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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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Number of pluripotential hematopoietic progenitors in the  BM 3 d after infection with LCMV-WE (2 × 106 PFU). 105 syngeneic  BM cells of uninfected (open symbols) or infected (closed symbols) wild-type  (129Sv/Ev, H-2b) or mutant (IFN-α/β R0/0 or IFN-γ R0/0, H-2b) donor  mice were injected intravenously into lethally irradiated LCMV-immune  recipient wild-type mice (129Sv/Ev, H-2b). CFU-S in the spleens were  determined 8 d later. Each dot shows the number of colonies of an individual recipient. The horizontal lines represent the mean number of colonies per femur transferred from one individual donor mouse. The mean  CFU-S of two individual donor mice per group are shown.
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Figure 3: Number of pluripotential hematopoietic progenitors in the BM 3 d after infection with LCMV-WE (2 × 106 PFU). 105 syngeneic BM cells of uninfected (open symbols) or infected (closed symbols) wild-type (129Sv/Ev, H-2b) or mutant (IFN-α/β R0/0 or IFN-γ R0/0, H-2b) donor mice were injected intravenously into lethally irradiated LCMV-immune recipient wild-type mice (129Sv/Ev, H-2b). CFU-S in the spleens were determined 8 d later. Each dot shows the number of colonies of an individual recipient. The horizontal lines represent the mean number of colonies per femur transferred from one individual donor mouse. The mean CFU-S of two individual donor mice per group are shown.

Mentions: We then examined the effect of LCMV-WE infection on the number of primitive clonal progenitors (CFU-S) depending on their expression of IFN R. Syngeneic lethally irradiated LCMV-WE immune mice of the 129Sv/Ev wildtype strain were used as recipients in these experiments. The absolute number of CFU-S per femur 3 d after infection with LCMV-WE was ∼10-fold reduced in wildtype and IFN-γ R0/0 mice as compared with uninfected control mice of the same genotype (Fig. 3). In contrast, IFN-α/β R0/0 mice had a normal or even higher frequency of CFU-S after LCMV-WE infection. Obvious differences in the mean size of the CFU-S obtained were observed, i.e., spleen colonies of uninfected wild-type and LCMV-WE-infected IFN-α/β R0/0 mice had a three- to fourfold increase in diameter as compared with infected wild-type and IFN-γ R0/0 mice.


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)

Number of pluripotential hematopoietic progenitors in the  BM 3 d after infection with LCMV-WE (2 × 106 PFU). 105 syngeneic  BM cells of uninfected (open symbols) or infected (closed symbols) wild-type  (129Sv/Ev, H-2b) or mutant (IFN-α/β R0/0 or IFN-γ R0/0, H-2b) donor  mice were injected intravenously into lethally irradiated LCMV-immune  recipient wild-type mice (129Sv/Ev, H-2b). CFU-S in the spleens were  determined 8 d later. Each dot shows the number of colonies of an individual recipient. The horizontal lines represent the mean number of colonies per femur transferred from one individual donor mouse. The mean  CFU-S of two individual donor mice per group are shown.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Number of pluripotential hematopoietic progenitors in the BM 3 d after infection with LCMV-WE (2 × 106 PFU). 105 syngeneic BM cells of uninfected (open symbols) or infected (closed symbols) wild-type (129Sv/Ev, H-2b) or mutant (IFN-α/β R0/0 or IFN-γ R0/0, H-2b) donor mice were injected intravenously into lethally irradiated LCMV-immune recipient wild-type mice (129Sv/Ev, H-2b). CFU-S in the spleens were determined 8 d later. Each dot shows the number of colonies of an individual recipient. The horizontal lines represent the mean number of colonies per femur transferred from one individual donor mouse. The mean CFU-S of two individual donor mice per group are shown.
Mentions: We then examined the effect of LCMV-WE infection on the number of primitive clonal progenitors (CFU-S) depending on their expression of IFN R. Syngeneic lethally irradiated LCMV-WE immune mice of the 129Sv/Ev wildtype strain were used as recipients in these experiments. The absolute number of CFU-S per femur 3 d after infection with LCMV-WE was ∼10-fold reduced in wildtype and IFN-γ R0/0 mice as compared with uninfected control mice of the same genotype (Fig. 3). In contrast, IFN-α/β R0/0 mice had a normal or even higher frequency of CFU-S after LCMV-WE infection. Obvious differences in the mean size of the CFU-S obtained were observed, i.e., spleen colonies of uninfected wild-type and LCMV-WE-infected IFN-α/β R0/0 mice had a three- to fourfold increase in diameter as compared with infected wild-type and IFN-γ R0/0 mice.

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