these kidney cells.
These findings are from interest since human-to-human SARS-CoV transmission was contained in the same year of the outbreak; however, animal-to-human transmission has been documented implying that the virus could reemerge as a human pathogen. Indeed, the full eradication of SARS-CoV might be extremely difficult since its natural host seems to be a wild rather than a domestic animal.


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