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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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Lineage-committed  precursor cells in wild-type (open  columns) or mutant (closed columns, IFN-α/β R0/0; hatched columns, IFN-γ R0/0) mice 3 d after  LCMV-WE (2 × 106 PFU) infection. Results are presented as  the mean number (± SD) of  BFU-E, CFU-GM, or CFUMeg for duplicate methylcellulose cultures of total BM cells per  femur. Pooled data from two independent experiments with 2–3  individual mice per group are  shown.
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Figure 2: Lineage-committed precursor cells in wild-type (open columns) or mutant (closed columns, IFN-α/β R0/0; hatched columns, IFN-γ R0/0) mice 3 d after LCMV-WE (2 × 106 PFU) infection. Results are presented as the mean number (± SD) of BFU-E, CFU-GM, or CFUMeg for duplicate methylcellulose cultures of total BM cells per femur. Pooled data from two independent experiments with 2–3 individual mice per group are shown.

Mentions: Analysis of committed hematopoietic progenitors 3 d after infection with LCMV-WE showed a distinct effect on different lineages in the BM of wild-type and IFN-γ R0/0 mice: the absolute numbers of BFU-E and CFU-GM per femur were 30-fold below baseline levels and, to some lesser extent, also the numbers of CFU-Meg were reduced (20-fold) (Fig. 2). This was in contrast with IFN-α/β R0/0 mice, which, when compared with uninfected control mice, had normal or slightly increased numbers of all lineagecommitted progenitors 3 d after LCMV-WE infection. Infection with LCMV of wild-type and of IFN-γ R0/0 mice resulted in much smaller sizes of colonies and the relative frequencies of all CFUs per plated BM cells were at least 10-fold reduced as compared with IFN-α/β 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)

Lineage-committed  precursor cells in wild-type (open  columns) or mutant (closed columns, IFN-α/β R0/0; hatched columns, IFN-γ R0/0) mice 3 d after  LCMV-WE (2 × 106 PFU) infection. Results are presented as  the mean number (± SD) of  BFU-E, CFU-GM, or CFUMeg for duplicate methylcellulose cultures of total BM cells per  femur. Pooled data from two independent experiments with 2–3  individual mice per group are  shown.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Lineage-committed precursor cells in wild-type (open columns) or mutant (closed columns, IFN-α/β R0/0; hatched columns, IFN-γ R0/0) mice 3 d after LCMV-WE (2 × 106 PFU) infection. Results are presented as the mean number (± SD) of BFU-E, CFU-GM, or CFUMeg for duplicate methylcellulose cultures of total BM cells per femur. Pooled data from two independent experiments with 2–3 individual mice per group are shown.
Mentions: Analysis of committed hematopoietic progenitors 3 d after infection with LCMV-WE showed a distinct effect on different lineages in the BM of wild-type and IFN-γ R0/0 mice: the absolute numbers of BFU-E and CFU-GM per femur were 30-fold below baseline levels and, to some lesser extent, also the numbers of CFU-Meg were reduced (20-fold) (Fig. 2). This was in contrast with IFN-α/β R0/0 mice, which, when compared with uninfected control mice, had normal or slightly increased numbers of all lineagecommitted progenitors 3 d after LCMV-WE infection. Infection with LCMV of wild-type and of IFN-γ R0/0 mice resulted in much smaller sizes of colonies and the relative frequencies of all CFUs per plated BM cells were at least 10-fold reduced as compared with IFN-α/β 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