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Virus-induced transient bone marrow aplasia: major role of interferon-alpha/beta during acute infection with the noncytopathic lymphocytic choriomeningitis virus.

Binder D, Fehr J, Hengartner H, Zinkernagel RM - J. Exp. Med. (1997)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University Hospital of Zurich, Switzerland.

ABSTRACT
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.

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Kinetics of BM cellularity after LCMV-WE infection. Mice  of wild type genotype (open columns) or mutant mice with inactivated α/β  IFN (closed columns) or γ IFN (hatched columns) receptors were infected intravenously with LCMV-WE (2 × 106 PFU). At the indicated timepoints, mice were killed and the absolute number of nucleated BM cells  per femur was determined. The data represent mean ± SD of 3–4 mice  per group.
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Figure 1: Kinetics of BM cellularity after LCMV-WE infection. Mice of wild type genotype (open columns) or mutant mice with inactivated α/β IFN (closed columns) or γ IFN (hatched columns) receptors were infected intravenously with LCMV-WE (2 × 106 PFU). At the indicated timepoints, mice were killed and the absolute number of nucleated BM cells per femur was determined. The data represent mean ± SD of 3–4 mice per group.

Mentions: BM function was evaluated in wild-type and IFN R mutants after acute infection with LCMV–WE (2 × 106 PFU). Femoral cellularity of wild-type and IFN-γ R0/0 mice was reduced by half on day 1 after infection and reduced to a minimum of 7% in wild-type mice and 11% of baseline values in IFN-γ R0/0 mice on day 3, respectively (Fig. 1). Thereafter, total cellularity returned to normal values in IFN-γ R0/0 mice by day 7 and in wild-type mice by day 10. In contrast, IFN-α/β R0/0 mice showed minimal changes in femoral cell content during the entire study period. In parallel, splenic cellularity decreased considerably until day 3 in wild-type and IFN-γ R0/0 mice but remained unchanged in IFN-α/β R0/0 mice (data not shown). Cytological analysis of BM preparations on day 3 after infection revealed a marked deficiency of the nonmitotic mature cell population in wild-type and IFN-γ R0/0 mice but not in IFN-α/β R0/0 mice (Table 3). In wild-type and IFN-γ R0/0 mice, LCMV-WE infection resulted in a 2–2.4-fold reduction of erythroid elements, which was more apparent when absolute cell numbers per femur were compared (wild type 0.4 × 106; IFN-γ R0/0, 0.7 × 106; IFN-α/β R0/0, 4.5 × 106). Polymorphnuclear granulocytes of wildtype and IFN-γ R0/0 mice were reduced 3–3.4-fold and the proportion of early myeloid precursors (blasts, promyelocytes) was significantly increased by a factor of 2.5 when compared with IFN-α/β R0/0 mice. The relative increase of marrow lymphocytes in wild-type and IFN-γ R0/0 mice on day 3 after infection had disappeared by day 7; monocytes were slightly increased in both mutants and wild-type mice 7 d after LCMV-WE infection. The amount of megakaryocytes was determined semiquantitatively and was two- to fourfold reduced in wild-type and IFN-γ R0/0 mice, but unchanged in IFN-α/β R0/0 mice during the entire study period.


Virus-induced transient bone marrow aplasia: major role of interferon-alpha/beta during acute infection with the noncytopathic lymphocytic choriomeningitis virus.

Binder D, Fehr J, Hengartner H, Zinkernagel RM - J. Exp. Med. (1997)

Kinetics of BM cellularity after LCMV-WE infection. Mice  of wild type genotype (open columns) or mutant mice with inactivated α/β  IFN (closed columns) or γ IFN (hatched columns) receptors were infected intravenously with LCMV-WE (2 × 106 PFU). At the indicated timepoints, mice were killed and the absolute number of nucleated BM cells  per femur was determined. The data represent mean ± SD of 3–4 mice  per group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196026&req=5

Figure 1: Kinetics of BM cellularity after LCMV-WE infection. Mice of wild type genotype (open columns) or mutant mice with inactivated α/β IFN (closed columns) or γ IFN (hatched columns) receptors were infected intravenously with LCMV-WE (2 × 106 PFU). At the indicated timepoints, mice were killed and the absolute number of nucleated BM cells per femur was determined. The data represent mean ± SD of 3–4 mice per group.
Mentions: BM function was evaluated in wild-type and IFN R mutants after acute infection with LCMV–WE (2 × 106 PFU). Femoral cellularity of wild-type and IFN-γ R0/0 mice was reduced by half on day 1 after infection and reduced to a minimum of 7% in wild-type mice and 11% of baseline values in IFN-γ R0/0 mice on day 3, respectively (Fig. 1). Thereafter, total cellularity returned to normal values in IFN-γ R0/0 mice by day 7 and in wild-type mice by day 10. In contrast, IFN-α/β R0/0 mice showed minimal changes in femoral cell content during the entire study period. In parallel, splenic cellularity decreased considerably until day 3 in wild-type and IFN-γ R0/0 mice but remained unchanged in IFN-α/β R0/0 mice (data not shown). Cytological analysis of BM preparations on day 3 after infection revealed a marked deficiency of the nonmitotic mature cell population in wild-type and IFN-γ R0/0 mice but not in IFN-α/β R0/0 mice (Table 3). In wild-type and IFN-γ R0/0 mice, LCMV-WE infection resulted in a 2–2.4-fold reduction of erythroid elements, which was more apparent when absolute cell numbers per femur were compared (wild type 0.4 × 106; IFN-γ R0/0, 0.7 × 106; IFN-α/β R0/0, 4.5 × 106). Polymorphnuclear granulocytes of wildtype and IFN-γ R0/0 mice were reduced 3–3.4-fold and the proportion of early myeloid precursors (blasts, promyelocytes) was significantly increased by a factor of 2.5 when compared with IFN-α/β R0/0 mice. The relative increase of marrow lymphocytes in wild-type and IFN-γ R0/0 mice on day 3 after infection had disappeared by day 7; monocytes were slightly increased in both mutants and wild-type mice 7 d after LCMV-WE infection. The amount of megakaryocytes was determined semiquantitatively and was two- to fourfold reduced in wild-type and IFN-γ R0/0 mice, but unchanged in IFN-α/β R0/0 mice during the entire study period.

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University Hospital of Zurich, Switzerland.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus