Functional antagonism of chemokine receptor CCR1 reduces mortality in acute pneumovirus infection in vivo.
We present an antiviral-immunomodulatory therapeutic strategy involving the chemokine receptor antagonist Met-RANTES, which yields significant survival in the setting of an otherwise fatal respiratory virus infection. In previous work, we demonstrated that infection with the natural rodent pathogen pneumonia virus of mice involves robust virus replication accompanied by cellular inflammation modulated by the CC chemokine macrophage inflammatory protein 1alpha (MIP-1alpha). We found that the antiviral agent ribavirin limited virus replication in vivo but had no impact on morbidity and mortality associated with this disease in the absence of immunomodulatory control. We show here that ribavirin reduces mortality, from 100% to 10 and 30%, respectively, in gene-deleted CCR1(-/-) mice and in wild-type mice treated with the small-molecule chemokine receptor antagonist, Met-RANTES. As MIP-1alpha-mediated inflammation is a common response to several distantly related respiratory virus pathogens, specific antiviral therapy in conjunction with blockade of the MIP-1alpha/CCR1 inflammatory cascade may ultimately prove to be a useful, generalized approach to severe respiratory virus infection and its pathological sequelae in human subjects.
Bonville
Cynthia A
CA
Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
Lau
Vincent K
VK
DeLeon
Jordana M
JM
Gao
Ji-Liang
JL
Easton
Andrew J
AJ
Rosenberg
Helene F
HF
Domachowske
Joseph B
JB
D000208:Acute Disease; D000818:Animals; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D007962:Leukocytes / Q000502:physiology; D008168:Lung / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018186:Pneumovirus Infections / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*
C515300:CCR1 protein, human; C515301:Ccr1 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019402:Macrophage Inflammatory Proteins; C108335:RANTES, Met-; D054389:Receptors, CCR1; D019707:Receptors, Chemokine