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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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Time kinetics of virus titers in the BM after infection with  LCMV. Mice were infected intravenously with LCMV-WE (2 × 106  PFU) and virus titers were determined in 106 nucleated BM cells at the  timepoints indicated. Data points are values for individual mice and the  horizontal lines represent the mean of the indicated group.
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Figure 4: Time kinetics of virus titers in the BM after infection with LCMV. Mice were infected intravenously with LCMV-WE (2 × 106 PFU) and virus titers were determined in 106 nucleated BM cells at the timepoints indicated. Data points are values for individual mice and the horizontal lines represent the mean of the indicated group.

Mentions: In vivo susceptibility to LCMV infection of wild-type and IFN R-deficient hematopoietic BM cells was evaluated for a high-dose (2 × 106 PFU) challenge with LCMV-WE. Wild-type and IFN-γ R0/0 mice showed a similar kinetics of LCMV replication with slightly higher titers in IFN-γ R0/0 mice 7 d after infection (Fig. 4). In contrast, IFN-α/β R0/0 mice exhibited an enhanced initial replication, i.e., the highest titer in the BM was reached already on day 1. All three groups showed a comparable maximal viral load of ∼5.6 log10 PFU/femur 3 d after virus inoculation. Thus, under high-dose conditions, absence of the IFN-α/β R favored uncontrolled viral replication maximally in the initial phase of infection, but overall maximal viral loads in BM were not affected by the expression of IFN receptors (note that IFN-α/β R0/0 mice become persistently infected with LCMV but titers are 1–2 log10 lower in the chronic state than the peak virus titer measured on day 3 [21, 41]). The kind of BM cell permissive for LCMV replication was characterized in wild-type, IFN-α/β R0/0, and IFN-γ R0/0 mice at different timepoints after infection (Fig. 5 A). Viral antigen was detected by an LCMV-WE–specific mAb on BM smears; in parallel, the type of infected hematopoietic cell was identified microscopically by cytomorphologic criteria by counterstaining with Meyer's hemalum. The prevalence of LCMVWE–positive morphologically differentiated hematopoietic cells in wild-type and IFN-γ R0/0 mice was low and did not exceed 20% of megakaryocytes and 0.5% of granulocytes at any timepoint of infection (Fig. 5 B). Virtually all detectable LCMV-specific antigen in wild-type and IFN-γ R0/0 mice was confined to stromal BM cells also on day 3, at times when highest LCMV titers were recovered. In contrast, in IFN-α/β R0/0 mice >90% of megakaryocytes were positive for viral antigen 1 d after virus inoculation, ∼60% stained positively on day 3 and ⩽50% of all megakaryocytes remained infected during the following week. In addition, ∼12% predominantly immature myeloid precursors (promyelocytes, myelocytes) of IFN-α/β R0/0 BM exhibited viral antigen peaking on day 3 after LCMV-WE infection (Fig. 5, A and B). In comparison to wild-type and IFN-γ R0/0 mice, stromal BM cells of IFN-α/β R0/0 mice were infected to a comparable extent. Interestingly, erythroblasts were resistant to LCMV-WE infection in all three mouse strains tested, i.e., the frequency of LCMV-positive erythroblasts in IFN-α/β R0/0 mice was less than 1:800.


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)

Time kinetics of virus titers in the BM after infection with  LCMV. Mice were infected intravenously with LCMV-WE (2 × 106  PFU) and virus titers were determined in 106 nucleated BM cells at the  timepoints indicated. Data points are values for individual mice and the  horizontal lines represent the mean of the indicated group.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196026&req=5

Figure 4: Time kinetics of virus titers in the BM after infection with LCMV. Mice were infected intravenously with LCMV-WE (2 × 106 PFU) and virus titers were determined in 106 nucleated BM cells at the timepoints indicated. Data points are values for individual mice and the horizontal lines represent the mean of the indicated group.
Mentions: In vivo susceptibility to LCMV infection of wild-type and IFN R-deficient hematopoietic BM cells was evaluated for a high-dose (2 × 106 PFU) challenge with LCMV-WE. Wild-type and IFN-γ R0/0 mice showed a similar kinetics of LCMV replication with slightly higher titers in IFN-γ R0/0 mice 7 d after infection (Fig. 4). In contrast, IFN-α/β R0/0 mice exhibited an enhanced initial replication, i.e., the highest titer in the BM was reached already on day 1. All three groups showed a comparable maximal viral load of ∼5.6 log10 PFU/femur 3 d after virus inoculation. Thus, under high-dose conditions, absence of the IFN-α/β R favored uncontrolled viral replication maximally in the initial phase of infection, but overall maximal viral loads in BM were not affected by the expression of IFN receptors (note that IFN-α/β R0/0 mice become persistently infected with LCMV but titers are 1–2 log10 lower in the chronic state than the peak virus titer measured on day 3 [21, 41]). The kind of BM cell permissive for LCMV replication was characterized in wild-type, IFN-α/β R0/0, and IFN-γ R0/0 mice at different timepoints after infection (Fig. 5 A). Viral antigen was detected by an LCMV-WE–specific mAb on BM smears; in parallel, the type of infected hematopoietic cell was identified microscopically by cytomorphologic criteria by counterstaining with Meyer's hemalum. The prevalence of LCMVWE–positive morphologically differentiated hematopoietic cells in wild-type and IFN-γ R0/0 mice was low and did not exceed 20% of megakaryocytes and 0.5% of granulocytes at any timepoint of infection (Fig. 5 B). Virtually all detectable LCMV-specific antigen in wild-type and IFN-γ R0/0 mice was confined to stromal BM cells also on day 3, at times when highest LCMV titers were recovered. In contrast, in IFN-α/β R0/0 mice >90% of megakaryocytes were positive for viral antigen 1 d after virus inoculation, ∼60% stained positively on day 3 and ⩽50% of all megakaryocytes remained infected during the following week. In addition, ∼12% predominantly immature myeloid precursors (promyelocytes, myelocytes) of IFN-α/β R0/0 BM exhibited viral antigen peaking on day 3 after LCMV-WE infection (Fig. 5, A and B). In comparison to wild-type and IFN-γ R0/0 mice, stromal BM cells of IFN-α/β R0/0 mice were infected to a comparable extent. Interestingly, erythroblasts were resistant to LCMV-WE infection in all three mouse strains tested, i.e., the frequency of LCMV-positive erythroblasts in IFN-α/β R0/0 mice was less than 1:800.

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