The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/2/517/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 3, February 3, 1997 517-530


Articles

Virus-induced Transient Bone Marrow Aplasia: Major Role of Interferon-{alpha}/β during Acute Infection with the Noncytopathic Lymphocytic Choriomeningitis Virus

Daniel Binder*,{ddagger}, Jörg Fehr{ddagger}, Hans Hengartner*, and Rolf M. Zinkernagel*

From the * Institute of Experimental Immunology, Department of Pathology, University Hospital of Zürich, CH-8091 Zürich, Switzerland; and the {ddagger} Division of Hematology, Department of Internal Medicine, University Hospital of Zürich, CH-8091 Zürich, Switzerland

The hematologic consequences of infection with the noncytopathic lymphocytic choriomeningitis virus (LCMV) were studied in wild-type mice with inherent variations in their interferon (IFN)-{alpha} responder ability and in mutant mice lacking {alpha}/β (IFN-{alpha} R0/0) or {gamma} IFN (IFN-{gamma} R0/0) receptors. During the first week of infection, wild type mice demonstrated a transient pancytopenia. Within a given genetic background, the extent of the blood cell abnormalities did not correlate with the virulence of the LCMV isolate but variations were detected between different mouse strains; they were found to depend on their IFN-{alpha}/β responder phenotype. Whereas IFN-{gamma} R0/0 mice were comparable to wild-type mice, IFN-{alpha}/β R0/0 mice exhibited unchanged peripheral blood values during acute LCMV infection. In parallel, the bone marrow (BM) cellularity, the pluripotential and committed progenitor compartments were up to 30-fold reduced in wild type and IFN-{gamma} R0/0, but remained unchanged in IFN-{alpha}/β R0/0 mice. Viral titers in BM 3 d after LCMV infection were similar in these mice, but antigen localization was different. Viral antigen was predominantly confined to stromal BM in normal mice and IFN-{gamma} R0/0 knockouts, whereas, in IFN-{alpha}/β R0/0 mice, LCMV was detected in >90% of megakaryocytes and 10–15% of myeloid precursors, but not in erythroblasts. Although IFN-{alpha} efficiently prevented viral replication in potentially susceptible hematopoietic cells, even in overwhelming LCMV infection, unlimited virus multiplication in platelet and myeloid precursors in IFN-{alpha}/β R0/0 mice did not interfere with the number of circulating blood cells. Natural killer (NK) cell expansion and activity in the BM was comparable on day 3 after infection in mutant and control mice. Adaptive immune responses did not play a major role because comparable kinetics of LCMV-induced pancytopenia and transient depletion of the pluripotential and committed progenitor compartments were observed in CD80/0 and CD40/0 mice, in mice depleted of NK cells, in lpr mice, and in perforin-deficient (P0/0) mice lacking lytic NK cells. Thus, the reversible depression of hematopoiesis during early LCMV infection was not mediated by LCMV-WE–specific cytotoxic T lymphocyte, cytolysis, or secreted IFN-{gamma} from virally induced NK cells but was a direct effect of IFN-{alpha}/β.


Address correspondence to Daniel Binder, the Institute of Experimental Immunology, Schmelzbergotrasse 12, CH-8091 Zürich, Switzerland.

Recombinant mTPO was kindly provided as a gift by Genentech, Inc. (South San Francisco, CA).

This work was supported by the Union Bank of Switzerland, the Swiss National Science Foundation, and the Kanton of Zürich.

1Abbrevations used in this paper: BFU-E, burst-forming unit-erythroid; BM, bone marrow; CBC, cellular blood count; CFU-GM, colony-forming unit-granulocyte/macrophage; CFU-Meg, colony-forming unit-megakaryocyte; CFU-S, colony-forming unit-spleen; hEpo, human erythropoietin; LCMV, lymphocytic choriomeningitis virus; mTPO, murine thrombopoietin.


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