INVESTIGADORES
D'ATRI Lina Paola
artículos
Título:
Junin virus infection of human hematopoietic progenitors impairs in vitro proplatelet formation and platelet release via a bystander effect involving type IFN I signaling
Autor/es:
POZNER RG; URE A; JAQUENOD DE GIUSTI C; D'ATRI LP; ITALIANO JE; TORRES O; SCHATTNER M; GÓMEZ RM,
Revista:
PLOS PATHOGENS
Editorial:
PUBLIC LIBRARY SCIENCE
Referencias:
Año: 2010 vol. 6 p. 1 - 14
ISSN:
1553-7366
Resumen:
Argentine hemorrhagic fever (AHF) is an endemo-epidemic disease caused
by Jun¨ªn virus (JUNV), a member of the arenaviridae family. Although a recently
introduced live attenuated vaccine has proven to be effective, AHF remains a
potentially lethal infection, and JUNV is considered to be a potential biological
weapon. Like in other viral hemorrhagic fevers (VHF), AHF patients present with
fever and hemorrhagic complications. Although the causes of the bleeding are
poorly understood, impaired hemostasis, endothelial cell dysfunction and low
platelet counts have been described. Thrombocytopenia is a common feature not
only in patients with AHF but also in other VHF syndromes, and it is a major sign
for its diagnosis. However, the underlying pathogenic mechanism has not yet been
elucidated. We hypothesized 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+
introduced live attenuated vaccine has proven to be effective, AHF remains a
potentially lethal infection, and JUNV is considered to be a potential biological
weapon. Like in other viral hemorrhagic fevers (VHF), AHF patients present with
fever and hemorrhagic complications. Although the causes of the bleeding are
poorly understood, impaired hemostasis, endothelial cell dysfunction and low
platelet counts have been described. Thrombocytopenia is a common feature not
only in patients with AHF but also in other VHF syndromes, and it is a major sign
for its diagnosis. However, the underlying pathogenic mechanism has not yet been
elucidated. We hypothesized 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+
arenaviridae family. Although a recently
introduced live attenuated vaccine has proven to be effective, AHF remains a
potentially lethal infection, and JUNV is considered to be a potential biological
weapon. Like in other viral hemorrhagic fevers (VHF), AHF patients present with
fever and hemorrhagic complications. Although the causes of the bleeding are
poorly understood, impaired hemostasis, endothelial cell dysfunction and low
platelet counts have been described. Thrombocytopenia is a common feature not
only in patients with AHF but also in other VHF syndromes, and it is a major sign
for its diagnosis. However, the underlying pathogenic mechanism has not yet been
elucidated. We hypothesized 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+in vitro model of human CD34+
cells stimulated with thrombopoietin. Our results showed that CD34+ cells are
infected with JUNV in a restricted fashion. Infection was transferrin receptor 1
(TfR1)-dependent and the surface expression of TfR1 was higher in infected
cultures, suggesting a novel arenaviral dissemination strategy in hematopoietic
progenitor cells. Although proliferation, survival, and commitment in 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 ¦Á/¦Â) was implicated as a key
paracrine mediator. Among the relevant molecules studied, only the transcription
factor NF-E2 showed a moderate decrease in expression in megakaryocytes from
3
either infected cultures or after type I IFN treatment. Moreover, type I IFN-treated
megakaryocytes presented ultrastructural abnormalities resembling the reported
thrombocytopenic NF-E2-/- mouse phenotype.
Our study introduces a potential mechanism for thrombocytopenia in VHF
and other diseases associated with increased bone marrow type I IFN levels.
Our study introduces a potential mechanism for thrombocytopenia in VHF
and other diseases associated with increased bone marrow type I IFN levels.
paracrine mediator. Among the relevant molecules studied, only the transcription
factor NF-E2 showed a moderate decrease in expression in megakaryocytes from
3
either infected cultures or after type I IFN treatment. Moreover, type I IFN-treated
megakaryocytes presented ultrastructural abnormalities resembling the reported
thrombocytopenic NF-E2-/- mouse phenotype.
Our study introduces a potential mechanism for thrombocytopenia in VHF
and other diseases associated with increased bone marrow type I IFN levels.
Our study introduces a potential mechanism for thrombocytopenia in VHF
and other diseases associated with increased bone marrow type I IFN levels.
bystander effect. The decrease in platelet release was also TfR1-dependent,
mimicked by poly(I:C), and type I interferon (IFN ¦Á/¦Â) was implicated as a key
paracrine mediator. Among the relevant molecules studied, only the transcription
factor NF-E2 showed a moderate decrease in expression in megakaryocytes from
3
either infected cultures or after type I IFN treatment. Moreover, type I IFN-treated
megakaryocytes presented ultrastructural abnormalities resembling the reported
thrombocytopenic NF-E2-/- mouse phenotype.
Our study introduces a potential mechanism for thrombocytopenia in VHF
and other diseases associated with increased bone marrow type I IFN levels.
Our study introduces a potential mechanism for thrombocytopenia in VHF
and other diseases associated with increased bone marrow type I IFN levels.