Virus-induced transient bone marrow aplasia: major role of interferon-alpha/beta during acute infection with the noncytopathic lymphocytic choriomeningitis virus.
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/beta responder ability and in mutant mice lacking alpha/beta (IFN-alpha/beta 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/beta responder phenotype. Whereas IFN-gamma R0/0 mice were comparable to wild-type mice, IFN-alpha/beta 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/beta 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/beta R0/0 mice, LCMV was detected in > 90% of megakaryocytes and 10-15% of myeloid precursors, but not in erythroblasts Although IFN-alpha/beta 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/beta 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 CD8(0/0) and CD4(0/0) 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/beta.
Binder
D
D
Department of Pathology, University Hospital of Zurich, Switzerland.
Fehr
J
J
Hengartner
H
H
Zinkernagel
R M
RM
D000208:Acute Disease; D000818:Animals; D001772:Blood Cell Count; D001853:Bone Marrow / Q000502:physiology*; D003602:Cytotoxicity, Immunologic; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells; D016898:Interferon-alpha / Q000502:physiology*; D016899:Interferon-beta / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000097:blood*; D051379:Mice; D008815:Mice, Inbred Strains; D017471:Receptors, Interferon / Q000032:analysis; D014779:Virus Replication
D016898:Interferon-alpha; D017471:Receptors, Interferon; D016899:Interferon-beta