Disruption of Parasite hmgb2 Gene Attenuates Plasmodium berghei ANKA Pathogenicity

Briquet, Sylvie; Lawson-Hogban, Nadou; Boisson, Bertrand; Soares, Miguel P; Péronet, Roger; Smith, Leanna; Ménard, Robert; Huerre, Michel; Mécheri, Salah; Vaquero, Catherine

Publication

Disruption of Parasite hmgb2 Gene Attenuates Plasmodium berghei ANKA Pathogenicity

2015-07Journal article

dc.contributor.author	Briquet, Sylvie
dc.contributor.author	Lawson-Hogban, Nadou
dc.contributor.author	Boisson, Bertrand
dc.contributor.author	Soares, Miguel P
dc.contributor.author	Péronet, Roger
dc.contributor.author	Smith, Leanna
dc.contributor.author	Ménard, Robert
dc.contributor.author	Huerre, Michel
dc.contributor.author	Mécheri, Salah
dc.contributor.author	Vaquero, Catherine
dc.date.accessioned	2015-10-13T10:55:51Z
dc.date.available	2015-10-13T10:55:51Z
dc.date.issued	2015-07
dc.description.abstract	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.	pt_PT
dc.description.sponsorship	Pitié-Salpêtrière, Institut Pasteur (Paris).	pt_PT
dc.identifier	10.1128/IAI.03129-14
dc.identifier.citation	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.	pt_PT
dc.identifier.doi	10.1128/IAI.03129-14
dc.identifier.uri	http://hdl.handle.net/10400.7/391
dc.language.iso	eng	pt_PT
dc.peerreviewed	yes	pt_PT
dc.publisher	American Society for Microbiology	pt_PT
dc.relation.publisherversion	http://iai.asm.org/content/83/7/2771.long	pt_PT
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/	pt_PT
dc.subject	Plasmodium	pt_PT
dc.title	Disruption of Parasite hmgb2 Gene Attenuates Plasmodium berghei ANKA Pathogenicity	pt_PT
dc.type	journal article
dspace.entity.type	Publication
oaire.citation.endPage	2784	pt_PT
oaire.citation.issue	7	pt_PT
oaire.citation.startPage	2771	pt_PT
oaire.citation.title	Infection and Immunity	pt_PT
oaire.citation.volume	83	pt_PT
rcaap.rights	openAccess	pt_PT
rcaap.type	article	pt_PT