Disruption of Parasite hmgb2 Gene Attenuates Plasmodium berghei ANKA Pathogenicity.
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.
Sorbonne Universités, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France INSERM, U1135, CIMI-Paris, Paris, France CNRS, ERL 8255, CIMI-Paris, Paris, France sylvie.briquet@upmc.fr catherine.vaquero@upmc.fr.
Sylvie
S
Briquet
Sorbonne Universités, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France INSERM, U1135, CIMI-Paris, Paris, France CNRS, ERL 8255, CIMI-Paris, Paris, France.
Nadou
N
Lawson-Hogban
Unité de Biologie et Génétique du Paludisme, Institut Pasteur, Paris, France.
Bertrand
B
Boisson
Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Miguel P
MP
Soares
Unité de Biologie des Interactions Hôtes Parasites, Institut Pasteur, Paris, France Centre National Scientifique, Unité de Recherche Associée 2581, Paris, France.
Roger
R
Péronet
Unité de Biologie des Interactions Hôtes Parasites, Institut Pasteur, Paris, France Centre National Scientifique, Unité de Recherche Associée 2581, Paris, France.
Leanna
L
Smith
Unité de Biologie et Génétique du Paludisme, Institut Pasteur, Paris, France.
Robert
R
Ménard
Unité de Recherche et Expertises en Histotechnologie et Pathologie, Institut Pasteur, Paris, France Centre National Scientifique, Unité de Recherche Associée 2581, Paris, France.
Michel
M
Huerre
Unité de Biologie des Interactions Hôtes Parasites, Institut Pasteur, Paris, France Centre National Scientifique, Unité de Recherche Associée 2581, Paris, France.
Salah
S
Mécheri
Sorbonne Universités, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France INSERM, U1135, CIMI-Paris, Paris, France CNRS, ERL 8255, CIMI-Paris, Paris, France sylvie.briquet@upmc.fr catherine.vaquero@upmc.fr.
Catherine
C
Vaquero
D000818:Animals; D001921:Brain / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D024261:HMGB2 Protein / Q000235:genetics / Q000378:metabolism*; D006651:Histocytochemistry; D016779:Malaria, Cerebral / Q000469:parasitology* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology; D010962:Plasmodium berghei / Q000235:genetics / Q000472:pathogenicity*; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D024261:HMGB2 Protein; D037521:Virulence Factors