Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.7/391
Título: Disruption of Parasite hmgb2 Gene Attenuates Plasmodium berghei ANKA Pathogenicity
Autor: Briquet, Sylvie
Lawson-Hogban, Nadou
Boisson, Bertrand
Soares, Miguel P
Péronet, Roger
Smith, Leanna
Ménard, Robert
Huerre, Michel
Mécheri, Salah
Vaquero, Catherine
Palavras-chave: Plasmodium
Data: Jul-2015
Editora: American Society for Microbiology
Citação: Briquet S, Lawson-Hogban N, Boisson B, Soares MP, Péronet R, Smith L, Ménard R, Huerre M, Mécheri S, Vaquero C. 2015. Disruption of parasite hmgb2 gene attenuates Plasmodium berghei ANKA pathogenicity. Infect Immun 83:2771–2784. doi:10.1128/IAI.03129-14.
Resumo: Eukaryotic high-mobility-group-box (HMGB) proteins are nuclear factors involved in chromatin remodeling and transcription regulation. When released into the extracellular milieu, HMGB1 acts as a proinflammatory cytokine that plays a central role in the pathogenesis of several immune-mediated inflammatory diseases. We found that the Plasmodium genome encodes two genuine HMGB factors, Plasmodium HMGB1 and HMGB2, that encompass, like their human counterparts, a proinflammatory domain. Given that these proteins are released from parasitized red blood cells, we then hypothesized that Plasmodium HMGB might contribute to the pathogenesis of experimental cerebral malaria (ECM), a lethal neuroinflammatory syndrome that develops in C57BL/6 (susceptible) mice infected with Plasmodium berghei ANKA and that in many aspects resembles human cerebral malaria elicited by P. falciparum infection. The pathogenesis of experimental cerebral malaria was suppressed in C57BL/6 mice infected with P. berghei ANKA lacking the hmgb2 gene (Δhmgb2 ANKA), an effect associated with a reduction of histological brain lesions and with lower expression levels of several proinflammatory genes. The incidence of ECM in pbhmgb2-deficient mice was restored by the administration of recombinant PbHMGB2. Protection from experimental cerebral malaria in Δhmgb2 ANKA-infected mice was associated with reduced sequestration in the brain of CD4(+) and CD8(+) T cells, including CD8(+) granzyme B(+) and CD8(+) IFN-γ(+) cells, and, to some extent, neutrophils. This was consistent with a reduced parasite sequestration in the brain, lungs, and spleen, though to a lesser extent than in wild-type P. berghei ANKA-infected mice. In summary, Plasmodium HMGB2 acts as an alarmin that contributes to the pathogenesis of cerebral malaria.
Peer review: yes
URI: http://hdl.handle.net/10400.7/391
DOI: 10.1128/IAI.03129-14
Versão do Editor: http://iai.asm.org/content/83/7/2771.long
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