CCL5-CCR5 interaction provides antiapoptotic signals for macrophage survival during viral infection

Jeffrey W Tyner¹, Osamu Uchida¹, Naohiro Kajiwara¹, Edy Y Kim¹, Anand C Patel², Mary P O'Sullivan¹, Michael J Walter¹, Reto A Schwendener³, Donald N Cook⁴, Theodore M Danoff⁵ & Michael J Holtzman^1, 6

¹  Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110,USA.

²  Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110,USA.

³  Department of Molecular Cell Biology, Paul Scherrer Institute, Villigen, Switzerland CH-5232.

⁴  Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27710, USA.

⁵  Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

⁶  Department of Cell Biology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110,USA.

Host defense against viruses probably depends on targeted death of infected host cells and then clearance of cellular corpses by macrophages. For this process to be effective, the macrophage must presumably avoid its own virus-induced death. Here we identify one such mechanism. We show that mice lacking the chemokine Ccl5 are immune compromised to the point of delayed viral clearance, excessive airway inflammation and respiratory death after mouse parainfluenza or human influenza virus infection. Virus-inducible levels of Ccl5 are required to prevent apoptosis of virus-infected mouse macrophages in vivo and mouse and human macrophages ex vivo. The protective effect of Ccl5 requires activation of the Ccr5 chemokine receptor and consequent bilateral activation of G_i-PI3K-AKT and G_i-MEK-ERK signaling pathways. The antiapoptotic action of chemokine signaling may therefore allow scavengers to finally stop the host cell-to-cell infectious process.

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