The antimicrobial molecule trappin-2/elafin has anti-parasitic properties and is protective in vivo in a murine model of cerebral malaria.
According to the WHO, and despite reduction in mortality rates, there were an estimated 438 000 malaria deaths in 2015. Therefore new antimalarials capable of limiting organ damage are still required. We show that systemic and lung adenovirus (Ad)-mediated over-expression of trappin-2 (T-2) an antibacterial molecule with anti-inflammatory activity, increased mice survival following infection with the cerebral malaria-inducing Plasmodium berghei ANKA (PbANKA) strain. Systemically, T-2 reduced PbANKA sequestration in spleen, lung, liver and brain, associated with a decrease in pro-inflammatory cytokines (eg TNF-α in spleen and lung) and an increase in IL-10 production in the lung. Similarly, local lung instillation of Ad-T-2 resulted in a reduced organ parasite sequestration and a shift towards an anti-inflammatory/repair response, potentially implicating monocytes in the protective phenotype. Relatedly, we demonstrated in vitro that human monocytes incubated with Plasmodium falciparum-infected red blood cells (Pf-iRBCs) and IgGs from hyper-immune African human sera produced T-2 and that the latter colocalized with merozoites and inhibited Pf multiplication. This array of data argues for the first time for the potential therapeutic usefulness of this host defense peptide in human malaria patients, with the aim to limit acute lung injury and respiratory distress syndrom often observed during malaria episodes.
Unité de génétique fonctionnelle des maladies infectieuses and CNRS Unité de recherche associée 3012; Paris, 75015, France.
Christian
C
Roussilhon
Unité de génétique fonctionnelle des maladies infectieuses and CNRS Unité de recherche associée 3012; Paris, 75015, France.
Gilles
G
Bang
Unité de Défense Innée et Inflammation, Institut Pasteur, 25 rue du Dr Roux, Paris, 75015, France.|INSERM U874, Institut Pasteur.|INSERM U1152, Faculté de Médicine site Bichat, Université Paris Diderot, Université Sorbonne Paris-Cité, 16, rue Henri Huchard, Paris, 75018, France.
Fabien
F
Bastaert
Unité de Défense Innée et Inflammation, Institut Pasteur, 25 rue du Dr Roux, Paris, 75015, France.|INSERM U874, Institut Pasteur.|INSERM U1152, Faculté de Médicine site Bichat, Université Paris Diderot, Université Sorbonne Paris-Cité, 16, rue Henri Huchard, Paris, 75018, France.
Brigitte
B
Solhonne
Unité de Défense Innée et Inflammation, Institut Pasteur, 25 rue du Dr Roux, Paris, 75015, France.|INSERM U874, Institut Pasteur.|INSERM U1152, Faculté de Médicine site Bichat, Université Paris Diderot, Université Sorbonne Paris-Cité, 16, rue Henri Huchard, Paris, 75018, France.
Ignacio
I
Garcia-Verdugo
Institut Pasteur, Unité de Biologie des Interactions Hôte Parasites, CNRS ERL9195 and INSERM U1201, Paris F-75015, France.|CNRS ERL9195 and INSERM U1201, Paris F-75015, France.|INSERM U1201, Paris F-75015, France.
Roger
R
Peronet
TheVac4all initiative, Institut Cochin, Paris, France.
Pierre
P
Druilhe
Unité de génétique fonctionnelle des maladies infectieuses and CNRS Unité de recherche associée 3012; Paris, 75015, France.
Anavaj
A
Sakuntabhai
Institut Pasteur, Unité de Biologie des Interactions Hôte Parasites, CNRS ERL9195 and INSERM U1201, Paris F-75015, France.|CNRS ERL9195 and INSERM U1201, Paris F-75015, France.|INSERM U1201, Paris F-75015, France.
Salaheddine
S
Mecheri
Unité de Défense Innée et Inflammation, Institut Pasteur, 25 rue du Dr Roux, Paris, 75015, France.|INSERM U874, Institut Pasteur.|INSERM U1152, Faculté de Médicine site Bichat, Université Paris Diderot, Université Sorbonne Paris-Cité, 16, rue Henri Huchard, Paris, 75018, France.
Jean-Michel
JM
Sallenave
D000281:Administration, Intranasal; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000977:Antiparasitic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D053492:Elafin / Q000494:pharmacology / Q000627:therapeutic use*; D004912:Erythrocytes / Q000469:parasitology; D005260:Female; D006801:Humans; D016779:Malaria, Cerebral / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology*; D052940:Merozoites / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology / Q000473:pathology; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000254:growth & development; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
D000890:Anti-Infective Agents; D000977:Antiparasitic Agents; D016207:Cytokines; D053492:Elafin; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor