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

Nature Medicine volume 11, pages 1180–1187 (2005)Cite this article

Abstract

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 Gαi-PI3K-AKT and Gαi-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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Figure 1: Excessive airway inflammation and respiratory failure after paramyxoviral infection in Ccl5−/− mice.
Figure 2: Excessive macrophage apoptosis after paramyxoviral infection in Ccl5−/− mice.
Figure 3: Ccl5- and Ccr5-dependent protection from virus-induced apoptosis in isolated macrophages.
Figure 4: CCL5 signals to Gαi-PI3K-Akt and MEK-ERK pathways that block virus-induced apoptosis.
Figure 5: Decreased activation of Akt and Erk1/2 in Ccl5−/− mice after viral infection.
Figure 6: Effects of macrophage depletion on viral infection in wild-type and Ccl5−/− mice.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health (Heart, Lung, and Blood Institute), the Martin Schaeffer Fund and the Alan A. and Edith L. Wolff Charitable Trust.

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Authors and Affiliations

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

    Jeffrey W Tyner, Osamu Uchida, Naohiro Kajiwara, Edy Y Kim, Mary P O'Sullivan, Michael J Walter & Michael J Holtzman

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

    Anand C Patel

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

    Reto A Schwendener

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

    Donald N Cook

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

    Theodore M Danoff

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

    Michael J Holtzman

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Supplementary information

Supplementary Fig. 1

Time course of viral replication and Ccl5 and Ccr5 expression. (PDF 2964 kb)

Supplementary Fig. 2

Similar T-cell activation in Ccl5-null and wild-type control mice. (PDF 129 kb)

Supplementary Fig. 3

Decreased survival and increased macrophage apoptosis after influenza virus infection in Ccl5- and Ccr5-null mice. (PDF 1257 kb)

Supplementary Fig. 4

Time course of viral persistence and macrophage accumulation and apoptosis in Ccl5-null mice. (PDF 3447 kb)

Supplementary Fig. 5

Ccr5 induction and Ccl5/Ccr5 protection from apoptosis in mouse macrophages after viral infection. (PDF 1328 kb)

Supplementary Fig. 6

CCL3, CCL4, and CCL5 signaling to ERK/AKT at low ligand levels and CCL5 signaling to Src/MEK/ERK at high ligand levels. (PDF 487 kb)

Supplementary Fig. 7

Ccl5 protection against virus-induced apoptosis in airway epithelial cells. (PDF 482 kb)

Supplementary Fig. 8

Scheme for mechanisms of apoptosis during viral infection. (PDF 559 kb)

Supplementary Methods (PDF 85 kb)

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Tyner, J., Uchida, O., Kajiwara, N. et al. CCL5-CCR5 interaction provides antiapoptotic signals for macrophage survival during viral infection. Nat Med 11, 1180–1187 (2005). https://doi.org/10.1038/nm1303

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