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1.
PLoS Biol ; 20(1): e3001515, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35025886

RESUMO

Anopheles gambiae melanization-based refractoriness to the human malaria parasite Plasmodium falciparum has rarely been observed in either laboratory or natural conditions, in contrast to the rodent model malaria parasite Plasmodium berghei that can become completely melanized by a TEP1 complement-like system-dependent mechanism. Multiple studies have shown that the rodent parasite evades this defense by recruiting the C-type lectins CTL4 and CTLMA2, while permissiveness to the human malaria parasite was not affected by partial depletion of these factors by RNAi silencing. Using CRISPR/Cas9-based CTL4 knockout, we show that A. gambiae can mount melanization-based refractoriness to the human malaria parasite, which is independent of the TEP1 complement-like system and the major anti-Plasmodium immune pathway Imd. Our study indicates a hierarchical specificity in the control of Plasmodium melanization and proves CTL4 as an essential host factor for P. falciparum transmission and one of the most potent mosquito-encoded malaria transmission-blocking targets.


Assuntos
Anopheles/imunologia , Lectinas Tipo C/genética , Plasmodium berghei/fisiologia , Plasmodium falciparum/fisiologia , Animais , Anopheles/genética , Anopheles/parasitologia , Sistemas CRISPR-Cas , Técnicas de Inativação de Genes , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Lectinas Tipo C/metabolismo , Melaninas/genética , Melaninas/imunologia
2.
Infect Immun ; 90(1): e0035921, 2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-34724388

RESUMO

Malaria begins when an infected mosquito injects saliva containing Plasmodium sporozoites into the skin of a vertebrate host. Passive immunization of mice with antiserum against the Anopheles gambiae mosquito saliva protein TRIO (AgTRIO) offers significant protection against Plasmodium infection of mice. Furthermore, passive transfer of both AgTRIO antiserum and an anti-circumsporozoite protein monoclonal antibody provides synergistic protection. In this study, we generated monoclonal antibodies against AgTRIO to delineate the regions of AgTRIO associated with protective immunity. Monoclonal antibody 13F-1 markedly reduced Plasmodium infection in mice and recognized a region (VDDLMAKFN) in the carboxyl terminus of AgTRIO. 13F-1 is an IgG2a isotype monoclonal antibody, and the Fc region is required for protection. These data will aid in the generation of future malaria vaccines that may include both pathogen and vector antigens.


Assuntos
Anopheles/imunologia , Anticorpos Monoclonais/imunologia , Culicidae/imunologia , Malária/imunologia , Malária/prevenção & controle , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Imunização Passiva , Fragmentos Fc das Imunoglobulinas , Proteínas de Insetos/química , Proteínas de Insetos/imunologia , Malária/parasitologia , Camundongos , Plasmodium berghei/imunologia , Ligação Proteica/imunologia , Domínios e Motivos de Interação entre Proteínas/imunologia
3.
Elife ; 102021 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-34939933

RESUMO

Background: Entomological surveillance for malaria is inherently resource-intensive and produces crude population-level measures of vector exposure which are insensitive in low-transmission settings. Antibodies against Anopheles salivary proteins measured at the individual level may serve as proxy biomarkers for vector exposure and malaria transmission, but their relationship is yet to be quantified. Methods: A systematic review of studies measuring antibodies against Anopheles salivary antigens (PROSPERO: CRD42020185449). Multilevel modelling (to account for multiple study-specific observations [level 1], nested within study [level 2], and study nested within country [level 3]) estimated associations between seroprevalence with Anopheles human biting rate (HBR) and malaria transmission measures. Results: From 3981 studies identified in literature searches, 42 studies across 16 countries were included contributing 393 study-specific observations of anti-Anopheles salivary antibodies determined in 42,764 samples. A positive association between HBR (log transformed) and seroprevalence was found; overall a twofold (100% relative) increase in HBR was associated with a 23% increase in odds of seropositivity (OR: 1.23, 95% CI: 1.10-1.37; p<0.001). The association between HBR and Anopheles salivary antibodies was strongest with concordant, rather than discordant, Anopheles species. Seroprevalence was also significantly positively associated with established epidemiological measures of malaria transmission: entomological inoculation rate, Plasmodium spp. prevalence, and malarial endemicity class. Conclusions: Anopheles salivary antibody biomarkers can serve as a proxy measure for HBR and malaria transmission, and could monitor malaria receptivity of a population to sustain malaria transmission. Validation of Anopheles species-specific biomarkers is important given the global heterogeneity in the distribution of Anopheles species. Salivary biomarkers have the potential to transform surveillance by replacing impractical, inaccurate entomological investigations, especially in areas progressing towards malaria elimination. Funding: Australian National Health and Medical Research Council, Wellcome Trust.


Assuntos
Anopheles/imunologia , Antígenos de Protozoários/imunologia , Proteínas de Insetos/imunologia , Malária/transmissão , Proteínas e Peptídeos Salivares/imunologia , Animais , Anticorpos Antiprotozoários/imunologia , Austrália , Biomarcadores , Humanos , Imunoglobulina G/imunologia , Mordeduras e Picadas de Insetos , Malária/epidemiologia , Malária/imunologia , Modelos Teóricos , Mosquitos Vetores/imunologia , Plasmodium falciparum/imunologia , Estudos Soroepidemiológicos
4.
mBio ; 12(6): e0309121, 2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-34903042

RESUMO

Malaria is caused when Plasmodium sporozoites are injected along with saliva by an anopheline mosquito into the dermis of a vertebrate host. Arthropod saliva has pleiotropic effects that can influence local host responses, pathogen transmission, and exacerbation of the disease. A mass spectrometry screen identified mosquito salivary proteins that are associated with Plasmodium sporozoites during saliva secretions. In this study, we demonstrate that one of these salivary antigens, Anopheles gambiae sporozoite-associated protein (AgSAP), interacts directly with Plasmodium falciparum and Plasmodium berghei sporozoites. AgSAP binds to heparan sulfate and inhibits local inflammatory responses in the skin. The silencing of AgSAP in mosquitoes reduces their ability to effectively transmit sporozoites to mice. Moreover, immunization with AgSAP decreases the Plasmodium burden in mice that are bitten by Plasmodium-infected mosquitoes. These data suggest that AgSAP facilitates early Plasmodium infection in the vertebrate host and serves as a target for the prevention of malaria. IMPORTANCE Malaria is a vector-borne disease caused by Plasmodium sporozoites. When an anopheline mosquito bites its host, it releases Plasmodium sporozoites as well as saliva components. Mosquito proteins have the potential to serve as antigens to prevent or influence malaria without directly targeting the pathogen. This may help set a new paradigm for vaccine development. In this study, we have elucidated the role of a novel salivary antigen, named Anopheles gambiae sporozoite-associated protein (AgSAP). The results presented here show that AgSAP interacts with Plasmodium falciparum and Plasmodium berghei sporozoites and modulates local inflammatory responses in the skin. Furthermore, our results show that AgSAP is a novel mosquito salivary antigen that influences the early stages of Plasmodium infection in the vertebrate host. Individuals living in countries where malaria is endemic generate antibodies against AgSAP, which indicates that AgSAP can serve as a biomarker for disease prevalence and epidemiological analysis.


Assuntos
Anopheles/imunologia , Proteínas de Insetos/imunologia , Malária/parasitologia , Mosquitos Vetores/imunologia , Plasmodium berghei/fisiologia , Plasmodium falciparum/fisiologia , Proteínas e Peptídeos Salivares/imunologia , Animais , Anopheles/genética , Anopheles/parasitologia , Feminino , Humanos , Proteínas de Insetos/genética , Malária/imunologia , Malária/transmissão , Camundongos , Camundongos Endogâmicos C57BL , Mosquitos Vetores/genética , Mosquitos Vetores/parasitologia , Plasmodium berghei/genética , Plasmodium falciparum/genética , Proteínas e Peptídeos Salivares/genética , Esporozoítos/genética , Esporozoítos/fisiologia
5.
J Immunol Res ; 2021: 7785180, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34790829

RESUMO

Malaria is a serious and, in some unfortunate cases, fatal disease caused by a parasite of the Plasmodium genus. It predominantly occurs in tropical areas where it is transmitted through the bite of an infected Anopheles mosquito. The pathogenesis of malaria is complex and incompletely elucidated. During blood-stage infection, in response to the presence of the parasite, the host's immune system produces proinflammatory cytokines including IL-6, IL-8, IFN-γ, and TNF, cytokines which play a pivotal role in controlling the growth of the parasite and its elimination. Regulatory cytokines such as transforming growth factor- (TGF-) ß and IL-10 maintain the balance between the proinflammatory and anti-inflammatory responses. However, in many cases, cytokines have a double role. On the one hand, they contribute to parasitic clearance, and on the other, they are responsible for pathological changes encountered in malaria. Cytokine-modulating strategies may represent a promising modern approach in disease management. In this review, we discuss the host immune response in malaria, analyzing the latest studies on the roles of pro- and anti-inflammatory cytokines.


Assuntos
Citocinas/imunologia , Inflamação/imunologia , Malária/imunologia , Animais , Anopheles/imunologia , Anopheles/parasitologia , Humanos , Inflamação/parasitologia , Malária/parasitologia , Plasmodium/imunologia
6.
PLoS One ; 16(10): e0259131, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34705869

RESUMO

BACKGROUND: Malaria prevalence in the highlands of Northern Tanzania is currently below 1% making this an elimination prone setting. As climate changes may facilitate increasing distribution of Anopheles mosquitoes in such settings, there is a need to monitor changes in risks of exposure to ensure that established control tools meet the required needs. This study explored the use of human antibodies against gambiae salivary gland protein 6 peptide 1 (gSG6-P1) as a biomarker of Anopheles exposure and assessed temporal exposure to mosquito bites in populations living in Lower Moshi, Northern Tanzania. METHODS: Three cross-sectional surveys were conducted in 2019: during the dry season in March, at the end of the rainy season in June and during the dry season in September. Blood samples were collected from enrolled participants and analysed for the presence of anti-gSG6-P1 IgG. Mosquitoes were sampled from 10% of the participants' households, quantified and identified to species level. Possible associations between gSG6-P1 seroprevalence and participants' characteristics were determined. RESULTS: The total number of Anopheles mosquitoes collected was highest during the rainy season (n = 1364) when compared to the two dry seasons (n = 360 and n = 1075, respectively). The gSG6-P1 seroprevalence increased from 18.8% during the dry season to 25.0% during the rainy season (χ2 = 2.66; p = 0.103) followed by a significant decline to 11.0% during the next dry season (χ2 = 12.56; p = 0.001). The largest number of mosquitoes were collected in one village (Oria), but the seroprevalence was significantly lower among the residents as compared to the rest of the villages (p = 0.039), explained by Oria having the highest number of participants owning and using bed nets. Both individual and household gSG6-P1 IgG levels had no correlation with numbers of Anopheles mosquitoes collected. CONCLUSION: Anti-gSG6-P1 IgG is a potential tool in detecting and distinguishing temporal and spatial variations in exposure to Anopheles mosquito bites in settings of extremely low malaria transmission where entomological tools may be obsolete. However studies with larger sample size and extensive mosquito sampling are warranted to further explore the association between this serological marker and abundance of Anopheles mosquito.


Assuntos
Anopheles/imunologia , Imunoglobulina G/sangue , Mordeduras e Picadas de Insetos/sangue , Proteínas de Insetos/imunologia , Malária , Proteínas e Peptídeos Salivares/imunologia , Animais , Biomarcadores/sangue , Estudos Transversais , Malária/diagnóstico , Malária/epidemiologia , Tanzânia
7.
Proc Natl Acad Sci U S A ; 118(44)2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34711682

RESUMO

Immune priming in Anopheles gambiae is mediated by the systemic release of a hemocyte differentiation factor (HDF), a complex of lipoxin A4 bound to Evokin, a lipid carrier. HDF increases the proportion of circulating granulocytes and enhances mosquito cellular immunity. Here, we show that Evokin is present in hemocytes and fat-body cells, and messenger RNA (mRNA) expression increases significantly after immune priming. The double peroxidase (DBLOX) enzyme, present in insects but not in vertebrates, is essential for HDF synthesis. DBLOX is highly expressed in oenocytes in the fat-body tissue, and these cells increase in number in primed mosquitoes. We provide direct evidence that the histone acetyltransferase AgTip60 (AGAP001539) is also essential for a sustained increase in oenocyte numbers, HDF synthesis, and immune priming. We propose that oenocytes may function as a population of cells that are reprogrammed, and orchestrate and maintain a broad, systemic, and long-lasting state of enhanced immune surveillance in primed mosquitoes.


Assuntos
Culicidae/imunologia , Histona Acetiltransferases/metabolismo , Memória Imunológica/imunologia , Animais , Anopheles/imunologia , Anopheles/metabolismo , Culicidae/metabolismo , Feminino , Granulócitos/metabolismo , Hemócitos/imunologia , Imunidade Inata/imunologia , Proteínas de Insetos/genética , Insetos/metabolismo , Lipoxinas/metabolismo , Malária/imunologia , Masculino , Peroxidase/metabolismo , Plasmodium/metabolismo , Plasmodium berghei/metabolismo
8.
Front Immunol ; 12: 729086, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512663

RESUMO

A successful malaria transmission blocking vaccine (TBV) requires the induction of a high antibody titer that leads to abrogation of parasite traversal of the mosquito midgut following ingestion of an infectious bloodmeal, thereby blocking the cascade of secondary human infections. Previously, we developed an optimized construct UF6b that elicits an antigen-specific antibody response to a neutralizing epitope of Anopheline alanyl aminopeptidase N (AnAPN1), an evolutionarily conserved pan-malaria mosquito midgut-based TBV target, as well as established a size-controlled lymph node targeting biodegradable nanoparticle delivery system that leads to efficient and durable antigen-specific antibody responses using the model antigen ovalbumin. Herein, we demonstrate that co-delivery of UF6b with the adjuvant CpG oligodeoxynucleotide immunostimulatory sequence (ODN ISS) 1018 using this biodegradable nanoparticle vaccine delivery system generates an AnAPN1-specific immune response that blocks parasite transmission in a standard membrane feeding assay. Importantly, this platform allows for antigen dose-sparing, wherein lower antigen payloads elicit higher-quality antibodies, therefore less antigen-specific IgG is needed for potent transmission-reducing activity. By targeting lymph nodes directly, the resulting immunopotentiation of AnAPN1 suggests that the de facto assumption that high antibody titers are needed for a TBV to be successful needs to be re-examined. This nanovaccine formulation is stable at -20°C storage for at least 3 months, an important consideration for vaccine transport and distribution in regions with poor healthcare infrastructure. Together, these data support further development of this nanovaccine platform for malaria TBVs.


Assuntos
Adjuvantes Imunológicos/farmacologia , Anopheles/imunologia , Linfonodos/efeitos dos fármacos , Vacinas Antimaláricas/farmacologia , Malária/prevenção & controle , Nanopartículas , Oligodesoxirribonucleotídeos/farmacologia , Plasmodium/imunologia , Animais , Anopheles/parasitologia , Anticorpos Neutralizantes/sangue , Anticorpos Antiprotozoários/sangue , Antígenos CD13/antagonistas & inibidores , Antígenos CD13/imunologia , Antígenos CD13/metabolismo , Composição de Medicamentos , Epitopos , Feminino , Interações Hospedeiro-Parasita , Imunoglobulina G/sangue , Linfonodos/imunologia , Linfonodos/parasitologia , Malária/imunologia , Malária/parasitologia , Malária/transmissão , Vacinas Antimaláricas/imunologia , Camundongos , Nanomedicina , Plasmodium/patogenicidade , Vacinação
9.
Front Immunol ; 12: 680020, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484178

RESUMO

Lipid-derived signaling molecules known as eicosanoids have integral roles in mediating immune and inflammatory processes across metazoans. This includes the function of prostaglandins and their cognate G protein-coupled receptors (GPCRs) to employ their immunological actions. In insects, prostaglandins have been implicated in the regulation of both cellular and humoral immune responses, yet in arthropods of medical importance, studies have been limited. Here, we describe a prostaglandin E2 receptor (AgPGE2R) in the mosquito Anopheles gambiae and demonstrate that its expression is most abundant in oenocytoid immune cell populations. Through the administration of prostaglandin E2 (PGE2) and AgPGE2R-silencing, we demonstrate that prostaglandin E2 signaling regulates a subset of prophenoloxidases (PPOs) and antimicrobial peptides (AMPs) that are strongly expressed in populations of oenocytoids. We demonstrate that PGE2 signaling via the AgPGE2R significantly limits both bacterial replication and Plasmodium oocyst survival. Additional experiments establish that PGE2 treatment increases phenoloxidase (PO) activity through the increased expression of PPO1 and PPO3, genes essential to anti-Plasmodium immune responses that promote oocyst killing. We also provide evidence that the mechanisms of PGE2 signaling are concentration-dependent, where high concentrations of PGE2 promote oenocytoid lysis, negating the protective effects of lower concentrations of PGE2 on anti-Plasmodium immunity. Taken together, our results provide new insights into the role of PGE2 signaling on immune cell function and its contributions to mosquito innate immunity that promote pathogen killing.


Assuntos
Anopheles/imunologia , Anopheles/microbiologia , Anopheles/parasitologia , Dinoprostona/metabolismo , Oocistos/imunologia , Plasmodium/imunologia , Transdução de Sinais , Animais , Anopheles/classificação , Hemócitos/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Viabilidade Microbiana , Mosquitos Vetores/imunologia , Mosquitos Vetores/microbiologia , Mosquitos Vetores/parasitologia , Filogenia , Plasmodium/crescimento & desenvolvimento , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Receptores de Prostaglandina E/genética , Receptores de Prostaglandina E/metabolismo
10.
Front Immunol ; 12: 584660, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248924

RESUMO

The immune response of Anopheles mosquitoes to Plasmodium invasion has been extensively studied and shown to be mediated mainly by the nitric oxide synthase (NOS), dual oxidase (DUOX), phenoloxidase (PO), and antimicrobial peptides activity. Here, we studied the correlation between a heat shock insult, transcription of immune response genes, and subsequent susceptibility to Plasmodium berghei infection in Anopheles albimanus. We found that transcript levels of many immune genes were drastically affected by the thermal stress, either positively or negatively. Furthermore, the transcription of genes associated with modifications of nucleic acid methylation was affected, suggesting an increment in both DNA and RNA methylation. The heat shock increased PO and NOS activity in the hemolymph, as well as the transcription of several immune genes. As consequence, we observed that heat shock increased the resistance of mosquitoes to Plasmodium invasion. The data provided here could help the understanding of infection transmission under the ever more common heat waves.


Assuntos
Anopheles/imunologia , Anopheles/parasitologia , Resposta ao Choque Térmico/imunologia , Hemolinfa/parasitologia , Malária/imunologia , Plasmodium berghei/imunologia , Animais , Anopheles/genética , Feminino , Resposta ao Choque Térmico/genética , Imunidade/genética , Malária/parasitologia
11.
Elife ; 102021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34318744

RESUMO

Mosquito immune cells, known as hemocytes, are integral to cellular and humoral responses that limit pathogen survival and mediate immune priming. However, without reliable cell markers and genetic tools, studies of mosquito immune cells have been limited to morphological observations, leaving several aspects of their biology uncharacterized. Here, we use single-cell RNA sequencing (scRNA-seq) to characterize mosquito immune cells, demonstrating an increased complexity to previously defined prohemocyte, oenocytoid, and granulocyte subtypes. Through functional assays relying on phagocytosis, phagocyte depletion, and RNA-FISH experiments, we define markers to accurately distinguish immune cell subtypes and provide evidence for immune cell maturation and differentiation. In addition, gene-silencing experiments demonstrate the importance of lozenge in defining the mosquito oenocytoid cell fate. Together, our scRNA-seq analysis provides an important foundation for future studies of mosquito immune cell biology and a valuable resource for comparative invertebrate immunology.


Assuntos
Anopheles/imunologia , Diferenciação Celular/imunologia , Hemócitos/imunologia , Mosquitos Vetores/imunologia , Fagócitos/imunologia , Animais , Anopheles/genética , Drosophila , Feminino , Inativação Gênica , Hemócitos/metabolismo , Imunidade Inata , Malária/imunologia , Malária/parasitologia , Mosquitos Vetores/genética , Fagócitos/metabolismo , Análise de Sequência de RNA , Análise de Célula Única
12.
PLoS Pathog ; 17(5): e1009486, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34015060

RESUMO

Vitellogenesis and oocyte maturation require anautogenous female Anopheles mosquitoes to obtain a bloodmeal from a vertebrate host. The bloodmeal is rich in proteins that are readily broken down into amino acids in the midgut lumen and absorbed by the midgut epithelial cells where they are converted into lipids and then transported to other tissues including ovaries. The stearoyl-CoA desaturase (SCD) plays a pivotal role in this process by converting saturated (SFAs) to unsaturated (UFAs) fatty acids; the latter being essential for maintaining cell membrane fluidity amongst other housekeeping functions. Here, we report the functional and phenotypic characterization of SCD1 in the malaria vector mosquito Anopheles coluzzii. We show that RNA interference (RNAi) silencing of SCD1 and administration of sterculic acid (SA), a small molecule inhibitor of SCD1, significantly impact on the survival and reproduction of female mosquitoes following blood feeding. Microscopic observations reveal that the mosquito thorax is quickly filled with blood, a phenomenon likely caused by the collapse of midgut epithelial cell membranes, and that epithelial cells are depleted of lipid droplets and oocytes fail to mature. Transcriptional profiling shows that genes involved in protein, lipid and carbohydrate metabolism and immunity-related genes are the most affected by SCD1 knock down (KD) in blood-fed mosquitoes. Metabolic profiling reveals that these mosquitoes exhibit increased amounts of saturated fatty acids and TCA cycle intermediates, highlighting the biochemical framework by which the SCD1 KD phenotype manifests as a result of a detrimental metabolic syndrome. Accumulation of SFAs is also the likely cause of the potent immune response observed in the absence of infection, which resembles an auto-inflammatory condition. These data provide insights into mosquito bloodmeal metabolism and lipid homeostasis and could inform efforts to develop novel interventions against mosquito-borne diseases.


Assuntos
Ração Animal/análise , Anopheles/crescimento & desenvolvimento , Comportamento Alimentar , Mosquitos Vetores/fisiologia , Reprodução , Estearoil-CoA Dessaturase/metabolismo , Animais , Anopheles/enzimologia , Anopheles/imunologia , Feminino , Perfilação da Expressão Gênica , Mosquitos Vetores/parasitologia , Estearoil-CoA Dessaturase/genética
13.
Nat Microbiol ; 6(6): 806-817, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33958765

RESUMO

The stalling global progress in the fight against malaria prompts the urgent need to develop new intervention strategies. Whilst engineered symbiotic bacteria have been shown to confer mosquito resistance to parasite infection, a major challenge for field implementation is to address regulatory concerns. Here, we report the identification of a Plasmodium-blocking symbiotic bacterium, Serratia ureilytica Su_YN1, isolated from the midgut of wild Anopheles sinensis in China that inhibits malaria parasites via secretion of an antimalarial lipase. Analysis of Plasmodium vivax epidemic data indicates that local malaria cases in Tengchong (Yunnan province, China) are significantly lower than imported cases and importantly, that the local vector A. sinensis is more resistant to infection by P. vivax than A. sinensis from other regions. Analysis of the gut symbiotic bacteria of mosquitoes from Yunnan province led to the identification of S. ureilytica Su_YN1. This bacterium renders mosquitoes resistant to infection by the human parasite Plasmodium falciparum or the rodent parasite Plasmodium berghei via secretion of a lipase that selectively kills parasites at various stages. Importantly, Su_YN1 rapidly disseminates through mosquito populations by vertical and horizontal transmission, providing a potential tool for blocking malaria transmission in the field.


Assuntos
Anopheles/microbiologia , Proteínas de Bactérias/imunologia , Lipase/imunologia , Mosquitos Vetores/microbiologia , Serratia/enzimologia , Serratia/isolamento & purificação , Animais , Anopheles/imunologia , Anopheles/parasitologia , Anopheles/fisiologia , Proteínas de Bactérias/genética , China , Feminino , Trato Gastrointestinal/microbiologia , Humanos , Lipase/genética , Malária Vivax/transmissão , Masculino , Mosquitos Vetores/imunologia , Mosquitos Vetores/parasitologia , Mosquitos Vetores/fisiologia , Plasmodium falciparum/fisiologia , Plasmodium vivax/fisiologia , Serratia/genética , Serratia/fisiologia , Simbiose
14.
PLoS Biol ; 19(5): e3001182, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33979323

RESUMO

Melanin, a black-brown pigment found throughout all kingdoms of life, has diverse biological functions including UV protection, thermoregulation, oxidant scavenging, arthropod immunity, and microbial virulence. Given melanin's broad roles in the biosphere, particularly in insect immune defenses, it is important to understand how exposure to ubiquitous environmental contaminants affects melanization. Glyphosate-the most widely used herbicide globally-inhibits melanin production, which could have wide-ranging implications in the health of many organisms, including insects. Here, we demonstrate that glyphosate has deleterious effects on insect health in 2 evolutionary distant species, Galleria mellonella (Lepidoptera: Pyralidae) and Anopheles gambiae (Diptera: Culicidae), suggesting a broad effect in insects. Glyphosate reduced survival of G. mellonella caterpillars following infection with the fungus Cryptococcus neoformans and decreased the size of melanized nodules formed in hemolymph, which normally help eliminate infection. Glyphosate also increased the burden of the malaria-causing parasite Plasmodium falciparum in A. gambiae mosquitoes, altered uninfected mosquito survival, and perturbed the microbial composition of adult mosquito midguts. Our results show that glyphosate's mechanism of melanin inhibition involves antioxidant synergy and disruption of the reaction oxidation-reduction balance. Overall, these findings suggest that glyphosate's environmental accumulation could render insects more susceptible to microbial pathogens due to melanin inhibition, immune impairment, and perturbations in microbiota composition, potentially contributing to declines in insect populations.


Assuntos
Anopheles/efeitos dos fármacos , Glicina/análogos & derivados , Melaninas/metabolismo , Mariposas/efeitos dos fármacos , Animais , Anopheles/imunologia , Cryptococcus neoformans/patogenicidade , Dípteros/efeitos dos fármacos , Dípteros/imunologia , Glicina/metabolismo , Glicina/farmacologia , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Infecções/imunologia , Infecções/metabolismo , Infecções/fisiopatologia , Insetos/efeitos dos fármacos , Insetos/imunologia , Lepidópteros/efeitos dos fármacos , Lepidópteros/imunologia , Mariposas/imunologia , Plasmodium falciparum/patogenicidade , Virulência
15.
Parasit Vectors ; 14(1): 209, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879250

RESUMO

BACKGROUND: Anopheles arabiensis is an opportunistic malaria vector that rests and feeds outdoors, circumventing current indoor vector control methods. Furthermore, this vector will readily feed on both animals and humans. Targeting this vector while feeding on animals can provide an additional intervention for the current vector control activities. Previous results have displayed the efficacy of using Subolesin/Akirin ortholog vaccines for the control of multiple ectoparasite infestations. This made Akirin a potential antigen for vaccine development against An. arabiensis. METHODS: The efficacy of three antigens, namely recombinant Akirin from An. arabiensis, recombinant Akirin from Aedes albopictus, and recombinant Q38 (Akirin/Subolesin chimera) were evaluated as novel interventions for An. arabiensis vector control. Immunisation trials were conducted based on the concept that mosquitoes feeding on vaccinated balb/c mice would ingest antibodies specific to the target antigen. The antibodies would interact with the target antigen in the arthropod vector, subsequently disrupting its function. RESULTS: All three antigens successfully reduced An. arabiensis survival and reproductive capacities, with a vaccine efficacy of 68-73%. CONCLUSIONS: These results were the first to show that hosts vaccinated with recombinant Akirin vaccines could develop a protective response against this outdoor malaria transmission vector, thus providing a step towards the development of a novel intervention for An. arabiensis vector control.


Assuntos
Anopheles/imunologia , Mordeduras e Picadas de Insetos/imunologia , Proteínas de Insetos/imunologia , Fatores de Transcrição/imunologia , Vacinas/imunologia , Animais , Anopheles/genética , Anopheles/fisiologia , Feminino , Humanos , Mordeduras e Picadas de Insetos/sangue , Mordeduras e Picadas de Insetos/parasitologia , Proteínas de Insetos/administração & dosagem , Proteínas de Insetos/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Controle de Mosquitos , Reprodução , Fatores de Transcrição/administração & dosagem , Fatores de Transcrição/genética , Vacinas/administração & dosagem , Vacinas/genética , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
16.
PLoS Pathog ; 17(2): e1009353, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33626094

RESUMO

Repeated blood meals provide essential nutrients for mosquito egg development and routes for pathogen transmission. The target of rapamycin, the TOR pathway, is essential for vitellogenesis. However, its influence on pathogen transmission remains to be elucidated. Here, we show that rapamycin, an inhibitor of the TOR pathway, effectively suppresses Plasmodium berghei infection in Anopheles stephensi. An. stephensi injected with rapamycin or feeding on rapamycin-treated mice showed increased resistance to P. berghei infection. Exposing An. stephensi to a rapamycin-coated surface not only decreased the numbers of both oocysts and sporozoites but also impaired mosquito survival and fecundity. Transcriptome analysis revealed that the inhibitory effect of rapamycin on parasite infection was through the enhanced activation of immune responses, especially the NF-κB transcription factor REL2, a regulator of the immune pathway and complement system. Knockdown of REL2 in rapamycin-treated mosquitoes abrogated the induction of the complement-like proteins TEP1 and SPCLIP1 and abolished rapamycin-mediated refractoriness to Plasmodium infection. Together, these findings demonstrate a key role of the TOR pathway in regulating mosquito immune responses, thereby influencing vector competence.


Assuntos
Anopheles/efeitos dos fármacos , Imunidade Inata/imunologia , Malária/tratamento farmacológico , Mosquitos Vetores/efeitos dos fármacos , Plasmodium berghei/patogenicidade , Sirolimo/farmacologia , Animais , Anopheles/imunologia , Anopheles/parasitologia , Feminino , Perfilação da Expressão Gênica , Imunidade Inata/efeitos dos fármacos , Imunossupressores/farmacologia , Malária/imunologia , Malária/parasitologia , Malária/transmissão , Camundongos , Camundongos Endogâmicos BALB C , Mosquitos Vetores/imunologia , Mosquitos Vetores/parasitologia , Oocistos/efeitos dos fármacos , Oocistos/crescimento & desenvolvimento , Oocistos/imunologia , Esporozoítos/efeitos dos fármacos , Esporozoítos/crescimento & desenvolvimento , Esporozoítos/imunologia
17.
Dev Comp Immunol ; 120: 104046, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33600838

RESUMO

In invertebrates, "immunological priming" is considered as the ability to acquire a protective (adaptive) immune response against a pathogen due to previous exposure to the same organism. To date, the mechanism by which this type of adaptive immune response originates in insects is not well understood. In the Anopheles albimanus - Plasmodium berghei model, a DNA synthesis that probably indicates an endoreplication process during priming induction has been evidenced. This work aimed to know the transcriptomic profile in the midguts of An. albimanus after priming induction. Our analysis indicates the participation of regulatory elements of the cell cycle in the immunological priming and points out the importance of the cell cycle regulation in the mosquito midgut.


Assuntos
Imunidade Adaptativa , Anopheles/imunologia , Interações Hospedeiro-Parasita/imunologia , Plasmodium berghei/imunologia , Animais , Anopheles/parasitologia , Ciclo Celular/imunologia , Epigênese Genética/imunologia , Perfilação da Expressão Gênica , Interações Hospedeiro-Parasita/genética , Masculino , Camundongos
18.
Dev Comp Immunol ; 114: 103830, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32805306

RESUMO

Different evidences suggest that pericardial cells play an important role during the immune response against pathogens that invade the mosquito hemocoel. Previously, we identified two lysozyme genes in Anopheles albimanus heart transcriptome. The present study showed that one of these genes (IDVB: AALB004517) has high percentage of identity to mosquito lysozyme genes related to immunity, suggesting its possible participation during the mosquito immune response. This An. albimanus gen, constitutively expressed lysozyme c-1 mRNA (albLys c-1) in mosquito heart; however, it was overexpressed in bacteria-injected mosquitoes. In heart extract samples, we identified a protein of approximately 14 kDa (likely lysozyme c-1), which lysed M. luteus. In addition, mRNA-FISH assay in heart samples, showed specific fluorescent hybridization signal in pericardial cells from M. luteus-injected mosquitos. We conclude that for the first time an inducible immune factor (lysozyme c-1) is identified in Anopheles albimanus mosquito pericardial cells, which could be a key component in the response against pathogens that interact with the mosquito heart.


Assuntos
Anopheles/imunologia , Escherichia coli/fisiologia , Infecções por Bactérias Gram-Positivas/imunologia , Proteínas de Insetos/metabolismo , Micrococcus luteus/fisiologia , Muramidase/metabolismo , Pericárdio/metabolismo , Animais , Clonagem Molecular , Biologia Computacional , Proteínas de Escherichia coli/imunologia , Imunidade Inata , Proteínas de Insetos/genética , Muramidase/genética , Pericárdio/patologia , Filogenia , Transcriptoma , Regulação para Cima
19.
J Innate Immun ; 13(2): 107-126, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33207342

RESUMO

Insect systemic immune responses to bacterial infections have been mainly studied using microinjections, whereby the microbe is directly injected into the hemocoel. While this methodology has been instrumental in defining immune signaling pathways and enzymatic cascades in the hemolymph, it remains unclear whether and to what extent the contribution of systemic immune defenses to host microbial resistance varies if bacteria invade the hemolymph after crossing the midgut epithelium subsequent to an oral infection. Here, we address this question using the pathogenic Serratia marcescens (Sm) DB11 strain to establish systemic infections of the malaria vector Anopheles gambiae, either by septic Sm injections or by midgut crossing after feeding on Sm. Using functional genetic studies by RNAi, we report that the two humoral immune factors, thioester-containing protein 1 and C-type lectin 4, which play key roles in defense against Gram-negative bacterial infections, are essential for defense against systemic Sm infections established through injection, but they become dispensable when Sm infects the hemolymph following oral infection. Similar results were observed for the mosquito Rel2 pathway. Surprisingly, blocking phagocytosis by cytochalasin D treatment did not affect mosquito susceptibility to Sm infections established through either route. Transcriptomic analysis of mosquito midguts and abdomens by RNA-seq revealed that the transcriptional response in these tissues is more pronounced in response to feeding on Sm. Functional classification of differentially expressed transcripts identified metabolic genes as the most represented class in response to both routes of infection, while immune genes were poorly regulated in both routes. We also report that Sm oral infections are associated with significant downregulation of several immune genes belonging to different families, specifically the clip-domain serine protease family. In sum, our findings reveal that the route of infection not only alters the contribution of key immunity genes to host antimicrobial defense but is also associated with different transcriptional responses in midguts and abdomens, possibly reflecting different adaptive strategies of the host.


Assuntos
Anopheles/imunologia , Hemolinfa/imunologia , Malária/imunologia , Infecções por Serratia/imunologia , Serratia marcescens/fisiologia , Animais , Células Cultivadas , Vetores de Doenças , Regulação para Baixo , Métodos de Alimentação , Feminino , Perfilação da Expressão Gênica , Imunidade Inata , Proteínas de Insetos/metabolismo , Lectinas Tipo C/metabolismo , Serina Proteases/genética , Transdução de Sinais
20.
Sci Rep ; 10(1): 21084, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33273588

RESUMO

Mosquito 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.


Assuntos
Anopheles/efeitos dos fármacos , Benzoatos/farmacologia , Interações Hospedeiro-Parasita , Hidrazinas/farmacologia , Inseticidas/farmacologia , Plasmodium berghei/patogenicidade , Animais , Anopheles/imunologia , Anopheles/parasitologia , Células Cultivadas , Ecdisterona/agonistas , Feminino , Masculino , Fagocitose , Receptores de Esteroides/metabolismo
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