Expression of CXC chemokine ligand 10 from the mouse hepatitis virus genome results in protection from viral-induced neurological and liver disease.
Using the recombinant murine coronavirus mouse hepatitis virus (MHV) expressing the T cell-chemoattractant CXCL10 (MHV-CXCL10), we demonstrate a potent antiviral role for CXCL10 in host defense. Instillation of MHV-CXCL10 into the CNS of CXCL10-deficient (CXCL10(-/-)) mice resulted in viral infection and replication in both brain and liver. Expression of virally encoded CXCL10 within the brain protected mice from death and correlated with increased infiltration of T lymphocytes, enhanced IFN-gamma secretion, and accelerated viral clearance when compared with mice infected with an isogenic control virus, MHV. Similarly, viral clearance from the livers of MHV-CXCL10-infected mice was accelerated in comparison to MHV-infected mice, yet was independent of enhanced infiltration of T lymphocytes and NK cells. Moreover, CXCL10(-/-) mice infected with MHV-CXCL10 were protected from severe hepatitis as evidenced by reduced pathology and serum alanine aminotransferase levels compared with MHV-infected mice. CXCL10-mediated protection within the liver was not dependent on CXC-chemokine receptor 2 (CXCR2) signaling as anti-CXCR2 treatment of MHV-CXCL10-infected mice did not modulate viral clearance or liver pathology. In contrast, treatment of MHV-CXCL10-infected CXCL10(-/-) mice with anti-CXCL10 Ab resulted in increased clinical disease correlating with enhanced viral recovery from the brain and liver as well as increased serum alanine aminotransferase levels. These studies highlight that CXCL10 expression promotes protection from coronavirus-induced neurological and liver disease.
Walsh
Kevin B
KB
Department of Molecular Biology & Biochemistry, University of California, Irvine, CA 92697, USA.
Edwards
Robert A
RA
Romero
Kimberley M
KM
Kotlajich
Matthew V
MV
Stohlman
Stephen A
SA
Lane
Thomas E
TE
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001921:Brain / Q000473:pathology / Q000821:virology; D002493:Central Nervous System Diseases / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018352:Coronavirus Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006524:Hepatitis, Viral, Animal / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008099:Liver / Q000473:pathology / Q000821:virology; D051379:Mice; D006517:Murine hepatitis virus / Q000235:genetics / Q000472:pathogenicity*; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000473:pathology / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D023063:Receptors, Interleukin-8B; D007371:Interferon-gamma; D000410:Alanine Transaminase