In late 2002, reports began to emerge from the Guangdong Province in southern China, of a potentially fatal atypical pneumonia with unknown etiology. Ultimately defined as severe acute respiratory syndrome (SARS), these initial cases were followed by rapid outbreaks throughout Southeast Asia, and according to the World Health Organization (WHO) by June 2003 had infected more than 8400 patients worldwide. A global emergency declared by WHO, and a coordinated international response has thus far succeeded in containing the spread of SARS; however, the potential for new outbreaks still exists. These events have led to the rapid identification and genomic sequencing of the infectious agent, a novel coronavirus (SARS-CoV) phylogenetically distinct from those described to date.1-5 At present, there is no consistently effective treatment for SARS, and scientists are searching for potential vaccines and/or therapeutic agents that specifically target SARS-CoV or host cell components necessary for viral replication. In order to gain access to cells, coronaviruses utilize host receptors that bind with spike (S) proteins extending from the viral envelope.6 A recent study by Li et al. reports that angiotensin-converting enzyme 2 (ACE-2) is the receptor critical for mediating SARS-CoV entry into host cells (Figure 1).7
|Figure 1. ACE-2 is the host cell receptor responsible for mediating infection by SARS-CoV, the novel coronavirus responsible for severe acute respiratory syndrome (SARS). Treatment with soluble ACE-2 or anti-ACE-2 antibodies disrupts the interaction between virus and receptor.
ACE-2 is a recently described type I transmembrane metallocarboxypeptidase with homology to ACE, an enzyme long-known to be a key player in the renin-angiotensin system (RAS) and a target for the treatment of hypertension.8 Although its roles continue to be elucidated, ACE-2 appears to be involved in cardiac function and may act as a negative regulator of RAS.9 PCR analysis reveals that ACE-2 is expressed in the heart, as well as the lung, kidney, and gastrointestinal tract, tissues shown to harbor SARS-CoV.1,10,11 Binding of the viral S protein S1 domain to Vero-E6 cells, a monkey kidney cell line known to permit SARS-CoV replication, is blocked by a soluble form of ACE-2.1,7 In addition, SARS-CoV-mediated infection and cytopathicity are inhibited in Vero-E6 cells by antibodies directed toward ACE-2.7 These effects are ACE-2-specific, since the use of soluble ACE or an anti-ACE antibody failed to do the same. Human kidney 293T cells exhibit low levels of ACE-2 expression and, consequently, support low levels of SARS-CoV replication.7 However, transfection with ACE-2 results in markedly enhanced viral replication and cytopathicity when compared to mock-transfected controls.7
These new findings could greatly impact the development of effective SARS therapies. For instance, soluble forms of ACE-2 or anti-ACE-2 antibodies might be used to block SARS-CoV-binding to the receptor.7 Stimulated by potential roles in cardiac function and RAS, small molecule inhibitors of ACE-2 proteolytic activity have already been designed.12 Future studies will likely reveal whether these compounds, or others more specifically intended to target the SARS-CoV binding site, will be effective in disrupting the interaction between virus and receptor.
- Ksiazek, T.G. et al. (2003) N. Engl. J. Med. 348:1953.
- Peiris, J.S. et al. (2003) Lancet 361:1319.
- Drosten, C. et al. (2003) N. Engl. J. Med. 348:1967.
- Rota, P.A. et al. (2003) Science 300:1394.
- Marra, M.A. et al. (2003) Science 300:1399.
- Suzuki, H. & F. Taguchi (1996) J. Virol. 70:2632.
- Li, W. et al. (2003) Nature 426:450.
- Riordan, J.F. et al. (2003) Genome Biol. 4:225.
- Crackower, M.A. et al. (2002) Nature 417:822.
- Harmer, D. et al. (2002) FEBS Lett. 532:107.
- Leung, W.K. et al. (2003) Gastroenterology 125:1011.
- Huang, L. et al. (2003) J. Biol. Chem. 278:15532