Junín virus infection of human hematopoietic progenitors impairs in vitro proplatelet formation and platelet release via a bystander effect involving type I IFN signaling

POZNER R.G; URE A; JAQUENOD DE GIUSTI C; D'ATRI LP; ITALIANO JE; TORRES O; ROMANOWSKI V; SCHATTNER M.; GOMEZ RM

PLOS PATHOGENS

PUBLIC LIBRARY SCIENCE

Año: 2010

1553-7366

Argentine hemorrhagic fever (AHF) is an endemo-epidemic disease caused by Junı´n virus (JUNV), a member of thearenaviridae family. Although a recently introduced live attenuated vaccine has proven to be effective, AHF remains apotentially lethal infection. Like in other viral hemorrhagic fevers (VHF), AHF patients present with fever and hemorrhagiccomplications. Although the causes of the bleeding are poorly understood, impaired hemostasis, endothelial celldysfunction and low platelet counts have been described. Thrombocytopenia is a common feature in VHF syndromes, and itis a major sign for its diagnosis. However, the underlying pathogenic mechanism has not yet been elucidated. Wehypothesized that thrombocytopenia results from a viral-triggered alteration of the megakaryo/thrombopoiesis process.Therefore, we evaluated the impact of JUNV on megakaryopoiesis using an in vitro model of human CD34+ cells stimulatedwith thrombopoietin. Our results showed that CD34+ cells are infected with JUNV in a restricted fashion. Infection wastransferrin receptor 1 (TfR1)-dependent and the surface expression of TfR1 was higher in infected cultures, suggesting anovel arenaviral dissemination strategy in hematopoietic progenitor cells. Although proliferation, survival, and commitmentin JUNV-infected cultures were normal, viral infection impaired thrombopoiesis by decreasing in vitro proplatelet formation,platelet release, and P-selectin externalization via a bystander effect. The decrease in platelet release was also TfR1-dependent, mimicked by poly(I:C), and type I interferon (IFN a/b) was implicated as a key paracrine mediator. Among therelevant molecules studied, only the transcription factor NF-E2 showed a moderate decrease in expression inmegakaryocytes from either infected cultures or after type I IFN treatment. Moreover, type I IFN-treated megakaryocytespresented ultrastructural abnormalities resembling the reported thrombocytopenic NF-E22/2 mouse phenotype. Our studyintroduces a potential mechanism for thrombocytopenia in VHF and other diseases associated with increased bone marrowtype I IFN levels.