If not treated promptly with effective medicines, malaria can cause severe illness and is often fatal. Most cases and deaths are in sub-Saharan Africa. In , malaria was present in 91 countries and territories. Early treatment of malaria will shorten its duration, prevent complications and avoid a majority of deaths. Because of its considerable drag on health in low-income countries, malaria disease management is an essential part of global health development.
Treatment aims to cure patients of the disease rather than to diminish the number of parasites carried by an infected person. The best available treatment, particularly for P. However, the growing potential for parasite resistance to these medicines is undermining malaria control efforts see below. There are no effective alternatives to artemisinins for the treatment of malaria either on the market or nearing the end of the drug development process. Drug resistance to commonly used antimalarial drugs has spread very rapidly.
In order to avoid this for artemisinins, they should be used in combination as ACTs, and artemisinin monotherapy use of one artemisinin drug versus the more effective combination pill should not be used. The less effective single-drug treatment increases the chance for parasites to evolve and become resistant to the medicine.
Intensive monitoring of drug potency is essential to protect against the spread of resistant malaria strains to other parts of the world.
WHO recommends continuous monitoring and is assisting countries as they work to strengthen drug observation efforts. Prevention focuses on reducing the transmission of the disease by controlling the malaria-bearing mosquito. Two main interventions for vector control are:. These core interventions can be locally complemented by other mosquito vector control methods for example, reducing standing water habitats where insects breed, among other approaches.
Insecticide resistance Mosquito control efforts are being strengthened in many areas, but there are significant challenges, including:. There are no equally effective and efficient insecticide alternatives to DDT and pyrethroids, and the development of new pesticides is an expensive, long-term endeavour.
Vector management practices that enforce the sound management of insecticides are essential. Insecticide resistance detection should be a routine feature of national control efforts to ensure that the most effective vector control methods are being used. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.
If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
This article has been corrected. See J Physiol Anthropol. This article has been cited by other articles in PMC. Abstract Malaria is one of the most devastating infectious diseases of humans. Background: battle of humans against malaria—past and present Malaria has been recognised as a serious health problem since the earliest historical times. Malaria and Plasmodium biology Life cycle of Plasmodium All Plasmodium species share a similar life cycle [ 31 ].
Table 1 Onset of gametocyte production and recurrence in human malaria. Open in a separate window. Gametocytes Throughout development in their vertebrate hosts, Plasmodium cells have a haploid genome.
Asymptomatic carriers In areas endemic for malaria, many people carry Plasmodium without developing symptoms because of acquired immunity [ 85 , 86 ]. Apicoplast and plant-like metabolism The genus Plasmodium belongs to a larger group of protozoans called the Apicomplexa, part of the superphylum Alveolata that also includes dinoflagellates and ciliates [ 96 ]. Antimalarial drugs and resistance From ancient times, various plant products have been used in folk medicine to treat malaria.
Host specificity The natural host range of Plasmodium depends on the species. Conclusions Humans have long suffered from malaria, the disease caused by Plasmodium. Acknowledgements The author thanks Iain Wilson and Tony Holder for careful reading of the manuscript.
The author read and approved the final manuscript. Funding Not applicable. Availability of data and materials Not applicable. Ethics approval and consent to participate Not applicable.
Consent for publication Not applicable. Competing interests The author declares that they have no competing interests. References 1. Hedrick PW. Population genetics of malaria resistance in humans. Heredity Edinb.
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Austin SC. The history of malariotherapy for neurosyphilis. Plasmodium vivax in hematopoietic niches: hidden and dangerous. Malariotherapy--insanity at the service of malariology. Adv Parasitol. Biology of Plasmodium falciparum gametocyte sex ratio and implications in malaria parasite transmission. Gametocyte sex ratio: the key to understanding Plasmodium falciparum transmission? Stress and sex in malaria parasites. Evol Med Public Heal. Inclusion of gametocyte parameters in anti-malarial drug efficacy studies: filling a neglected gap needed for malaria elimination.
Gametocyte clearance in children, from western Kenya, with uncomplicated Plasmodium falciparum malaria after artemether—lumefantrine or dihydroartemisinin—piperaquine treatment. Life-span of in vitro differentiated Plasmodium falciparum gametocytes. Gametocytaemia after drug treatment of asymptomatic Plasmodium falciparum. Plos Clin Trials. Gametocytemia and infectivity to mosquitoes of patients with uncomplicated Plasmodium falciparum malaria attacks treated with chloroquine or sulfadoxine plus pyrimethamine.
Naturally acquired immunity against immature Plasmodium falciparum gametocytes. Sci Transl Med. Very high carriage of gametocytes in asymptomatic low-density Plasmodium falciparum and P. Asymptomatic carriers of Plasmodium spp.
Clin Microbiol Rev In addition to the asexual stages, gametocytes also circulate in the blood. If a gametocyte is not ingested by a mosquito during blood-feeding, it decays and evidence suggests that it is eventually removed from circulation by the host immune system resulting in the production of gametocyte-specific antibodies Baird et al.
Evidence for specific suppression of gametocytemia by Plasmodium falciparum in residents of hyperendemic Irian Jaya. Why so few transmission stages? Reproductive restraint by malaria parasites. Parasitol Today Plasmodium falciparum antigens on the surface of the gametocyte-infected erythrocyte. Such antibodies would also be ingested by the mosquito and could interfere with progression of the developmental cycle in the midgut lumen Fig.
Immune sera of individuals living in malaria endemic regions have TB activity against the mosquito midgut stages of both P. Malaria transmission-blocking activity in experimental infections of Anopheles gambiae from naturally infected Plasmodium falciparum gametocyte carriers. Mechanisms that reduce transmission of Plasmodium falciparum malaria in semiimmune and nonimmune persons. Plasmodium vivax: transmission-blocking immunity in a malaria-endemic area of Colombia. Human immune responses that reduce the transmission of Plasmodium falciparum in African populations.
Int J Parasitol Transmission-blocking immunity to Plasmodium falciparum in malaria-immune individuals is associated with antibodies to the gamete surface protein Pfs Parasitology Parasite infectivity and immunity to Plasmodium falciparum gametocytes in Gambian children.
A longitudinal study of immune responses to Plasmodium falciparum sexual stage antigens in Tanzanian adults. Cell Malaria transmission-blocking antigen, Pfs, mediates human red blood cell binding to exflagellating male parasites and oocyst production. Mol Microbiol These proteins are stored in the parasitophorous vacuole membrane of the gametocyte and relocate to the surface of the gamete during activation in the mosquito midgut Williamson et al. Stage-specific processing of Pfs, a Plasmodium falciparum transmission-blocking vaccine candidate.
It appears that anti-Pfs antibodies hinder fertilisation by a mechanism different from interference with gamete adhesion. Plasmodium falciparum transmission blocking monoclonal antibodies recognize monovalently expressed epitopes.
Dev Biol Stand Later studies showed that anti-Pfs antibodies inhibit P. The kDa gamete surface protein of Plasmodium falciparum is also a target for transmission-blocking antibodies. Transmission-blocking antibodies against multiple, non-variant target epitopes of the Plasmodium falciparum gamete surface antigen Pfs are all complement-fixing.
Complement-mediated lysis of Plasmodium falciparum gametes by malaria-immune human sera is associated with antibodies to the gamete surface antigen Pfs These antibodies activate the classical complement pathway resulting in the formation of the membrane-attack complex causing lysis of the parasite Fig.
In summary, these studies highlight the possible applications of an antibody-based TB vaccine to reduce parasite development in its mosquito host and could have a profound influence on the transmission of malaria in endemic countries. Midgut microbiota - Mosquitoes, as all higher organisms including humans, carry an intestinal microbiota that is mostly composed of bacteria and yeast [reviewed in Dillon and Dillon Dillon RJ, Dillon VM The gut bacteria of insects: nonpathogenic interactions.
Annu Rev Entomol There is evidence to suggest that the symbiotic relationship between bacteria and the mosquito confers to the latter some protection against invading pathogens like malaria. Several studies using laboratory-reared and field-captured Anopheles mosquitoes have shown that midgut bacteria primarily Gram-negative bacteria have a negative effect on P. Concomitant infections of Anopheles stephensi with Plasmodium berghei and Serratia marcescens: additive detrimental effects.
Zentralbl Bakteriol Mikrobiol Hyg A Plasmodium falciparum: inhibition of sporogonic development in Anopheles stephensi by Gram-negative bacteria. Exp Parasitol Bacterial population dynamics in three anopheline species: the impact on Plasmodium sporogonic development.
Midgut bacteria in Anopheles gambiae and An. Bacteria in midguts of field-collected Anophe- les albimanus block Plasmodium vivax sporogonic development. Implication of the mosquito midgut microbiota in the defense against malaria parasites. Natural microbe-mediated refractoriness to Plasmodium infection in Anopheles gambiae. Science For instance, infections after removal of endogenous microbiota by antibiotic treatment lead to higher parasite numbers when compared with infections of untreated mosquitoes Beier et al.
Effects of para-aminobenzoic acid, insulin and gentamicin on Plasmodium falciparum development in anopheline mosquitoes Diptera: Culicidae. In addition, when antisera raised against An. Mosquito ingestion of antibodies against mosquito midgut microbiota improves conversion of ookinetes to oocysts for Plasmodium falciparum, but not P. These results are in contrast to previous reports where similar experiments resulted into a reduced parasite load due to antibodies targeting mosquito proteins required for parasite development Srikrishnaraj et al.
Antibodies to Anopheles midgut reduce vector competence for Plasmodium vivax malaria. Med Vet Entomol 9: Anti-mosquito midgut antibodies block development of Plasmodium falciparum and Plasmodium vivax in multiple species of Anopheles mosquitoes and reduce vector fecundity and survivorship.
Blocking of malaria parasite development in mosquito and fecundity reduction by midgut antibodies in Anopheles stephensi Diptera: Culicidae. Arch Insect Biochem Physiol Effect of anti-mosquito midgut antibodies on development of malaria parasite, Plasmodium vivax and fecundity in vector mosquito Anopheles culicifacies Diptera: Culicidae.
Indian J Exp Biol The reasons for these discrepancies are unclear and require further investigation. Recent studies have shown that certain variants of Serratia marcescens , a bacterium commonly found in the midgut of laboratory and field mosquitoes, are able to inhibit Plasmodium in the mosquito Bando et al.
Intra-specific diversity of Serratia marcescens in Anopheles mosquito midgut defines Plasmodium transmission capacity. Sci Rep 3: Increased Plasmodium inhibition was correlated to increased flagella length and abundance and with reduced ability of the ookinete to invade the midgut Bando et al. The authors hypothesise that a physical barrier imposed by the flagella may contribute to the decreased success of ookinetes to invade the midgut epithelium. Recent evidence has also emerged that bacteria may influence Plasmodium development directly through the production of antimalarial compounds Fig.
Cirimotich et al. The antiparasitic effect of this bacterium, which is observed at the zygote to ookinete transition, can be rescued by addition of the antioxidant vitamin C to the infectious blood meal. Additional evidence suggests that the midgut microbiota play a direct role in the activation of the mosquito immune response.
Shortly after blood ingestion, the resident microbiota undergo dramatic proliferation about 2 orders of magnitude peaking at about 24 h Pumpuni et al. This strong bacterial proliferation is likely to result in an immune response independent of parasite presence. Dong et al. This is true for the induction of SRPN6 in response to Enterobacter infection, which in turn contributes to the anti- Plasmodium response of the mosquito Eappen et al.
Moreover, Rodrigues et al. A delicate balance exists between the commensal gut microbiota and its mosquito host to limit bacterial over-proliferation and the subsequent immune response that may have negative effects towards mosquito fitness. To reduce hyperactivation of the mosquito immune system by the midgut bacteria, the mosquito is thought to form a dityrosine network that restricts contact of bacteria with the midgut epithelium, thus reducing the antimicrobial response Kumar et al.
As a result, proliferation of the normal gut flora is not impaired and malaria parasite development is unhindered Kumar et al.
In addition, dual oxidase expression by the mosquito midgut epithelium likely results in ROS production, playing a similar role to that in Drosophila of limiting bacterial numbers Ha et al. Coordination of multiple dual oxidase-regulatory pathways in responses to commensal and infectious microbes in Drosophila gut.
Nature Immunol Hemocyte differentiation mediates innate immune memory in Anopheles gambiae mosquitoes. Physical barriers to Plasmodium development - The PM - The distension of the mosquito midgut by a blood meal induces midgut epithelial cells to secrete components of an extracellular layer, known as the PM, which completely surrounds the ingested blood.
The PM is composed of proteins, glycoproteins and proteoglycans that are structurally linked by chitin Shao et al. The peritrophic matrix of hematophagous insects. The Anopheles gambiae adult midgut peritrophic matrix proteome. The PM constitutes a physical barrier that prevents direct contact of commensal bacteria and of components of the blood meal with the midgut epithelium.
Initially soft and fragile, the PM polymerises and gradually thickens reaching maximal rigidity at about 24 h after the blood meal Shao et al. As the PM completely surrounds the blood meal, it constitutes the first significant physical barrier to Plasmodium development in the mosquito. As ookinetes mature approximately h after blood ingestion they migrate to the periphery of the blood bolus, presumably guided by environmental or sensory cues.
Upon contact with the PM, the ookinete secretes a chitinase and possibly other proteases from its micronemes to locally disrupt and penetrate the chitinous PM. Inactivation of the chitinase genes dramatically reduces the ability of the ookinete to traverse the PM Dessens et al. Knockout of the rodent malaria parasite chitinase pbCHT1 reduces infectivity to mosquitoes. Disruption of Plasmodium falciparum chitinase markedly impairs parasite invasion of mosquito midgut.
In some parasite species, ookinetes secrete a chitinase precursor or zymogen that is activated by mosquito midgut proteases Shahabuddin et al.
Transmission-blocking activity of a chitinase inhibitor and activation of malarial parasite chitinase by mosquito protease. Plasmodium: parasite chitinase and its role in malaria transmission. The midgut epithelium - After traversal of the PM it is believed that ookinetes display extensive gliding motility along the lumenal surface of the midgut epithelium. Invasion in vitro of mosquito midgut cells by the malaria parasite proceeds by a conserved mechanism and results in death of the invaded midgut cells.
A cell surface mucin specifically expressed in the midgut of the malaria mosquito Anopheles gambiae. Partial characterization of oligosaccharides expressed on midgut microvillar glycoproteins of the mosquito, Anopheles stephensi Liston. Disruption of Plasmodium falciparum development by antibodies against a conserved mosquito midgut antigen. Carbohydrate moieties on the midgut epithelium seem to play an important role in ookinete binding to the midgut Zieler et al. Plasmodium gallinaceum ookinetes adhere specifically to the midgut epithelium of Aedes aegypti by interaction with a carbohydrate ligand.
J Exp Biol Plasmodium falciparum ookinetes require mosquito midgut chondroitin sulfate proteoglycans for cell invasion. However, very little is known regarding the specific protein-protein interactions that mediate this process since these carbohydrate moieties are post-translational modifications of yet unknown proteins.
Given the implications as possible TB vaccine targets, identifying these specific interactions is a high priority area of research. Using a phage display library, a peptide termed SM1 was identified that interacts with the lumenal surface of the mosquito midgut epithelium Ghosh et al. Targeting Plasmodium ligands on mosquito salivary glands and midgut with a phage display peptide library.
The SM1 dodecapeptide strongly inhibits P. Transgenic mosquitoes engineered to express SM1 in the midgut following blood-feeding are impaired in the transmission of the malaria parasite Ito et al.
Transgenic anopheline mosquitoes impaired in transmission of a malaria parasite. Nature Further studies have identified that SM1 is a mimotope its conformation resembles of Plasmodium enolase, a protein secreted onto the surface of the ookinete where it acts as an invasion ligand Ghosh et al. Plasmodium ookinetes coopt mammalian plasminogen to invade the mosquito midgut. Ookinete surface enolase also interacts with plasminogen from the blood serum to locally promote its conversion into the proteolytically active plasmin that in turn, is required for midgut invasion Ghosh et al.
Multiple pathways for Plasmodium ookinete invasion of the mosquito midgut. EBP is expressed on the lumenal surface of the mosquito midgut and is required for P.
However, some ookinetes still invade the mosquito midgut in the presence of excess SM1 and this served as the basis for the selection of SM1-resistant parasites that do not require EBP for midgut invasion.
While further work is needed to characterise additional midgut receptor s , these findings suggest that the process of ookinete midgut invasion is complex and involves multiple parasite-mosquito interactions. Characterisation of these interactions remains a major goal for future research and has the potential to lead to novel intervention strategies. The process of ookinete invasion is thought to produce severe damage to the midgut as the ookinete traverses multiple epithelial cells during its journey to the basal lamina.
Invaded cells undergo dramatic cytoskeletal changes and increase the production of reactive oxygen and nitrogen species that trigger apoptosis and cell death Han et al. Molecular interactions between Anopheles stephensi midgut cells and Plasmodium berghei: the time bomb theory of ookinete invasion of mosquitoes.
During this time ookinetes are likely exposed to a highly toxic cellular environment. To ensure its survival, the ookinete must rapidly escape before it is damaged or before the damaged cell is extruded from the midgut epithelium. How do malaria ookinetes cross the mosquito midgut wall?
Cell death and regeneration in the midgut of the mosquito, Culex quinquefasciatus. J Insect Physiol Recent evidence further supports the concept that midgut traversal is a critical step in the mosquito anti- Plasmodium response. Invaded cells produce high levels of NOS and peroxidases that in turn increase the levels of midgut nitration Kumar et al. Inducible peroxidases mediate nitration of Anopheles midgut cells undergoing apoptosis in response to Plasmodium invasion.
The JNK pathway is a key mediator of Anopheles gambiae antiplasmodial immunity. Thus, midgut nitration appears to be a major determinant of Plasmodium survival, yet many questions remain regarding how nitration mediates immune recognition. What proteins on the surface of the ookinete undergo modifications as a result of increased nitration?
How are these modifications subsequently recognised by the mosquito complement system? Components of the anti-Plasmodium immune response - A great deal of effort has been invested in the identification of components that contribute to parasite developmental success in the mosquito in the hope that this knowledge can be translated to the development of alternative strategies for parasite killing. Through the use of dsRNA-mediated gene-silencing, several genes have been described that positively or negatively influence parasite development in the mosquito Blandin et al.
Antimalarial responses in Anopheles gambiae: from a complement-like protein to a complement-like pathway. Cell Host Microbe 3: While more research is required to fully understand the contributions of individual mosquito genes to anti- Plasmodium immunity, evidence suggests that parasite killing after traversal of the midgut epithelium occurs primarily during two separate stages or phases of parasite development Fig.
Fz2 and cdc42 mediate melanization and actin polymerization, but are dispensable for Plasmodium killing in the mosquito midgut. PLoS Pathog 2: e At this point, ookinetes are exposed to the haemocoel and to the complement-like soluble immune proteins that circulate in the haemolymph Blandin et al. Complement-like protein TEP1 is a determinant of vectorial capacity in the malaria vector Anopheles gambiae.
The thioester protein 1 TEP1 was initially identified in view of its high similarity to the vertebrate complement factor C3 and to the related family of alphamacroglobulins Levashina et al. Conserved role of a complement-like protein in phagocytosis revealed by dsRNA knockout in cultured cells of the mosquito, Anopheles gambiae.
Similar to the role of C3 in the complement pathway of mammals, TEP1 behaves as an opsonin promoting the phagocytosis of bacteria Levashina et al. In the haemolymph, TEP1 is expressed constitutively as full-length inactive and processed active forms that require the scaffolding proteins leucine-rich immune molecule 1 LRIM1 and Anopheles Plasmodium -responsive leucine-rich repeat protein 1 APL1 to direct TEP1 to pathogen surfaces and prevent self-recognition Fraiture et al.
Leucine-rich repeat protein complex activates mosquito complement in defense against Plasmodium parasites. APL1A expression is required for protection against P.
Fine pathogen discrimination within the APL1 gene family protects Anopheles gambiae against human and rodent malaria species. Although it is unclear how the mosquito immune system is able to distinguish their targets, it is reasonable to assume that members of the APL1 gene family have important functions in parasite recognition as part of the mosquito complement-like pathway.
Upon binding to the ookinete, TEP1 is thought to promote parasite killing through lysis or melanisation Blandin et al. A similar amplification of the complement response is also seen in the vertebrate complement system where C3b, the cleavage product of C3 equivalent to TEP1 , binds factor B on the surface of the pathogen.
This complex is then activated by factor D into the C3 convertase that in turn mediates the recruitment of additional C3b molecules to the pathogen surface [reviewed in Walport Walport MJ However, our knowledge of this process in the mosquito is incomplete and additional proteins that promote parasite killing may be recruited to the ookinete surface, as is the case for the vertebrate complement system.
Multiple proteins and co-factors are known to assemble onto pathogen surfaces as part of the mammalian complement pathways and further investigation of the components of the mosquito complement-like pathway remains an important goal for future investigation.
Furthermore, many questions remain regarding the mechanisms involved in directing TEP1 binding to the ookinete surface. As mentioned previously, midgut nitration appears to be a critical determinant of parasite recognition by the mosquito complement-like pathway Oliveira et al. However, it is unclear if TEP1 directly recognises these protein modifications on the parasite surface or if this is mediated by other supporting molecules. First proposed by Gupta et al.
In An. This results in a near refractory phenotype that elevates NOS expression in the mosquito midgut and carcass Gupta et al. In addition to this study, there is a great deal of evidence suggesting that NOS and subsequent NO production are important determinants of oocyst development Luckhart et al. Parasite killing in malaria non-vector mosquito Anopheles culicifacies species B: implication of nitric oxide synthase upregulation. NOS expression appears to be induced throughout the entire mosquito in response to Plasmodium infection Luckhart et al.
Much work remains to be done to better define the mechanisms of late-phase immune response and how it interferes with oocyst development. Immune pathways that limit parasite development - Much of our knowledge of the mosquito innate immune response stems from Drosophila research and from other insect systems.
Orthologous immune signalling pathways have been described in mosquitoes that respond to a variety of pathogens and regulate anti- Plasmodium immunity. However, compared to Drosophila , there have been rapid expansions of mosquito immune gene families, suggesting a functional broadening of the mosquito defense systems Waterhouse et al.
Evolutionary dynamics of immune-related genes and pathways in disease-vector mosquitoes. As a result, the mosquito represents a unique model to study host-parasite interactions and the innate immune response.
The host defense of Drosophila melanogaster. Annu Rev Immunol While these pathways certainly exist in mosquitoes [reviewed by Cirimotich et al. Mosquito immune defenses against Plasmodium infection. Dev Comp Immunol However, given current technology that relies primarily on systemic gene-silencing, the contributions of individual mosquito tissues midgut, haemocytes, fat body to the immune defenses has been difficult to ascertain.
Similar experiments in Anophe-les suggest that this pathway is evolutionarily conserved in mosquitoes Frolet et al. Boosting NF-kappaB-dependent basal immunity of Anopheles gambiae aborts development of Plasmodium berghei.
Immunity Caspar controls resistance to Plasmodium falciparum in diverse anopheline species. REL1, originally described as Gambif1, is an anopheline nuclear factor kappa B-like transcription factor orthologous to Drosophila Dorsal Barillas-Mury et al. Immune factor Gambif1, a new rel family member from the human malaria vector, Anopheles gambiae.
Upon immune activation, Toll signalling results in the directed degradation of Cactus, a negative regulator of REL1, thus allowing translocation of REL1 to the nucleus and the expression of its downstream effector genes Frolet et al. Silencing cactus expression by dsRNA injection results in the constitutive activation of the Toll pathway, even without immune challenge Frolet et al. Frolet et al. Recent evidence implicates mosquito haemocytes as critical mediators of this anti- Plasmodium response Ramirez et al.
The role of hemocytes in Anopheles gambiae antiplasmodial immunity. J Innate Immun 6: Further studies suggest that Toll activation may be more efficient at limiting P.
This would imply that immune recognition of rodent and human malaria parasites may occur through different mechanisms Dong et al. Anopheles gambiae immune responses to human and rodent Plasmodium parasite species. How the mosquito distinguishes these two parasites is a very interesting question that remains to be answered.
Pathogen recognition is mediated by peptidoglycan recognition protein LC and the adaptor protein IMD, triggering the cleavage of the transcription factor REL2 Drosophila Relish , which results in its nuclear translocation Meister et al. Immune signaling pathways regulating bacterial and malaria parasite infection of the mosquito Anopheles gambiae. Expression of immune responsive genes in cell lines from two different Anopheline species.
Insect Mol Biol Currently, it is unclear what role the IMD pathway plays in TAK1 signalling and mitogen-activated protein kinase MAPK activation in mosquitoes, however recent evidence implies that JNK activation plays a key role in the mosquito immune response to Plasmodium Garver et al.
As a result, the Anopheles IMD pathway appears to be highly complex and further research is required to fully understand its intricacies.
Based on Drosophila research, the Anopheles IMD pathway is likely regulated at several different steps [reviewed by Cirimotich et al. In mosquitoes, it has been suggested that immune regulation of one IMD pathway component occurs through the differential splicing of the transcription factor REL2 Meister et al.
Whereas the short form is constitutively active and thought to be responsible for basal immune function, REL2-F is localised in the cytoplasm and thus transcriptionally inactive Meister et al.
Caspar, a suppressor of antibacterial immunity in Drosophila. Due to the inability to distinguish the REL2 short and full-length forms by RNAi, their effect on parasite infection have been difficult to elucidate Meister et al. Caspar-silencing renders mosquitoes refractory to malaria parasites and it appears that activation of the IMD pathway is more efficient in limiting P. However, additional work is needed to understand the precise mechanisms of REL2 activation and the contributions made by the various mosquito immune tissues to this process.
Development Drosophila intestinal response to bacterial infection: activation of host defense and stem cell proliferation. This is in contrast to Drosophila and other mosquito species that contain only a single STAT transcription factor Gupta et al. Following immune activation, STAT is phosphorylated leading to its translocation to the nucleus and activation of downstream effector genes.
Gupta et al. PLoS Pathog 8: e LL3 expression is strongly up-regulated in response to ookinete invasion of the midgut and directly influences the expression of SRPN6 Smith et al. An immune-responsive serpin, SRPN6, mediates mosquito defense against malaria parasites.
The parasite invasion marker SRPN6 reduces sporozoite numbers in salivary glands of Anophe- les gambiae. Cell Microbiol Clarification of the mechanisms of LL3 activation and the role of LL3 in the overall context of mosquito immunity are the subjects of further study. Emerging evidence suggests that components of the ingested blood meal also affect mosquito immune function Pakpour et al.
The effects of ingested mammalian blood factors on vector arthropod immunity and physiology.
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