Molecular Determinants of Severe Acute Respiratory Syndrome Coronavirus Pathogenesis and Virulence in Young and Aged Mouse Models of Human Disease
Identifieur interne : 000912 ( PascalFrancis/Curation ); précédent : 000911; suivant : 000913Molecular Determinants of Severe Acute Respiratory Syndrome Coronavirus Pathogenesis and Virulence in Young and Aged Mouse Models of Human Disease
Auteurs : Matthew Frieman [États-Unis] ; Boyd Yount [États-Unis] ; Sudhakar Agnihothram [États-Unis] ; Carly Page [États-Unis] ; Eric Donaldson [États-Unis] ; Anjeanette Roberts [États-Unis] ; Leatrice Vogel [États-Unis] ; Becky Woodruff [États-Unis] ; Diana Scorpio [États-Unis] ; Kanta Subbarao [États-Unis] ; Ralph S. Baric [États-Unis]Source :
- Journal of virology [ 0022-538X ] ; 2012.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Homme.
English descriptors
- KwdEn :
Abstract
SARS coronavirus (SARS-CoV) causes severe acute respiratory tract disease characterized by diffuse alveolar damage and hyaline membrane formation. This pathology often progresses to acute respiratory distress (such as acute respiratory distress syndrome [ARDS]) and atypical pneumonia in humans, with characteristic age-related mortality rates approaching 50% or more in immunosenescent populations. The molecular basis for the extreme virulence of SARS-CoV remains elusive. Since young and aged (1-year-old) mice do not develop severe clinical disease following infection with wild-type SARS-CoV, a mouse-adapted strain of SARS-CoV (called MA15) was developed and was shown to cause lethal infection in these animals. To understand the genetic contributions to the increased pathogenesis of MA15 in rodents, we used reverse genetics and evaluated the virulence of panels of derivative viruses encoding various combinations of mouse-adapted mutations. We found that mutations in the viral spike (S) glycoprotein and, to a much less rigorous extent, in the nsp9 nonstructural protein, were primarily associated with the acquisition of virulence in young animals. The mutations in S likely increase recognition of the mouse angiotensin-converting enzyme 2 (ACE2) receptor not only in MA15 but also in two additional, independently isolated mouse-adapted SARS-CoVs. In contrast to the findings for young animals, mutations to revert to the wild-type sequence in nsp9 and the S glycoprotein were not sufficient to significantly attenuate the virus compared to other combinations of mouse-adapted mutations in 12-month-old mice. This panel of SARS-CoVs provides novel reagents that we have used to further our understanding of differential, age-related pathogenic mechanisms in mouse models of human disease.
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<front><div type="abstract" xml:lang="en">SARS coronavirus (SARS-CoV) causes severe acute respiratory tract disease characterized by diffuse alveolar damage and hyaline membrane formation. This pathology often progresses to acute respiratory distress (such as acute respiratory distress syndrome [ARDS]) and atypical pneumonia in humans, with characteristic age-related mortality rates approaching 50% or more in immunosenescent populations. The molecular basis for the extreme virulence of SARS-CoV remains elusive. Since young and aged (1-year-old) mice do not develop severe clinical disease following infection with wild-type SARS-CoV, a mouse-adapted strain of SARS-CoV (called MA15) was developed and was shown to cause lethal infection in these animals. To understand the genetic contributions to the increased pathogenesis of MA15 in rodents, we used reverse genetics and evaluated the virulence of panels of derivative viruses encoding various combinations of mouse-adapted mutations. We found that mutations in the viral spike (S) glycoprotein and, to a much less rigorous extent, in the nsp9 nonstructural protein, were primarily associated with the acquisition of virulence in young animals. The mutations in S likely increase recognition of the mouse angiotensin-converting enzyme 2 (ACE2) receptor not only in MA15 but also in two additional, independently isolated mouse-adapted SARS-CoVs. In contrast to the findings for young animals, mutations to revert to the wild-type sequence in nsp9 and the S glycoprotein were not sufficient to significantly attenuate the virus compared to other combinations of mouse-adapted mutations in 12-month-old mice. This panel of SARS-CoVs provides novel reagents that we have used to further our understanding of differential, age-related pathogenic mechanisms in mouse models of human disease.</div>
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<fC03 i1="02" i2="X" l="FRE"><s0>Homme</s0>
<s5>02</s5>
</fC03>
<fC03 i1="02" i2="X" l="ENG"><s0>Human</s0>
<s5>02</s5>
</fC03>
<fC03 i1="02" i2="X" l="SPA"><s0>Hombre</s0>
<s5>02</s5>
</fC03>
<fC03 i1="03" i2="X" l="FRE"><s0>Pathogénie</s0>
<s5>05</s5>
</fC03>
<fC03 i1="03" i2="X" l="ENG"><s0>Pathogenesis</s0>
<s5>05</s5>
</fC03>
<fC03 i1="03" i2="X" l="SPA"><s0>Patogenia</s0>
<s5>05</s5>
</fC03>
<fC03 i1="04" i2="X" l="FRE"><s0>Virulence</s0>
<s5>06</s5>
</fC03>
<fC03 i1="04" i2="X" l="ENG"><s0>Virulence</s0>
<s5>06</s5>
</fC03>
<fC03 i1="04" i2="X" l="SPA"><s0>Virulencia</s0>
<s5>06</s5>
</fC03>
<fC03 i1="05" i2="X" l="FRE"><s0>Modèle animal</s0>
<s5>07</s5>
</fC03>
<fC03 i1="05" i2="X" l="ENG"><s0>Animal model</s0>
<s5>07</s5>
</fC03>
<fC03 i1="05" i2="X" l="SPA"><s0>Modelo animal</s0>
<s5>07</s5>
</fC03>
<fC03 i1="06" i2="X" l="FRE"><s0>Syndrome respiratoire aigu sévère</s0>
<s2>NM</s2>
<s5>14</s5>
</fC03>
<fC03 i1="06" i2="X" l="ENG"><s0>Severe acute respiratory syndrome</s0>
<s2>NM</s2>
<s5>14</s5>
</fC03>
<fC03 i1="06" i2="X" l="SPA"><s0>Síndrome respiratorio agudo severo</s0>
<s2>NM</s2>
<s5>14</s5>
</fC03>
<fC07 i1="01" i2="X" l="FRE"><s0>Coronaviridae</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="01" i2="X" l="ENG"><s0>Coronaviridae</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="01" i2="X" l="SPA"><s0>Coronaviridae</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="02" i2="X" l="FRE"><s0>Nidovirales</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="02" i2="X" l="ENG"><s0>Nidovirales</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="02" i2="X" l="SPA"><s0>Nidovirales</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="03" i2="X" l="FRE"><s0>Virus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="03" i2="X" l="ENG"><s0>Virus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="03" i2="X" l="SPA"><s0>Virus</s0>
<s2>NW</s2>
</fC07>
<fC07 i1="04" i2="X" l="FRE"><s0>Pathologie de l'appareil respiratoire</s0>
<s5>13</s5>
</fC07>
<fC07 i1="04" i2="X" l="ENG"><s0>Respiratory disease</s0>
<s5>13</s5>
</fC07>
<fC07 i1="04" i2="X" l="SPA"><s0>Aparato respiratorio patología</s0>
<s5>13</s5>
</fC07>
<fC07 i1="05" i2="X" l="FRE"><s0>Virose</s0>
</fC07>
<fC07 i1="05" i2="X" l="ENG"><s0>Viral disease</s0>
</fC07>
<fC07 i1="05" i2="X" l="SPA"><s0>Virosis</s0>
</fC07>
<fC07 i1="06" i2="X" l="FRE"><s0>Infection</s0>
</fC07>
<fC07 i1="06" i2="X" l="ENG"><s0>Infection</s0>
</fC07>
<fC07 i1="06" i2="X" l="SPA"><s0>Infección</s0>
</fC07>
<fC07 i1="07" i2="X" l="FRE"><s0>Pathologie des poumons</s0>
<s5>16</s5>
</fC07>
<fC07 i1="07" i2="X" l="ENG"><s0>Lung disease</s0>
<s5>16</s5>
</fC07>
<fC07 i1="07" i2="X" l="SPA"><s0>Pulmón patología</s0>
<s5>16</s5>
</fC07>
<fN21><s1>072</s1>
</fN21>
<fN44 i1="01"><s1>OTO</s1>
</fN44>
<fN82><s1>OTO</s1>
</fN82>
</pA>
</standard>
</inist>
</record>
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