title: Plasmodium falciparum evades mosquito immunity by disrupting JNK-mediated apoptosis of invaded midgut cells.
abstract: The malaria parasite, Plasmodium, must survive and develop in the mosquito vector to be successfully transmitted to a new host. The Plasmodium falciparum Pfs47 gene is critical for malaria transmission. Parasites that express Pfs47 (NF54 WT) evade mosquito immunity and survive, whereas Pfs47 knockouts (KO) are efficiently eliminated by the complement-like system. Two alternative approaches were used to investigate the mechanism of action of Pfs47 on immune evasion. First, we examined whether Pfs47 affected signal transduction pathways mediating mosquito immune responses, and show that the Jun-N-terminal kinase (JNK) pathway is a key mediator of Anopheles gambiae antiplasmodial responses to P. falciparum infection and that Pfs47 disrupts JNK signaling. Second, we used microarrays to compare the global transcriptional responses of A. gambiae midguts to infection with WT and KO parasites. The presence of Pfs47 results in broad and profound changes in gene expression in response to infection that are already evident 12 h postfeeding, but become most prominent at 26 h postfeeding, the time when ookinetes invade the mosquito midgut. Silencing of 15 differentially expressed candidate genes identified caspase-S2 as a key effector of Plasmodium elimination in parasites lacking Pfs47. We provide experimental evidence that JNK pathway regulates activation of caspases in Plasmodium-invaded midgut cells, and that caspase activation is required to trigger midgut epithelial nitration. Pfs47 alters the cell death pathway of invaded midgut cells by disrupting JNK signaling and prevents the activation of several caspases, resulting in an ineffective nitration response that makes the parasite undetectable by the mosquito complement-like system.
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
authors.forename: Urvashi N
authors.initials: UN
authors.lastname: Ramphul
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
authors.forename: Lindsey S
authors.initials: LS
authors.lastname: Garver
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Molina-Cruz
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
authors.forename: Gaspar E
authors.initials: GE
authors.lastname: Canepa
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852 cbarillas@niaid.nih.gov.
authors.forename: Carolina
authors.initials: C
authors.lastname: Barillas-Mury
mesh_terms: D000818:Animals; D000852:Anopheles / Q000276:immunology* / Q000469:parasitology; D017209:Apoptosis / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D010963:Plasmodium falciparum / Q000235:genetics / Q000502:physiology*; D015800:Protozoan Proteins / Q000235:genetics / Q000502:physiology
chemical_list: D008562:Membrane Glycoproteins; C526772:Pfs47 protein, Plasmodium falciparum; D015800:Protozoan Proteins; D048670:MAP Kinase Kinase 4
keywords: JNK apoptosis; Plasmodium; immune evasion; malaria transmission; mosquito immunity