Limits...
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.

Show MeSH

Related in: MedlinePlus

Expansion of NK cells in the BM in response to LCMV  studied by FACS® analysis 3 d after infection with LCMV-WE (2 × 106  PFU). NK cells in the BM were detected by positive expression of the  NK 1.1 marker and absence of CD8 and CD4. CD4/CD8 (FITC) and  NK 1.1 (PE) staining is shown for cells electronically gated on the erythroid (TER 119 Tricolor) negative BM population. Percentages are given  for dot plot quadrants. Plots are repesentative for three mice per group.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2196026&req=5

Figure 7: Expansion of NK cells in the BM in response to LCMV studied by FACS® analysis 3 d after infection with LCMV-WE (2 × 106 PFU). NK cells in the BM were detected by positive expression of the NK 1.1 marker and absence of CD8 and CD4. CD4/CD8 (FITC) and NK 1.1 (PE) staining is shown for cells electronically gated on the erythroid (TER 119 Tricolor) negative BM population. Percentages are given for dot plot quadrants. Plots are repesentative for three mice per group.

Mentions: Because IFN-α/β plays an important role in NK responses and because NK cells might be involved in regulation of differentiation of stem cells, probably dependent upon MHC expression, the various mice used in this study were tested for NK activation in the BM. Earlier studies had shown that NK activity in spleens generated in IFN-α/β R0/0 mice was drastically reduced when compared with wild-type or IFN-γ R0/0 mice (21). Primary ex vivo NK-mediated cytolysis was measured on YAC-1 targets. When compared at maximal effector to target ratios, a vigorous cytolytic NK activity was observed in the wild-type mice and, to some lesser extent, in the IFNα/β R0/0 and IFN-γ R0/0 mice after infection with 2 × 106 PFU LCMV-WE (Fig. 6). Given the three- to fourfold reduction of marrow cellularity of wild-type and IFN-γ R0/0 mice, the absolute number of cytolytic NK cells in the BM (expressed as LU per femur) was two- to threefold higher in IFN-α/β R0/0 mice. Interestingly, a comparable NK response was seen in BM after infection with a low dose of LCMV-WE (2 × 102 PFU; data not shown) in both mutants and the wild-type strain, but not in IFN-α/β R0/0 mice treated with poly I/C. Next, we examined the LCMV-WE–induced NK proliferation in the BM by flow cytometry. A triple staining of total marrow cells using an erythroid-specific mAb (TER 119), a NK cell–specific mAb (NK 1.1), and a mixture of anti-CD8 and anti-CD4 was performed 3 d after infection with 2 × 106 PFU LCMV-WE. To increase sensitivity and detection levels of NK cells, subset analysis was performed with cells gated negatively on TER 119; this eliminated the high number of erythroid cells in uninfected mice. Baseline NK and CD4/CD8 percentages were comparable for uninfected wild-type and IFN R-deficient mice (<2%). After infection, the percentage of NK 1.1-positive cells in the BM increased ninefold in wild-type mice, four- to fivefold in IFN-α/β R0/0 mice, and six- to sevenfold in IFN-γ R0/0 mice (Fig. 7). To a lesser extent, an expansion of the CD4/ CD8+ population was observed in the BM of wild-type and IFN-γ R0/0 mice, whereas in the IFN-α/β R0/0 mutant mice no significant increase in the percentage of CD4/ CD8+ cells was detected on day 3 after infection. Thus, there was no correlation between NK activity in BM and susceptibility to LCMV-induced BM suppression.


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)

Expansion of NK cells in the BM in response to LCMV  studied by FACS® analysis 3 d after infection with LCMV-WE (2 × 106  PFU). NK cells in the BM were detected by positive expression of the  NK 1.1 marker and absence of CD8 and CD4. CD4/CD8 (FITC) and  NK 1.1 (PE) staining is shown for cells electronically gated on the erythroid (TER 119 Tricolor) negative BM population. Percentages are given  for dot plot quadrants. Plots are repesentative for three mice per group.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 7: Expansion of NK cells in the BM in response to LCMV studied by FACS® analysis 3 d after infection with LCMV-WE (2 × 106 PFU). NK cells in the BM were detected by positive expression of the NK 1.1 marker and absence of CD8 and CD4. CD4/CD8 (FITC) and NK 1.1 (PE) staining is shown for cells electronically gated on the erythroid (TER 119 Tricolor) negative BM population. Percentages are given for dot plot quadrants. Plots are repesentative for three mice per group.
Mentions: Because IFN-α/β plays an important role in NK responses and because NK cells might be involved in regulation of differentiation of stem cells, probably dependent upon MHC expression, the various mice used in this study were tested for NK activation in the BM. Earlier studies had shown that NK activity in spleens generated in IFN-α/β R0/0 mice was drastically reduced when compared with wild-type or IFN-γ R0/0 mice (21). Primary ex vivo NK-mediated cytolysis was measured on YAC-1 targets. When compared at maximal effector to target ratios, a vigorous cytolytic NK activity was observed in the wild-type mice and, to some lesser extent, in the IFNα/β R0/0 and IFN-γ R0/0 mice after infection with 2 × 106 PFU LCMV-WE (Fig. 6). Given the three- to fourfold reduction of marrow cellularity of wild-type and IFN-γ R0/0 mice, the absolute number of cytolytic NK cells in the BM (expressed as LU per femur) was two- to threefold higher in IFN-α/β R0/0 mice. Interestingly, a comparable NK response was seen in BM after infection with a low dose of LCMV-WE (2 × 102 PFU; data not shown) in both mutants and the wild-type strain, but not in IFN-α/β R0/0 mice treated with poly I/C. Next, we examined the LCMV-WE–induced NK proliferation in the BM by flow cytometry. A triple staining of total marrow cells using an erythroid-specific mAb (TER 119), a NK cell–specific mAb (NK 1.1), and a mixture of anti-CD8 and anti-CD4 was performed 3 d after infection with 2 × 106 PFU LCMV-WE. To increase sensitivity and detection levels of NK cells, subset analysis was performed with cells gated negatively on TER 119; this eliminated the high number of erythroid cells in uninfected mice. Baseline NK and CD4/CD8 percentages were comparable for uninfected wild-type and IFN R-deficient mice (<2%). After infection, the percentage of NK 1.1-positive cells in the BM increased ninefold in wild-type mice, four- to fivefold in IFN-α/β R0/0 mice, and six- to sevenfold in IFN-γ R0/0 mice (Fig. 7). To a lesser extent, an expansion of the CD4/ CD8+ population was observed in the BM of wild-type and IFN-γ R0/0 mice, whereas in the IFN-α/β R0/0 mutant mice no significant increase in the percentage of CD4/ CD8+ cells was detected on day 3 after infection. Thus, there was no correlation between NK activity in BM and susceptibility to LCMV-induced BM suppression.

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