The Human Malaria Parasite
            <i>Pfs47</i>
            Gene Mediates Evasion of the Mosquito Immune System

Molina-Cruz, Alvaro; Garver, Lindsey S.; Alabaster, Amy; Bangiolo, Lois; Haile, Ashley; Winikor, Jared; Ortega, Corrie; Schaijk, Ben C. L. van; Sauerwein, Robert W.; Taylor-Salmon, Emma; Barillas‐Mury, Carolina

doi:10.1126/science.1235264

Cited by 191 publications

(188 citation statements)

References 32 publications

(32 reference statements)

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“…However, we cannot rule out the possibility that other selective pressures have also affected parasite population structuring, for example, widespread deforestation and climate change altering the diversity of Anopheline vectors or evolving host-parasite interactions within mosquito vectors. In P. vivax, a strong New World vs. Old World divide correlates with genetic variation in pvs47, the ortholog of pfs47, which has been associated with differential infectivity in different mosquito species (63,64). However, both Anopheles dirus s.s. and Anopheles minimus s.s., the main malaria vectors in Cambodia, are adept at transmitting both P. falciparum and P. vivax (65,66).…”

Section: Discussionmentioning

confidence: 99%

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Parobek

Lin

Saunders

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cambodia, in which both Plasmodium vivax and Plasmodium falciparum are endemic, has been the focus of numerous malaria-control interventions, resulting in a marked decline in overall malaria incidence. Despite this decline, the number of P. vivax cases has actually increased. To understand better the factors underlying this resilience, we compared the genetic responses of the two species to recent selective pressures. We sequenced and studied the genomes of 70 P. vivax and 80 P. falciparum isolates collected between 2009 and 2013. We found that although P. falciparum has undergone population fracturing, the coendemic P. vivax population has grown undisrupted, resulting in a larger effective population size, no discernable population structure, and frequent multiclonal infections. Signatures of selection suggest recent, species-specific evolutionary differences. Particularly, in contrast to P. falciparum, P. vivax transcription factors, chromatin modifiers, and histone deacetylases have undergone strong directional selection, including a particularly strong selective sweep at an AP2 transcription factor. Together, our findings point to different population-level adaptive mechanisms used by P. vivax and P. falciparum parasites. Although population substructuring in P. falciparum has resulted in clonal outgrowths of resistant parasites, P. vivax may use a nuanced transcriptional regulatory approach to population maintenance, enabling it to preserve a larger, more diverse population better suited to facing selective threats. We conclude that transcriptional control may underlie P. vivax's resilience to malaria control measures. Novel strategies to target such processes are likely required to eradicate P. vivax and achieve malaria elimination.D uring the last decade, western Cambodia has been the focus of numerous and multimodal interventions to control the spread of artemisinin-resistant Plasmodium falciparum (1, 2). Such interventions, including increased vector control, increased surveillance, and improved access to quality artemisinin-combination therapy (ACT), would be expected to curtail coendemic Plasmodium vivax as well. However, even as P. falciparum infections in Cambodia decreased by 81% between 2009 and 2013, P. vivax cases have increased, making it the predominant species in the Mekong region (3-6). This scenario, repeated in Brazil and other areas of coendemicity, has led to growing awareness that P. vivax, although infecting the same populations and transmitted by the same mosquito vectors, will likely be the more challenging species to eradicate (6-9). In this study, we use population genomics to gain insight into the evolutionary factors underlying P. vivax's resilience to malaria control measures.Population genetic studies have previously hinted at the resilience of P. vivax populations in comparison with P. falciparum. Studies of microsatellites and highly variable antigens of sympatric P. vivax and P. falciparum populations in Southeast Asia and the Southwest Pacific have consistently shown P. viv...

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Section: Discussionmentioning

confidence: 99%

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Parobek

Lin

Saunders

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Wild-type (WT) P. falciparum NF54 parasites effectively evade the A. gambiae immune system, and Pfs47 knockout (KO) parasites (NF54 background) are efficiently eliminated by the mosquito complement-like system (33). Silencing TEP1 had no significant effect on the intensity or prevalence of infection with NF54 WT, indicating that this defense system was not actively limiting parasite survival.…”

Section: Significancementioning

confidence: 99%

“…Silencing TEP1 had no significant effect on the intensity or prevalence of infection with NF54 WT, indicating that this defense system was not actively limiting parasite survival. In contrast, reducing TEP1 expression had a dramatic effect on infections with the Pfs47 KO line, greatly increasing parasite survival (33). The presence of Pfs47 suppresses the midgut nitration responses (33), a critical step needed to activate TEP1-mediated lysis (5).…”

Section: Significancementioning

confidence: 99%

“…Recent studies revealed that the P. falciparum Pfs47 gene is critical for malaria transmission, because it allows the parasite to evade the A. gambiae complement-like system and escape unharmed (33). Wild-type (WT) P. falciparum NF54 parasites effectively evade the A. gambiae immune system, and Pfs47 knockout (KO) parasites (NF54 background) are efficiently eliminated by the mosquito complement-like system (33).…”

Section: Significancementioning

confidence: 99%

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Plasmodium falciparum evades mosquito immunity by disrupting JNK-mediated apoptosis of invaded midgut cells

Ramphul

Garver

Molina-Cruz

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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104

102

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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.

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“…Noteworthy, P . falciparum is able to evade this TEP1‐related killing with the help of the surface‐associated Ps47 via suppression of nitration processes involved in the activation of the complement‐like pathway in the mosquito (Molina‐Cruz et al ., 2013). …”

Section: The Effect Of Midgut Factors On Parasite Developmentmentioning

confidence: 99%

The development of malaria parasites in the mosquito midgut

Bennink

Kiesow

Pradel

2016

Cellular Microbiology

157

146

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SummaryThe mosquito midgut stages of malaria parasites are crucial for establishing an infection in the insect vector and to thus ensure further spread of the pathogen. Parasite development in the midgut starts with the activation of the intraerythrocytic gametocytes immediately after take‐up and ends with traversal of the midgut epithelium by the invasive ookinetes less than 24 h later. During this time period, the plasmodia undergo two processes of stage conversion, from gametocytes to gametes and from zygotes to ookinetes, both accompanied by dramatic morphological changes. Further, gamete formation requires parasite egress from the enveloping erythrocytes, rendering them vulnerable to the aggressive factors of the insect gut, like components of the human blood meal. The mosquito midgut stages of malaria parasites are unprecedented objects to study a variety of cell biological aspects, including signal perception, cell conversion, parasite/host co‐adaptation and immune evasion. This review highlights recent insights into the molecules involved in gametocyte activation and gamete formation as well as in zygote‐to‐ookinete conversion and ookinete midgut exit; it further discusses factors that can harm the extracellular midgut stages as well as the measures of the parasites to protect themselves from any damage.

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The Human Malaria Parasite Pfs47 Gene Mediates Evasion of the Mosquito Immune System

Cited by 191 publications

References 32 publications

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

Plasmodium falciparum evades mosquito immunity by disrupting JNK-mediated apoptosis of invaded midgut cells

The development of malaria parasites in the mosquito midgut

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