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

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)-/β responder ability and in mutant mice lacking /β (IFN-/β 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-/β responder phenotype. Whereas IFN- R^0/0 mice were comparable to wild-type mice, IFN-/β 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-/β 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-/β R^0/0 mice, LCMV was detected in >90% of megakaryocytes and 10–15% of myeloid precursors, but not in erythroblasts. Although IFN-/β efficiently prevented viral replication in potentially susceptible hematopoietic cells, even in overwhelming LCMV infection, unlimited virus multiplication in platelet and myeloid precursors in IFN-/β 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-/β.

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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