Induction of interferon-gamma-inducible protein 10 by SARS-CoV infection, interferon alfacon 1 and interferon inducer in human bronchial epithelial Calu-3 cells and BALB/c mice.
BACKGROUND
The pathogenesis of severe acute respiratory syndrome coronavirus (SARS-CoV) is poorly understood. Several mechanisms involving both direct effects on target cells and indirect effects via the immune system might exist. SARS-CoV has been shown in vitro to induce changes of cytokines and chemokines in various human and animal cells. We previously reported that interferon (IFN) alfacon-1 was more active against SARS-CoV infection in human bronchial epithelial Calu-3 cells than in African green monkey kidney epithelial cells on day 3 post-infection.


METHODS
In the current study, we first evaluated the efficacy of IFN-alfacon 1 in Calu-3 cells during the first 7 days of virus infection. We then used the two-antibody sandwich ELISA method to detect IFN-gamma-inducible protein 10 (IP-10). We further evaluated the efficacy of antivirals directed against SARS-CoV infection in BALB/c mice.


RESULTS
A potent, prolonged inhibition of SARS-CoV replication in Calu-3 cells with IFN-alfacon 1 was observed. Furthermore, IP-10, an IFN-inducible leukocyte chemoattractant, was detected in Calu-3 cells after SARS-CoV infection. Interestingly, IP-10 expression was shown to be significantly increased when SARS-CoV-infected Calu-3 cells were treated with IFN alfacon-1. IP-10 expression was detected in the lungs of SARS-CoV-infected BALB/c mice. Significantly high levels of mouse IP-10 in BALB/c mice was also detected when SARS-CoV-infected mice were treated with the interferon inducer, polyriboinosinic-polyribocytidylic acid stabilized with poly-L-lysine and carboxymethyl cellulose (poly IC:LC). Treatment with poly IC:LC by intranasal route were effective in protecting mice against a lethal infection with mouse-adapted SARS-CoV and reduced the viral lung titres.


CONCLUSIONS
Our data might provide an important insight into the mechanism of pathogenesis of SARS-CoV and these properties might be therapeutically advantageous.
Kumaki
Yohichi
Y
Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA.
Day
Craig W
CW
Bailey
Kevin W
KW
Wandersee
Miles K
MK
Wong
Min-Hui
MH
Madsen
Jason R
JR
Madsen
Justin S
JS
Nelson
Nathan M
NM
Hoopes
Justin D
JD
Woolcott
John D
JD
McLean
Tyler Z
TZ
Blatt
Lawrence M
LM
Salazar
Andres M
AM
Smee
Donald F
DF
Barnard
Dale L
DL
D000818:Animals; D002266:Carboxymethylcellulose Sodium / Q000031:analogs & derivatives* / Q000494:pharmacology; D054357:Chemokine CXCL10 / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000821:virology; D005260:Female; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology*; D007370:Interferon Type I / Q000494:pharmacology*; D016898:Interferon-alpha; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011070:Poly I-C / Q000494:pharmacology*; D011107:Polylysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011994:Recombinant Proteins; D045473:Severe acute respiratory syndrome-related coronavirus / Q000502:physiology*; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D013047:Specific Pathogen-Free Organisms; D014779:Virus Replication / Q000187:drug effects
D054357:Chemokine CXCL10; D007369:Interferon Inducers; D007370:Interferon Type I; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011107:Polylysine; C050739:interferon alfacon-1; C019531:poly ICLC; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C