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Protein Protects Lung Tissues from Influenza Virus

By BiotechDaily International staff writers
Posted on 28 Jan 2014
Image: Lung tissue from cIAP2-deficient mice showing effects on epithelial cells of influenza infection (Photo courtesy of McGill University).
Image: Lung tissue from cIAP2-deficient mice showing effects on epithelial cells of influenza infection (Photo courtesy of McGill University).
Researchers studying how the body responds to influenza infection have found that the protein called "cellular inhibitor of apoptosis protein 2" (cIAP2) protects the lungs against pulmonary tissue necrosis during virus infection to promote host survival.

cIAP2 is a multifunctional protein that regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, mitogenic kinase signaling, and in cancer cells, cell proliferation, cell invasion, and metastasis. It acts as an E3 ubiquitin- protein ligase regulating NF-kappa-B signaling, and regulates both canonical and non-canonical NF-kappa-B signaling. The target proteins for its E3 ubiquitin-protein ligase activity include RIPK1, RIPK2, RIPK3, RIPK4, CASP3, CASP7, CASP8, TRAF1, and BCL10.

In order to study the role of cIAP2 in H1N1type A influenza, investigators at McGill University (Montreal, Canada) genetically engineered a line of mice to lack the gene for this protein.

They reported in the January 15, 2014, issue of the journal Cell Host & Microbe that mice deficient in cIAP2 exhibited increased susceptibility and mortality to influenza A virus infection. The lethality was not due to impaired antiviral immune functions, but rather because of death-receptor-induced programmed necrosis of airway epithelial cells that led to severe bronchiole epithelial degeneration, despite control of viral replication. Drugs that blocked RIPK1 or genetic deletion of RIPK3, both kinases involved in programmed necrosis, rescued cIAP2-deficient mice from influenza-induced lethality. Genetic deletion of the death receptor agonists Fas ligand or TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) also reversed the susceptibility of cIAP2-deficient mice.

These results indicated that lung tissues were protected from the H1N1 influenza virus by cIAP2 inhibition of RIPK3-mediated programmed necrosis rather than through control of the virus by the immune system.

“It is a discovery that offers exciting new avenues for controlling influenza, since until now attempts to target the virus itself have proven challenging, especially in the face of emerging new strains of the virus,” said senior author Dr. Maya Saleh, associate professor of medicine and biochemistry at McGill University. “The results from our study now suggest that one effective way of countering influenza infections may instead be offered by enhancing the body’s resistance to the virus.”

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McGill University



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