The 20-hydroxyecdysone agonist, halofenozide, promotes anti-Plasmodium immunity in Anopheles gambiae via the ecdysone receptor

AbstractMosquito physiology and immunity are integral determinants of malaria vector competence. This includes the principal role of hormonal signaling in Anopheles gambiae initiated shortly after blood-feeding, which stimulates immune induction and promotes vitellogenesis through the function of 20-hydroxyecdysone (20E). Previous studies demonstrated that manipulating 20E signaling through the direct injection of 20E or the application of a 20E agonist can significantly impact Plasmodium infection outcomes, reducing oocyst numbers and the potential for malaria transmission. In support of these findings, we demonstrate that a 20E agonist, halofenozide, is able to induce anti-Plasmodium immune responses that limit Plasmodium ookinetes. We demonstrate that halofenozide requires the function of ultraspiracle (USP), a component of the canonical heterodimeric ecdysone receptor, to induce malaria parasite killing responses. Additional experiments suggest that the effects of halofenozide treatment are temporal, such that its application only limits malaria parasites when applied prior to infection. Unlike 20E, halofenozide does not influence cellular immune function or AMP production. Together, our results further demonstrate the potential of targeting 20E signaling pathways to reduce malaria parasite infection in the mosquito vector and provide new insight into the mechanisms of halofenozide-mediated immune activation that differ from 20E.

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The 20-hydroxyecdysone agonist, halofenozide, promotes anti-Plasmodium immunity in Anopheles gambiae via the ecdysone receptor

10.1101/2020.06.19.162081 ◽

2020 ◽

Author(s):

Rebekah A. Reynolds ◽

Hyeogsun Kwon ◽

Thiago Luiz Alves e Silva ◽

Janet Olivas ◽

Joel Vega-Rodriguez ◽

...

Keyword(s):

Anopheles Gambiae ◽

Malaria Parasite ◽

Vector Competence ◽

Direct Injection ◽

Blood Feeding ◽

Mosquito Vector ◽

Ecdysone Receptor ◽

Principal Role ◽

Cellular Immune

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20-Hydroxyecdysone Primes Innate Immune Responses That Limit Bacterial and Malarial Parasite Survival in Anopheles gambiae

mSphere ◽

10.1128/msphere.00983-19 ◽

2020 ◽

Vol 5 (2) ◽

Cited By ~ 5

Author(s):

Rebekah A. Reynolds ◽

Hyeogsun Kwon ◽

Ryan C. Smith

Keyword(s):

Immune Function ◽

Anopheles Gambiae ◽

Blood Meal ◽

Egg Production ◽

Blood Feeding ◽

Innate Immune ◽

Content Type ◽

Innate Immune Function ◽

Cellular Immune Function ◽

Cellular Immune

ABSTRACT Blood feeding is an integral behavior of mosquitoes to acquire nutritional resources needed for reproduction. This requirement also enables mosquitoes to serve as efficient vectors to acquire and potentially transmit a multitude of mosquito-borne diseases, most notably malaria. Recent studies suggest that mosquito immunity is stimulated following a blood meal, independent of infection status. Since blood feeding promotes production of the hormone 20-hydroxyecdysone (20E), we hypothesized that 20E plays an important role in priming the immune response for pathogen challenge. Here, we examine the immunological effects of priming Anopheles gambiae with 20E prior to pathogen infection, demonstrating a significant reduction in bacteria and Plasmodium berghei survival in the mosquito host. Transcriptome sequencing (RNA-seq) analysis following 20E treatment identifies several known 20E-regulated genes, as well as several immune genes with previously reported function in antipathogen defense. Together, these data demonstrate that 20E influences cellular immune function and antipathogen immunity following mosquito blood feeding, arguing the importance of hormones in the regulation of mosquito innate immune function. IMPORTANCE Blood feeding is required to provide nutrients for mosquito egg production and serves as a mechanism to acquire and transmit pathogens. Shortly after a blood meal is taken, there is a peak in the production of 20-hydroxyecdysone (20E), a mosquito hormone that initiates physiological changes, including yolk protein production and mating refractoriness. Here, we examine additional roles of 20E in the regulation of mosquito immunity, demonstrating that priming the immune system with 20E increases mosquito resistance to pathogens. We identify differentially expressed genes in response to 20E treatment, including several involved in innate immune function as well as lipid metabolism and transport. Together, these data argue that 20E stimulates mosquito cellular immune function and innate immunity shortly after blood feeding.

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The malaria parasite, Plasmodium falciparum, increases the frequency of multiple feeding of its mosquito vector, Anopheles gambiae

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.1998.0358 ◽

1998 ◽

Vol 265 (1398) ◽

pp. 763-768 ◽

Cited By ~ 158

Author(s):

J.C. Koella ◽

F.L. Sørensen ◽

R.A. Anderson

Keyword(s):

Plasmodium Falciparum ◽

Anopheles Gambiae ◽

Malaria Parasite ◽

Mosquito Vector ◽

Parasite Plasmodium ◽

Parasite Plasmodium Falciparum ◽

Multiple Feeding

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The Role of Temperature in Transmission of Zoonotic Arboviruses

Viruses ◽

10.3390/v11111013 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1013 ◽

Cited By ~ 7

Author(s):

Ciota ◽

Keyel

Keyword(s):

Climate Change ◽

Life History ◽

Indirect Effects ◽

Temperature Effects ◽

Life History Traits ◽

Vector Competence ◽

Adult Life ◽

Blood Feeding ◽

Population Vector

We reviewed the literature on the role of temperature in transmission of zoonotic arboviruses. Vector competence is affected by both direct and indirect effects of temperature, and generally increases with increasing temperature, but results may vary by vector species, population, and viral strain. Temperature additionally has a significant influence on life history traits of vectors at both immature and adult life stages, and for important behaviors such as blood-feeding and mating. Similar to vector competence, temperature effects on life history traits can vary by species and population. Vector, host, and viral distributions are all affected by temperature, and are generally expected to change with increased temperatures predicted under climate change. Arboviruses are generally expected to shift poleward and to higher elevations under climate change, yet significant variability on fine geographic scales is likely. Temperature effects are generally unimodal, with increases in abundance up to an optimum, and then decreases at high temperatures. Improved vector distribution information could facilitate future distribution modeling. A wide variety of approaches have been used to model viral distributions, although most research has focused on the West Nile virus. Direct temperature effects are frequently observed, as are indirect effects, such as through droughts, where temperature interacts with rainfall. Thermal biology approaches hold much promise for syntheses across viruses, vectors, and hosts, yet future studies must consider the specificity of interactions and the dynamic nature of evolving biological systems.

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The Peptidoglycan Recognition Proteins PGRPLA and PGRPLB Regulate Anopheles Immunity to Bacteria and Affect Infection by Plasmodium

Journal of Innate Immunity ◽

10.1159/000452797 ◽

2017 ◽

Vol 9 (4) ◽

pp. 333-342 ◽

Cited By ~ 16

Author(s):

Mathilde Gendrin ◽

Fanny Turlure ◽

Faye H. Rodgers ◽

Anna Cohuet ◽

Isabelle Morlais ◽

...

Keyword(s):

Immune Deficiency ◽

Rna Interference ◽

Plasmodium Berghei ◽

Vector Competence ◽

Blood Feeding ◽

Plasmodium Infection ◽

Imd Pathway ◽

Vector Mosquito ◽

Epithelial Immunity

Peptidoglycan recognition proteins (PGRPs) form a family of immune regulators that is conserved from insects to mammals. In the malaria vector mosquito Anophelescoluzzii, the peptidoglycan receptor PGRPLC activates the immune-deficiency (Imd) pathway limiting both the microbiota load and Plasmodium infection. Here, we carried out an RNA interference screen to examine the role of all 7 Anopheles PGRPs in infections with Plasmodium berghei and P. falciparum. We show that, in addition to PGRPLC, PGRPLA and PGRPS2/PGRPS3 also participate in antiparasitic defenses, and that PGRPLB promotes mosquito permissiveness to P. falciparum. We also demonstrate that following a mosquito blood feeding, which promotes growth of the gut microbiota, PGRPLA and PGRPLB positively and negatively regulate the activation of the Imd pathway, respectively. Our data demonstrate that PGRPs are important regulators of the mosquito epithelial immunity and vector competence.

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20-hydroxyecdysone (20E) primes innate immune responses that limit bacteria and malaria parasite survival in Anopheles gambiae

10.1101/818526 ◽

2019 ◽

Author(s):

Rebekah A. Reynolds ◽

Hyeogsun Kwon ◽

Ryan C. Smith

Keyword(s):

Immune Function ◽

Anopheles Gambiae ◽

Blood Feeding ◽

Innate Immune ◽

Innate Immune Responses ◽

Temporal Regulation ◽

Immune Genes ◽

Pathogen Challenge ◽

Immunological Effects ◽

Cellular Immune

AbstractBlood-feeding is an integral behavior of mosquitoes to acquire nutritional resources needed for reproduction. This requirement also enables mosquitoes to serve as efficient vectors to acquire and potentially transmit a multitude of mosquito-borne diseases, most notably malaria. Recent studies suggest that mosquito immunity is stimulated following a blood meal, independent of infection status. Since blood-feeding results in the increased production of the hormone 20-hydroxyecdysone (20E), we hypothesized that 20E may play an important role in priming the immune response for pathogen challenge. Herein, we examine the immunological effects of priming in Anopheles gambiae with 20E prior to pathogen infection, demonstrating a significant reduction in bacteria and Plasmodium berghei survival in the mosquito host. RNA-seq analysis following 20E treatment identifies several known 20E-regulated genes, as well as several immune genes with previously reported function in anti-pathogen defense. This includes the anti-microbial peptide cecropin 3, which we demonstrate its role as an antagonist of bacteria and Plasmodium in Anopheles gambiae and provide support that these responses are under temporal regulation. Together, these data demonstrate that 20E influences cellular immune function and anti-pathogen immunity following mosquito blood-feeding, arguing the importance of hormones in the regulation of mosquito innate immune function.

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The native European Aedes geniculatus mosquito species can transmit Chikungunya virus

10.1101/527382 ◽

2019 ◽

Author(s):

Jorian Prudhomme ◽

Albin Fontaine ◽

Guillaume Lacour ◽

Jean-Charles Gantier ◽

Laure Diancourt ◽

...

Keyword(s):

Chikungunya Virus ◽

Vector Competence ◽

Mosquito Species ◽

Cumulative Distribution ◽

Mosquito Vector ◽

Indigenous Species ◽

Chikv Infection ◽

Invasive Mosquito ◽

Virus Emergence

AbstractEurope is the world’s leading tourism destination and is receiving every year travelers from areas with active arbovirus transmission. There is thus a threat of mosquito-borne virus emergence in Europe due to the presence of the invasive mosquito vector Aedes albopictus. Little attention has been paid about the possible role of indigenous mosquito species as vectors of emerging arboviruses. Here, we assessed the vector competence dynamic of Ae. geniculatus, a European anthropophilic mosquito species, for chikungunya virus (CHIKV) in comparison with Ae. albopictus.We revealed that Ae. geniculatus was highly susceptible to CHIKV infection and could transmit the virus. By specifically exploring the vector competence dynamic in both mosquito species, we revealed that the cumulative distribution of CHIKV incubation period in Ae. geniculatus was delayed by several days as compared to Ae. albopictus.Our results strengthen the importance of considering indigenous species as potential vectors for emerging arboviruses. They also revealed the importance of considering variation in arbovirus dissemination or transmission dynamics in mosquitoes when performing vector competence assays. We will discuss the implications of our results on a CHIKV outbreak dynamic in a theoretical framework.Sentence summaryThe European mosquito Aedes geniculatus is highly susceptible to CHIKV infection but disseminate and transmit the virus several days later than Ae. albopictus.

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Chemical depletion of phagocytic immune cells inAnopheles gambiaereveals dual roles of mosquito hemocytes in anti-Plasmodiumimmunity

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1900147116 ◽

2019 ◽

Vol 116 (28) ◽

pp. 14119-14128 ◽

Cited By ~ 14

Author(s):

Hyeogsun Kwon ◽

Ryan C. Smith

Keyword(s):

Immune Cells ◽

Vector Competence ◽

Morphological Characteristics ◽

Innate Immune ◽

Parasite Development ◽

Mosquito Vector ◽

Dual Roles ◽

Humoral Factors ◽

Innate Immune Signaling

Mosquito immunity is composed of both cellular and humoral factors that provide protection from invading pathogens. Immune cells known as hemocytes, have been intricately associated with phagocytosis and innate immune signaling. However, the lack of genetic tools has limited hemocyte study despite their importance in mosquito anti-Plasmodiumimmunity. To address these limitations, we employ the use of a chemical-based treatment to deplete phagocytic immune cells inAnopheles gambiae,demonstrating the role of phagocytes in complement recognition and prophenoloxidase production that limit the ookinete and oocyst stages of malaria parasite development, respectively. Through these experiments, we also define specific subtypes of phagocytic immune cells inAn. gambiae, providing insights beyond the morphological characteristics that traditionally define mosquito hemocyte populations. Together, this study represents a significant advancement in our understanding of the roles of mosquito phagocytes in mosquito vector competence and demonstrates the utility of clodronate liposomes as an important tool in the study of invertebrate immunity.

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The Coming-Out of Malaria Gametocytes

Journal of Biomedicine and Biotechnology ◽

10.1155/2010/976827 ◽

2010 ◽

Vol 2010 ◽

pp. 1-11 ◽

Cited By ~ 58

Author(s):

Andrea Kuehn ◽

Gabriele Pradel

Keyword(s):

Coming Out ◽

Molecular Mechanisms ◽

Blood Feeding ◽

Tropical Disease ◽

Mosquito Vector ◽

Rapid Adjustment ◽

Sexual Stages ◽

Crucial Part ◽

Anopheline Mosquitoes

The tropical disease malaria, which results in more than one million deaths annually, is caused by protozoan parasites of the genusPlasmodiumand transmitted by blood-feeding Anopheline mosquitoes. Parasite transition from the human host to the mosquito vector is mediated by gametocytes, sexual stages that are formed in human erythrocytes, which therefore play a crucial part in the spread of the tropical disease. The uptake by the blood-feeding mosquito triggers important molecular and cellular changes in the gametocytes, thus mediating the rapid adjustment of the parasite from the warm-blooded host to the insect host and subsequently initiating reproduction. The contact with midgut factors triggers gametocyte activation and results in their egress from the enveloping erythrocyte, which then leads to gamete formation and fertilization. This review summarizes recent findings on the role of gametocytes during transmission to the mosquito and particularly focuses on the molecular mechanisms underlying gametocyte activation and emergence from the host erythrocyte during gametogenesis.

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Infection of Mammals and Mosquitoes by Alphaviruses: Involvement of Cell Death

Cells ◽

10.3390/cells9122612 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2612

Author(s):

Lucie Cappuccio ◽

Carine Maisse

Keyword(s):

Cell Death ◽

Current Knowledge ◽

Blood Feeding ◽

Mosquito Vector ◽

Global Public Health ◽

Emerging Viruses ◽

Pathological Effect ◽

Host Interactions ◽

Regulated Cell Death

Alphaviruses, such as the chikungunya virus, are emerging and re-emerging viruses that pose a global public health threat. They are transmitted by blood-feeding arthropods, mainly mosquitoes, to humans and animals. Although alphaviruses cause debilitating diseases in mammalian hosts, it appears that they have no pathological effect on the mosquito vector. Alphavirus/host interactions are increasingly studied at cellular and molecular levels. While it seems clear that apoptosis plays a key role in some human pathologies, the role of cell death in determining the outcome of infections in mosquitoes remains to be fully understood. Here, we review the current knowledge on alphavirus-induced regulated cell death in hosts and vectors and the possible role they play in determining tolerance or resistance of mosquitoes.

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