Virus-induced Transient Bone Marrow Aplasia: Major Role of Interferon-α/β during Acute Infection with the Noncytopathic Lymphocytic Choriomeningitis Virus

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)-α/β responder ability and in mutant mice lacking α/β (IFN-α/β R0/0) or γ IFN (IFN-γ 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-α/β responder phenotype. Whereas IFN-γ R0/0 mice were comparable to wild-type mice, IFN-α/β 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-γ R0/0, but remained unchanged in IFN-α/β 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-γ R0/0 knockouts, whereas, in IFN-α/β R0/0 mice, LCMV was detected in >90% of megakaryocytes and 10–15% of myeloid precursors, but not in erythroblasts. Although IFN-α/β efficiently prevented viral replication in potentially susceptible hematopoietic cells, even in overwhelming LCMV infection, unlimited virus multiplication in platelet and myeloid precursors in IFN-α/β 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 CD80/0 and CD40/0 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-γ from virally induced NK cells but was a direct effect of IFN-α/β.

Mechanisms of self-renewal in hematopoietic stem cells

“…In addition to molecules that maintain the G0 state or support self-renewal in HSCs, molecules are desired that drive HSCs into the cell cycle or revert HSCs back to the G0 state IFN-γ was also found to stimulate quiescent HSCs in vivo [72]. However, the culture of highly purified HSCs in vitro showed the suppressive effect of IFN-γ, and virus infection induced a delayed recovery of the HSC pool [73], consistent with in vitro culture data with progenitor cells [64,67]. More recently, Pietras et al attempted to clarify this paradoxical effect of IFN on HSCs.…”

“…IFN-γ could markedly reduce the number of B cells and myeloid progenitors in the bone marrow and spleen [67]. In contrast, IFN-α/β receptor inactivation in mice showed minor change in the progenitor cell number [64]. Recently, a positive effect of IFN signaling on HSCs was reported [68,69].…”

“…Interferon (IFN) is a cytokine produced primarily in response to tumor cells or infection, especially viral infection [64]. In vitro studies demonstrated that IFN can suppress myeloid [65] or erythroid [66] colony formation.…”

Anti-inflammatory action of type I interferons deduced from mice expressing interferon β

“…26,27,34,35 Among type I IFNs, IFN-␤ has potent antiproliferative activity against most human tumor cells in vitro in addition to its known immunomodulatory activities. [36][37][38][39][40] For these reasons, the availability of an animal model expressing IFN-␤ might help to understand the biological properties of this cyto- …”

“…These data reinforce the view of an impaired macrophage activation in those situations in which type I IFN synthesis occurs, for example, after viral infection, or in patients treated pharmacologically with IFN-␤, such as those suffering multiple sclerosis. 26,27 Results Increased macrophage extravasation in animals carrying a hIFN-␤ transgene To study the potential role of IFN-␤ in counteracting macrophage activation, we used a transgenic animal model that expressed human IFN-␤ specifically in pancreatic ␤-cells. 25 These animals had a CD-1 genetic background, since they were obtained by backcrossing C57/Bl6/SJL transgenic mice (RIP-I/hIFN-␤ transgene) to CD-1 mice.…”