SARS virus infection of cats and ferrets

Martina, Byron; Haagmans, Bart L.; Kuiken, Thijs; Fouchier, Ron A. M.; Rimmelzwaan, Guus F.; Amerongen, Geert van; Peiris, J. S. Malik; Lim, Wilina; Osterhaus, Albert D. M. E.

doi:10.1038/425915a

Cited by 560 publications

(598 citation statements)

References 5 publications

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“…Conceivably, unpaired cysteine residues are available for the creation of additional bonding at some stage of envelope evolution, and such plasticity may have contributed to the capacity of this coronavirus to infect many species (35,36) and adapt to human cell-surface ligands (9,33).…”

Section: Discussionmentioning

confidence: 99%

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Significant Redox Insensitivity of the Functions of the SARS-CoV Spike Glycoprotein

Lavillette

Barbouche

Yao

et al. 2006

Journal of Biological Chemistry

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The capacity of the surface glycoproteins of enveloped viruses to mediate virus/cell binding and membrane fusion requires a proper thiol/disulfide balance. Chemical manipulation of their redox state using reducing agents or free sulfhydryl reagents affects virus/cell interaction. Conversely, natural thiol/disulfide rearrangements often occur during the cell interaction to trigger fusogenicity, hence the virus entry. We examined the relationship between the redox state of the 20 cysteine residues of the SARS-CoV (severe acute respiratory syndrome coronavirus) Spike glycoprotein S1 subdomain and its functional properties. Mature S1 exhibited ϳ4 unpaired cysteines, and chemically reduced S1 displaying up to ϳ6 additional unpaired cysteines still bound ACE2 and enabled fusion. In addition, virus/cell membrane fusion occurred in the presence of sulfhydryl-blocking reagents and oxidoreductase inhibitors. Thus, in contrast to various viruses including HIV (human immunodeficiency virus) examined in parallel, the functions of the SARS-CoV Spike glycoprotein exhibit a significant and surprising independence of redox state, which may contribute to the wide host range of the virus. These data suggest clues for molecularly engineering vaccine immunogens.SARS 3 -CoV is a new human coronavirus that causes a severe acute respiratory syndrome, sometimes with a fatal outcome. Its Spike glycoprotein is the major surface antigen and induces potent neutralizing antibodies (1-8). It is made up of S1 and S2 subdomains (2, 3). The S1 region interacts with angiotensin-converting enzyme 2 (ACE2), the primary cellular receptor (9 -12), L-SIGN (13), and L-SECtin (14), whereas S2 mediates membrane fusion (2, 3). Here, we investigated the functional role of the 20 conserved cysteine residues of mature S1.A variety of evidence has shown that the capacity of the viral envelope glycoproteins to mediate virus/cell membrane fusion depends on a precise thiol/disulfide balance within the viral surface complex (15-29). On one hand, manipulation of the native disulfide network of mature envelopes at the virus surface using reducing or alkylating reagents has important consequences for their subsequent capacity to carry out the virus/cell interaction process (15, 16, 19, 20, 23, 24, 26, and 28). On the other hand, natural and specific thiol/disulfide rearrangements occur within several viral envelopes to trigger conformational changes that insert the fusion peptide into the cell surface leading to virus entry (20,21,23,(25)(26)(27). For HIV, gentle chemical reduction of Env efficiently prevents viral infectivity by inhibiting the capacity of the surface subunit (SU) to bind its ligands on the target cell surface (15,19). In contrast, after receptor binding, fusion mediated by the transmembrane subunit occurs solely following reduction of SU by a cell-surface protein-disulfide isomerase (PDI) activity (19,(25)(26)(27). For these reasons, reducing or free sulfhydryl reagents and nonpermeant inhibitors of PDI (e.g. the thiol reagent DTNB and bacitracin, ...

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Section: Discussionmentioning

confidence: 99%

“…2A), may be properties that allow the envelope complex to be flexible and escape dependence on redox reactions induced by cell-surface catalysts prior to entry. Such independence toward the redox changes may be part of the reason for the wide host range of the virus and contributed to the zoonosis that led to human infection (35,36).…”

Section: Discussionmentioning

confidence: 99%

Significant Redox Insensitivity of the Functions of the SARS-CoV Spike Glycoprotein

Lavillette

Barbouche

Yao

et al. 2006

Journal of Biological Chemistry

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“…After incubation for 9 h, plates were washed twice with PBS and fixed by 4% formaldehyde for 15 min and 70% ethanol plus 0.5% H 2 O 2 for 15 min at room temperature. After washing the plates twice with PBS plus 0.5% Tween 20 and twice with PBS, the fixed and permeabilized cells were incubated for 1 h at 37°C with a polyclonal antiserum obtained from SARS-CoV-infected ferrets (1:40) (18). Horseradish peroxidase (HRP)-labeled goat-anti-ferret antibodies (Dako) were used as a conjugate in a 1:50 dilution.…”

Section: Methodsmentioning

confidence: 99%

Severe acute respiratory syndrome coronavirus (SARS-CoV) infection inhibition using spike protein heptad repeat-derived peptides

Bosch

Martina

Zee

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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370

432

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The coronavirus SARS-CoV is the primary cause of the life-threatening severe acute respiratory syndrome (SARS). With the aim of developing therapeutic agents, we have tested peptides derived from the membrane-proximal (HR2) and membrane-distal (HR1) heptad repeat region of the spike protein as inhibitors of SARS-CoV infection of Vero cells. It appeared that HR2 peptides, but not HR1 peptides, were inhibitory. Their efficacy was, however, significantly lower than that of corresponding HR2 peptides of the murine coronavirus mouse hepatitis virus (MHV) in inhibiting MHV infection. Biochemical and electron microscopical analyses showed that, when mixed, SARS-CoV HR1 and HR2 peptides assemble into a six-helix bundle consisting of HR1 as a central triple-stranded coiled coil in association with three HR2 ␣-helices oriented in an antiparallel manner. The stability of this complex, as measured by its resistance to heat dissociation, appeared to be much lower than that of the corresponding MHV complex, which may explain the different inhibitory potencies of the HR2 peptides. Analogous to other class I viral fusion proteins, the six-helix complex supposedly represents a postfusion conformation that is formed after insertion of the fusion peptide, proposed here for coronaviruses to be located immediately upstream of HR1, into the target membrane. The resulting close apposition of fusion peptide and spike transmembrane domain facilitates membrane fusion. The inhibitory potency of the SARS-CoV HR2-peptides provides an attractive basis for the development of a therapeutic drug for SARS.

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“…In this regard, the virus has been reported to infect ferrets, domestic cats, and various species of monkeys (13,14). Moreover, recently Subbarao et al (15) demonstrated that BALB/c mice could be productively infected with a human clinical isolate of SARS-CoV although no clinical disease manifestations were identified.…”

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confidence: 99%

Mechanisms of Host Defense following Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) Pulmonary Infection of Mice

Glass¹,

Subbarao

Murphy

et al. 2004

The Journal of Immunology

332

325

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We describe a model of severe acute respiratory syndrome-coronavirus (SARS-CoV) infection in C57BL/6 mice. A clinical isolate of the virus introduced intranasally replicated transiently to high levels in the lungs of these mice, with a peak on day 3 and clearance by day 9 postinfection. Viral RNA localized to bronchial and bronchiolar epithelium. Expression of mRNA for angiotensin converting enzyme 2, the SARS-CoV receptor, was detected in the lung following infection. The virus induced production in the lung of the proinflammatory chemokines CCL2, CCL3, CCL5, CXCL9, and CXCL10 with differential kinetics. The receptors for these chemokines were also detected. Most impressively, mRNA for CXCR3, the receptor for CXCL9 and CXCL10, was massively up-regulated in the lungs of SARS-CoV-infected mice. Surprisingly Th1 (and Th2) cytokines were not detectable, and there was little local accumulation of leukocytes and no obvious clinical signs of pulmonary dysfunction. Moreover, beige, CD1−/−, and RAG1−/− mice cleared the virus normally. Infection spread to the brain as it was cleared from the lung, again without leukocyte accumulation. Infected mice had a relative failure to thrive, gaining weight significantly more slowly than uninfected mice. These data indicate that C57BL/6 mice support transient nonfatal systemic infection with SARS-CoV in the lung, which is able to disseminate to brain. In this species, proinflammatory chemokines may coordinate a rapid and highly effective innate antiviral response in the lung, but NK cells and adaptive cellular immunity are not required for viral clearance.

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SARS virus infection of cats and ferrets

Cited by 560 publications

References 5 publications

Significant Redox Insensitivity of the Functions of the SARS-CoV Spike Glycoprotein

Significant Redox Insensitivity of the Functions of the SARS-CoV Spike Glycoprotein

Severe acute respiratory syndrome coronavirus (SARS-CoV) infection inhibition using spike protein heptad repeat-derived peptides

Mechanisms of Host Defense following Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) Pulmonary Infection of Mice

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