Platelets prevent IFN-α/β-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus

doi:10.1073/pnas.0711200105

Platelets prevent IFN-α/β-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus

Departments of *Molecular and Experimental Medicine and
^‡Molecular and Integrative Neurosciences, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; and
^†Immunopathogenesis of Liver Infections Unit, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy

Contributed by Francis V. Chisari, November 30, 2007 (received for review October 26, 2007)

Abstract

We found that mice infected with different isolates of lymphocytic choriomeningitis virus (LCMV) develop a mild hemorrhagic anemia, which becomes severe and eventually lethal in animals depleted of platelets or lacking integrin β3. Lethal hemorrhagic anemia is mediated by virus-induced IFN-α/β that causes platelet dysfunction, mucocutaneous blood loss and suppression of erythropoiesis. In addition to the life-threatening hemorrhagic anemia, platelet-depleted mice fail to mount an efficient cytotoxic T lymphocyte (CTL) response and cannot clear LCMV. Transfusion of functional platelets into these animals reduces hemorrhage, prevents death and restores CTL-induced viral clearance in a manner partially dependent on CD40 ligand (CD40L). These results indicate that, upon activation, platelets expressing integrin β3 and CD40L are required for protecting the host against the induction of an IFN-α/β-dependent lethal hemorrhagic diathesis and for clearing LCMV infection through CTLs.

Footnotes

^§To whom correspondence may be addressed. E-mail: fchisari{at}scripps.edu or guidotti{at}scripps.edu
Author contributions: M. Iannacone and L.G.G. designed research; M. Iannacone, G.S., and L.G.G. performed research; M. Isogawa, J.K.W., and P.M. contributed new reagents/analytic tools; M. Iannacone, F.V.C., Z.M.R., and L.G.G. analyzed data; and M. Iannacone, Z.M.R., and L.G.G. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0711200105/DC1.