Mice lacking both TNF and IL-1 receptors exhibit reduced lung inflammation and delay in onset of death following infection with a highly virulent H5N1 virus.
BACKGROUND
Highly pathogenic avian influenza viruses of the H5N1 subtype continue to cross the species barrier to infect humans and cause severe disease. It has been suggested that an exaggerated immune response contributes to the pathogenesis of H5N1 virus infection in mammals. In particular, H5N1 virus infections are associated with a high expression of the proinflammatory cytokines, including interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α).


METHODS
We investigated the compounding affects of both cytokines on the outcome of H5N1 virus disease by using triple mutant mice deficient in 3 signaling receptors, TNF-R1, TNF-R2, and IL-1-RI.


RESULTS
Triple mutant mice exhibited reduced morbidity and a significant delay in mortality following lethal challenge with a lethal H5N1 virus, whereas no such differences were observed with the less virulent A/PR/8/34 (H1N1) virus. H5N1-infected triple mutant mice displayed diminished cytokine production in lung tissue and a quantifiable decrease of macrophages and neutrophils in the lungs postinfection. Moreover, morphometric analysis of airway sections revealed less extensive inflammation in H5N1-infected triple mutant mice, compared with infected wild-type mice.


CONCLUSIONS
The combined signaling from the TNF or IL-1 receptors promotes maximal lung inflammation that may contribute to the severity of disease caused by H5N1 virus infection.
Perrone
Lucy A
LA
Immunology and Pathogenesis Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Szretter
Kristy J
KJ
Katz
Jacqueline M
JM
Mizgerd
Joseph P
JP
Tumpey
Terrence M
TM
D000818:Animals; D001921:Brain / Q000821:virology; D002452:Cell Count; D016207:Cytokines / Q000172:deficiency / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000401:mortality; D053124:Influenza A Virus, H5N1 Subtype; D008171:Lung Diseases / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000503:physiopathology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009504:Neutrophils / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000235:genetics* / Q000276:immunology / Q000401:mortality* / Q000503:physiopathology; D017472:Receptors, Interleukin-1 / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D015398:Signal Transduction; D019562:Viral Load
D016207:Cytokines; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor
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