J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/02/517/14 $2.00
Volume 185 February 1997 517-530

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

By Daniel Binder,^* Jörg Fehr, 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  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)-/ responder ability and in mutant mice lacking / (IFN-/ R^0/0) or  IFN (IFN- R^0/0) 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-/ responder phenotype. Whereas IFN- R^0/0 mice were comparable to wild-type mice, IFN-/ R^0/0 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- R^0/0, but remained unchanged in IFN-/ R^0/0 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- R^0/0 knockouts, whereas, in IFN-/ R^0/0 mice, LCMV was detected in >90% of megakaryocytes and 10-15% of myeloid precursors, but not in erythroblasts. Although IFN-/ efficiently prevented viral replication in potentially susceptible hematopoietic cells, even in overwhelming LCMV infection, unlimited virus multiplication in platelet and myeloid precursors in IFN-/ R^0/0 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 CD8^0/0 and CD4^0/0 mice, in mice depleted of NK cells, in lpr mice, and in perforin-deficient (P^0/0) 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- from virally induced NK cells but was a direct effect of IFN-/.

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