Participation of both host and virus factors in induction of severe acute respiratory syndrome (SARS) in F344 rats infected with SARS coronavirus.
To understand the pathogenesis and develop an animal model of severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV), the Frankfurt 1 SARS-CoV isolate was passaged serially in young F344 rats. Young rats were susceptible to SARS-CoV but cleared the virus rapidly within 3 to 5 days of intranasal inoculation. After 10 serial passages, replication and virulence of SARS-CoV were increased in the respiratory tract of young rats without clinical signs. By contrast, adult rats infected with the passaged virus showed respiratory symptoms and severe pathological lesions in the lung. Levels of inflammatory cytokines in sera and lung tissues were significantly higher in adult F344 rats than in young rats. During in vivo passage of SARS-CoV, a single amino acid substitution was introduced within the binding domain of the viral spike protein recognizing angiotensin-converting enzyme 2 (ACE2), which is known as a SARS-CoV receptor. The rat-passaged virus more efficiently infected CHO cells expressing rat ACE2 than did the original isolate. These results strongly indicate that host and virus factors such as advanced age and virus adaptation are critical for the development of SARS in rats.
Nagata
Noriyo
N
Department of Pathology, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo 208-0011, Japan. nnagata@nih.go.jp
Iwata
Naoko
N
Hasegawa
Hideki
H
Fukushi
Shuetsu
S
Yokoyama
Masaru
M
Harashima
Ayako
A
Sato
Yuko
Y
Saijo
Masayuki
M
Morikawa
Shigeru
S
Sata
Tetsutaro
T
D000367:Age Factors; D019943:Amino Acid Substitution; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D006389:Hemagglutinins, Viral / Q000502:physiology; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000502:physiology; D008958:Models, Molecular; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D011991:Receptors, Virus / Q000378:metabolism; D045473:Severe acute respiratory syndrome-related coronavirus / Q000737:chemistry / Q000235:genetics / Q000472:pathogenicity*; D012692:Serial Passage; D045169:Severe Acute Respiratory Syndrome / Q000821:virology*; D064370:Spike Glycoprotein, Coronavirus; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000502:physiology; D014774:Virulence
D016207:Cytokines; D006389:Hemagglutinins, Viral; D008562:Membrane Glycoproteins; D011991:Receptors, Virus; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins; C578557:spike glycoprotein, SARS-CoV; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2