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• W2178554527 abstract "Mosquitoes are natural vectors that allow systematic and persistent arbovirus infection. The infection in mosquitoes is usually associated with few fitness costs, allowing the mosquitoes to transmit the virus efficiently. Mosquitoes have evolved systemic and tissue-specific antiviral mechanisms to limit viral propagation to nonpathogenic levels. Mosquitoes ingest an arbovirus-infected blood meal into the midgut. The virus subsequently infects the midgut epithelial cells and spreads systematically through the hemolymph to other tissues. RNAi and several conserved innate immune pathways play systemic roles against arbovirus infection of mosquitoes. Specific antiviral strategies are armed in the mosquito midgut, hemolymph, salivary glands, and neural tissues for the control of arboviral propagation. Mosquito-borne viral diseases are a major concern of global health and result in significant economic losses in many countries. As natural vectors, mosquitoes are very permissive to and allow systemic and persistent arbovirus infection. Intriguingly, persistent viral propagation in mosquito tissues neither results in dramatic pathological sequelae nor impairs the vectorial behavior or lifespan, indicating that mosquitoes have evolved mechanisms to tolerate persistent infection and developed efficient antiviral strategies to restrict viral replication to nonpathogenic levels. Here we provide an overview of recent progress in understanding mosquito antiviral immunity and advances in the strategies by which mosquitoes control viral infection in specific tissues. Mosquito-borne viral diseases are a major concern of global health and result in significant economic losses in many countries. As natural vectors, mosquitoes are very permissive to and allow systemic and persistent arbovirus infection. Intriguingly, persistent viral propagation in mosquito tissues neither results in dramatic pathological sequelae nor impairs the vectorial behavior or lifespan, indicating that mosquitoes have evolved mechanisms to tolerate persistent infection and developed efficient antiviral strategies to restrict viral replication to nonpathogenic levels. Here we provide an overview of recent progress in understanding mosquito antiviral immunity and advances in the strategies by which mosquitoes control viral infection in specific tissues. Mosquitoes are primary vectors for hundreds of human pathogens throughout the world. Mosquito-borne viruses are etiological agents of severe human diseases including hemorrhagic fever, biphasic fever, encephalitis, and meningitis. These viruses infect hundreds of millions of people each year and cause a large number of deaths [1Bhatt S. et al.The global distribution and burden of dengue.Nature. 2013; 496: 504-507Crossref PubMed Scopus (5727) Google Scholar, 2Caraballo H. King K. Emergency department management of mosquito-borne illness: malaria, dengue, and West Nile virus.Emerg. Med. Pract. 2014; 16: 1-23PubMed Google Scholar]. Human viruses transmitted by mosquitoes are generally categorized into five genera: Flavivirus (Flaviviridae family), Alphavirus (Togaviridae family), Orthobunyavirus and Phlebovirus (Bunyaviridae family), and Seadornavirus (Reoviridae family) [3Rückert C. et al.Antiviral responses of arthropod vectors: an update on recent advances.Virus Dis. 2014; 25: 249-260Crossref Scopus (25) Google Scholar, 4Liu H. et al.Banna virus, China, 1987–2007.Emerg. Infect. Dis. 2010; 16: 514-517Crossref PubMed Scopus (43) Google Scholar]. Dengue virus (DENV), Chikungunya virus (CHIKV), Japanese encephalitis virus (JEV), and West Nile virus (WNV) are the most prevalent arboviruses throughout the world [2Caraballo H. King K. Emergency department management of mosquito-borne illness: malaria, dengue, and West Nile virus.Emerg. Med. Pract. 2014; 16: 1-23PubMed Google Scholar, 5Weaver S.C. Lecuit M. Chikungunya virus and the global spread of a mosquito-borne disease.N. Engl. J. Med. 2015; 372: 1231-1239Crossref PubMed Scopus (534) Google Scholar]. For example, DENV transmitted by Aedes aegypti and Aedes albopictus is estimated to result in 390 million infections per year worldwide, 96 million of which manifest with apparent clinical symptoms [1Bhatt S. et al.The global distribution and burden of dengue.Nature. 2013; 496: 504-507Crossref PubMed Scopus (5727) Google Scholar]. In 2013, CHIKV, a member of the Alphavirus genus, emerged in 43 countries and territories in the Americas causing acute fever and arthralgia in more than 1000 000 suspected cases [5Weaver S.C. Lecuit M. Chikungunya virus and the global spread of a mosquito-borne disease.N. Engl. J. Med. 2015; 372: 1231-1239Crossref PubMed Scopus (534) Google Scholar]. While the majority of mosquito-borne diseases occur in endemic tropical and subtropical regions, burgeoning international travel and expanded urbanization have increased their prevalence in new territories [6Jones K.E. et al.Global trends in emerging infectious diseases.Nature. 2008; 451: 990-993Crossref PubMed Scopus (4513) Google Scholar]. Unfortunately, there are no vaccines or therapeutics available for most mosquito-borne diseases. Together, these factors have led to rapid increases in endemics and epidemics over the past decade. A better understanding of mosquito–virus interactions may provide novel strategies to target virus transmission in nature. Mosquito-borne viruses are generally maintained in a cycle between mosquitoes and vertebrate animals. After transmission to the hosts through mosquito bites, the viruses can rapidly replicate to a high level of viremia in the blood circulation system that is sufficient for acquisition by other mosquitoes taking a blood meal. The viruses subsequently infect the midgut epithelial cells and spread systematically through the hemocoel to other tissues, such as the salivary glands and neural system. Then, the infected mosquitoes are ready to transmit the virus to other hosts through bites [7Bosio C.F. et al.Quantitative trait loci that control vector competence for dengue-2 virus in the mosquito Aedes aegypti.Genetics. 2000; 156: 687-698PubMed Google Scholar, 8Girard Y.A. et al.West Nile virus dissemination and tissue tropisms in orally infected Culex pipiens quinquefasciatus.Vector Borne Zoonotic Dis. 2004; 4: 109-122Crossref PubMed Scopus (87) Google Scholar, 9Liu Y. et al.Transmission-blocking antibodies against mosquito C-type lectins for dengue prevention.PLoS Pathog. 2014; 10: e1003931Crossref PubMed Scopus (73) Google Scholar]. In contrast to the severe diseases observed in vertebrates, persistent viral replication in mosquitoes neither results in dramatic pathological sequelae nor influences mosquito behavior or lifespan [10Xiao X. et al.A neuron-specific antiviral mechanism prevents lethal flaviviral infection of mosquitoes.PLoS Pathog. 2015; 11: e1004848Crossref PubMed Scopus (19) Google Scholar]. The infection in mosquitoes is usually associated with few fitness costs, thereby allowing the mosquitoes to transmit the virus efficiently [11Lambrechts L. Scott T.W. Mode of transmission and the evolution of arbovirus virulence in mosquito vectors.Proc. Biol. Sci. 2009; 276: 1369-1378Crossref PubMed Scopus (96) Google Scholar]. Our knowledge of the mosquito immune system has advanced rapidly in the past decade and was aided by complete genome sequencing and annotation (https://www.vectorbase.org/). The advances in mosquito genomics and molecular biology have significantly facilitated the study of virus–mosquito interactions and antiviral mechanisms at the molecular level [12Christophides G.K. et al.Immunity-related genes and gene families in Anopheles gambiae.Science. 2002; 298: 159-165Crossref PubMed Scopus (782) Google Scholar, 13Nene V. et al.Genome sequence of Aedes aegypti, a major arbovirus vector.Science. 2015; 316: 1718-1723Crossref Scopus (852) Google Scholar, 14Waterhouse R.M. et al.Evolutionary dynamics of immune-related genes and pathways in disease-vector mosquitoes.Science. 2007; 316: 1738-1743Crossref PubMed Scopus (468) Google Scholar, 15Arensburger P. et al.Sequencing of Culex quinquefasciatus establishes a platform for mosquito comparative genomics.Science. 2010; 330: 86-88Crossref PubMed Scopus (344) Google Scholar, 16Neafsey D.E. et al.Highly evolvable malaria vectors: the genomes of 16 Anopheles mosquitoes.Science. 2015; 347: 1258522Crossref PubMed Scopus (350) Google Scholar]. Mosquitoes have evolved efficient antiviral strategies to restrict viral replication to nonpathogenic levels. The mosquito antiviral mechanisms are very different from those of mammals. Unlike mammals, which have both innate and adaptive immune systems, mosquitoes lack immunoglobulin-based humoral responses and instead rely heavily on intrinsic intracellular antiviral mechanisms such as RNAi and analogous innate immune responses to limit viral propagation [17Wang X.H. et al.RNA interference directs innate immunity against viruses in adult Drosophila.Science. 2006; 312: 452-454Crossref PubMed Scopus (563) Google Scholar, 18Arjona A. et al.Innate immune control of West Nile virus infection.Cell. Microbiol. 2011; 13: 1648-1658Crossref PubMed Scopus (36) Google Scholar]. Knowledge gained over the past decade suggests that RNAi is an essential and systemic antiviral response in mosquitoes and other insects [17Wang X.H. et al.RNA interference directs innate immunity against viruses in adult Drosophila.Science. 2006; 312: 452-454Crossref PubMed Scopus (563) Google Scholar, 19Sánchez-Vargas I. et al.Dengue virus type 2 infections of Aedes aegypti are modulated by the mosquito's RNA interference pathway.PLoS Pathog. 2009; 5: e1000299Crossref PubMed Scopus (334) Google Scholar]. In addition to RNAi, mosquitoes also possess several immune machineries and organ-specific antiviral effectors against arbovirus infections (Figure 1, Key Figure). Dissection of antiviral immunity in mosquito tissues permissive for arbovirus infection will provide insights into the sophisticated interactions between mosquitoes and their transmitted arboviruses. Mosquitoes ingest an arbovirus-infected blood meal into the midgut. After replication in midgut epithelial cells, the tracheal system or muscle may act as a conduit for viral escape into the hemolymph [8Girard Y.A. et al.West Nile virus dissemination and tissue tropisms in orally infected Culex pipiens quinquefasciatus.Vector Borne Zoonotic Dis. 2004; 4: 109-122Crossref PubMed Scopus (87) Google Scholar, 20Romoser W.S. et al.Evidence for arbovirus dissemination conduits from the mosquito (Diptera: Culicidae) midgut.J. Med. Entomol. 2004; 41: 467-475Crossref PubMed Scopus (55) Google Scholar, 21Salazar M.I. et al.Dengue virus type 2: replication and tropisms in orally infected Aedes aegypti mosquitoes.BMC Microbiol. 2007; 7: 9Crossref PubMed Scopus (311) Google Scholar]. Subsequently, the virus spreads via the hemolymph circulation to the fat body, muscles, salivary glands, and neural tissue (Figure 1), while the amount of viral antigen and viral titers in the midgut may decline over time [8Girard Y.A. et al.West Nile virus dissemination and tissue tropisms in orally infected Culex pipiens quinquefasciatus.Vector Borne Zoonotic Dis. 2004; 4: 109-122Crossref PubMed Scopus (87) Google Scholar, 21Salazar M.I. et al.Dengue virus type 2: replication and tropisms in orally infected Aedes aegypti mosquitoes.BMC Microbiol. 2007; 7: 9Crossref PubMed Scopus (311) Google Scholar]. Once a mosquito is infected with an arbovirus, the infection can be persistent in its tissues and the infected mosquito can transmit the virus throughout its whole lifespan. The extrinsic incubation period (defined as ‘the interval between the acquisition of an infectious agent by a vector and the vector's ability to transmit the agent to other susceptible vertebrate hosts’ [22Editors of the American Heritage Dictionaries The American Heritage Medical Dictionary. Houghton Mifflin Harcourt, 2007Google Scholar]) is an index that is representative of the kinetics and tropism of virus dissemination in its vector. The length of the extrinsic incubation period varies significantly with different arboviruses, mosquito species, and their combinations [23Miller B.R. et al.Replication, tissue tropisms and transmission of yellow fever virus in Aedes albopictus.Trans. R. Soc. Trop. Med. Hyg. 1989; 83: 252-255Abstract Full Text PDF PubMed Scopus (59) Google Scholar, 24Scott T.W. Burrage T.G. Rapid infection of salivary glands in Culiseta melanura with eastern equine encephalitis virus: an electron microscopic study.Am. J. Trop. Med. Hyg. 1984; 33: 961-964Crossref PubMed Scopus (25) Google Scholar, 25Weaver S.C. Electron microscopic analysis of infection patterns for Venezuelan equine encephalomyelitis virus in the vector mosquito, Culex (Melanoconion) taeniopus.Am. J. Trop. Med. Hyg. 1986; 35: 624-631Crossref PubMed Scopus (29) Google Scholar]. Mosquito antiviral immunity modulates the dynamics of viral dissemination and replication in tissues, thereby acting as a key determinant in the regulation of the extrinsic incubation period during arboviral infection. Multiple studies have reported that RNAi and several other conserved innate immune responses such as the Toll, immune deficiency factor (Imd), and Janus kinase (JAK)–signal transduction and activators of transcription (STAT) pathways play systemic roles against arbovirus infection in mosquitoes (Figure 1A). The mechanisms regulating these immune pathways have been elucidated in Drosophila. There are orthologs of the core components of these pathways present in the genomes of major vector mosquitoes. Therefore, we hypothesize that the immune signaling pathways might be highly conserved between Drosophila and mosquitoes [12Christophides G.K. et al.Immunity-related genes and gene families in Anopheles gambiae.Science. 2002; 298: 159-165Crossref PubMed Scopus (782) Google Scholar, 14Waterhouse R.M. et al.Evolutionary dynamics of immune-related genes and pathways in disease-vector mosquitoes.Science. 2007; 316: 1738-1743Crossref PubMed Scopus (468) Google Scholar, 26Bartholomay L.C. et al.Pathogenomics of Culex quinquefasciatus and meta-analysis of infection responses to diverse pathogens.Science. 2010; 330: 88-90Crossref PubMed Scopus (117) Google Scholar]. However, it is important to note that Drosophila is not a vector for arboviruses. Thus, the antiviral responses triggered by Drosophila viruses such as Drosophila C virus (DCV) may be different from the responses induced by arboviruses in mosquitoes. The RNAi mechanism is an important antiviral response in invertebrates that comprises three independent pathways: siRNA, miRNA, and piwi-interacting RNA (piRNA) [27Blair C.D. Olson K.E. The role of RNA interference (RNAi) in arbovirus–vector interactions.Viruses. 2015; 17: 820-843Crossref Scopus (104) Google Scholar]. The antiviral role of the siRNA pathway is the most thoroughly studied because virus-derived siRNA is a potent and common antiviral immune response in mosquitoes and Drosophila [17Wang X.H. et al.RNA interference directs innate immunity against viruses in adult Drosophila.Science. 2006; 312: 452-454Crossref PubMed Scopus (563) Google Scholar, 19Sánchez-Vargas I. et al.Dengue virus type 2 infections of Aedes aegypti are modulated by the mosquito's RNA interference pathway.PLoS Pathog. 2009; 5: e1000299Crossref PubMed Scopus (334) Google Scholar]. The antiviral mechanism of the intracellular siRNA pathway is depicted in Figure 1 and systemically reviewed elsewhere [27Blair C.D. Olson K.E. The role of RNA interference (RNAi) in arbovirus–vector interactions.Viruses. 2015; 17: 820-843Crossref Scopus (104) Google Scholar, 28Blair C.D. Mosquito RNAi is the major innate immune pathway controlling arbovirus infection and transmission.Future Microbiol. 2011; 6: 265-277Crossref PubMed Scopus (180) Google Scholar]. Several recent studies have characterized the antiviral siRNA response to diverse arboviral infections in mosquitoes. Knockdown of the core components of the siRNA pathway resulted in uncontrolled arbovirus replication in mosquitoes, a shortened extrinsic incubation period, and decreased arboviral transmission efficiency [19Sánchez-Vargas I. et al.Dengue virus type 2 infections of Aedes aegypti are modulated by the mosquito's RNA interference pathway.PLoS Pathog. 2009; 5: e1000299Crossref PubMed Scopus (334) Google Scholar, 29Keene K.M. et al.RNA interference acts as a natural antiviral response to O’nyong-nyong virus (Alphavirus; Togaviridae) infection of Anopheles gambiae.Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 17240-17245Crossref PubMed Scopus (277) Google Scholar, 30Franz A.W. et al.Engineering RNA interference-based resistance to dengue virus type 2 in genetically modified Aedes aegypti.Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 4198-4203Crossref PubMed Scopus (302) Google Scholar, 31Campbell C.L. et al.Aedes aegypti uses RNA interference in defense against Sindbis virus infection.BMC Microbiol. 2008; 8: 47Crossref PubMed Scopus (182) Google Scholar, 32Cirimotich C.M. et al.Suppression of RNA interference increases Alphavirus replication and virus-associated mortality in Aedes aegypti mosquitoes.BMC Microbiol. 2009; 9: 49Crossref PubMed Scopus (106) Google Scholar, 33Carissimo G. et al.Antiviral immunity of Anopheles gambiae is highly compartmentalized, with distinct roles for RNA interference and gut microbiota.Proc. Natl. Acad. Sci. U.S.A. 2015; 112: E176-E185Crossref PubMed Scopus (106) Google Scholar]. In addition to the siRNA pathway, recent studies suggested that the piRNA pathway also acted as a virus-restricting player. piRNA-like virus-specific small RNAs were detected by deep sequencing the genomes of mosquitoes and cell lines infected with arboviruses such as DENV [34Hess A.M. et al.Small RNA profiling of dengue virus–mosquito interactions implicates the PIWI RNA pathway in anti-viral defense.BMC Microbiol. 2011; 11: 45Crossref PubMed Scopus (134) Google Scholar], Sindbis virus (SINV) [35Vodovar N. et al.Arbovirus-derived piRNAs exhibit a Ping-Pong signature in mosquito cells.PLoS ONE. 2012; 7: e30861Crossref PubMed Scopus (150) Google Scholar], CHIKV [36Morazzani E.M. et al.Production of virus-derived Ping-Pong-dependent piRNA-like small RNAs in the mosquito soma.PLoS Pathog. 2012; 8: e1002470Crossref PubMed Scopus (224) Google Scholar], and La Crosse virus (LACV) [37Brackney D.E. et al.C6/36 Aedes albopictus cells have a dysfunctional antiviral RNA interference response.PLoS Negl. Trop. Dis. 2010; 4: e856Crossref PubMed Scopus (231) Google Scholar]. Furthermore, knockdown of key components of the piRNA pathway can enhance the replication of alphaviruses. This demonstrates the contribution of piRNAs to mosquito antiviral defenses [38Schnettler E. et al.Knockdown of piRNA pathway proteins results in enhanced Semliki Forest virus production in mosquito cells.J. Gen. Virol. 2013; 94: 1680-1689Crossref PubMed Scopus (147) Google Scholar, 39Miesen P. et al.Distinct sets of PIWI proteins produce arbovirus and transposon-derived piRNAs in Aedes aegypti mosquito cells.Nucleic Acids Res. 2015; 43: 6545-6556Crossref PubMed Scopus (105) Google Scholar]. Moreover, little is known about the miRNA pathway in mosquito antiviral immunity. Differential expression of miRNAs has been observed in WNV-infected Culex quinquefasciatus mosquitoes [40Skalsky R.L. et al.Identification of microRNAs expressed in two mosquito vectors, Aedes albopictus and Culex quinquefasciatus.BMC Genomics. 2010; 11: 119Crossref PubMed Scopus (144) Google Scholar]. There is a specific miRNA that restricts WNV infection in A. aegypti [41Slonchak A. et al.Expression of mosquito microRNA Aae-miR-2940-5p is downregulated in response to West Nile virus infection to restrict viral replication.J. Virol. 2014; 88: 8457-8467Crossref PubMed Scopus (68) Google Scholar], which suggests an antiviral role for miRNA in arbovirus infection of mosquitoes. In addition to RNAi, several evolutionarily conserved innate immune pathways also play important roles in the control of arbovirus infection in insects (Figure 1A). The Drosophila Toll and Imd pathways, whose core components share large similarities with the mammalian Toll-like receptor (TLR) and tumor necrosis factor (TNF) pathways, have been shown to mediate nuclear factor kappa light chain enhancer of activated B cells (NF-κB)-dependent immune responses during the elimination of invading microorganisms. In accordance with comparative genomic analysis between Drosophila and mosquitoes, the core signaling components of the Toll and Imd pathways are highly conserved [12Christophides G.K. et al.Immunity-related genes and gene families in Anopheles gambiae.Science. 2002; 298: 159-165Crossref PubMed Scopus (782) Google Scholar, 14Waterhouse R.M. et al.Evolutionary dynamics of immune-related genes and pathways in disease-vector mosquitoes.Science. 2007; 316: 1738-1743Crossref PubMed Scopus (468) Google Scholar, 26Bartholomay L.C. et al.Pathogenomics of Culex quinquefasciatus and meta-analysis of infection responses to diverse pathogens.Science. 2010; 330: 88-90Crossref PubMed Scopus (117) Google Scholar], indicating that these pathways may play a similar role in antimicrobial immunity in mosquitoes. The Drosophila Imd pathway plays important antiviral roles against insect viruses such as cricket paralysis virus (CrPV) [42Costa A. et al.The Imd pathway is involved in antiviral immune responses in Drosophila.PLoS ONE. 2009; 15: e7436Crossref Scopus (175) Google Scholar] and Drosophila melanogaster sigma virus (DMelSV) [43Tsai C.W. et al.Drosophila melanogaster mounts a unique immune response to the rhabdovirus sigma virus.Appl. Environ. Microbiol. 2008; 74: 3251-3256Crossref PubMed Scopus (53) Google Scholar]. Additionally, SINV infection augments the expression of antimicrobial peptides (AMPs) downstream of the Imd pathway in Drosophila [44Huang Z. et al.An antiviral role for antimicrobial peptides during the arthropod response to Alphavirus replication.J. Virol. 2013; 87: 4272-4280Crossref PubMed Scopus (60) Google Scholar]. The antiviral function of the Imd pathway has also been reported in mosquitoes. DENV infection induces multiple immune components of the Imd pathway in A. aegypti salivary glands [45Luplertlop N. et al.Induction of a peptide with activity against a broad spectrum of pathogens in the Aedes aegypti salivary gland, following infection with dengue virus.PLoS Pathog. 2011; 7: e1001252Crossref PubMed Scopus (130) Google Scholar]. Additionally, Anopheles gambiae infection with O’nyong’nyong virus (ONNV) is enhanced by knockdown of Imd components in the mosquito midgut. These findings indicate that there is an antiviral role for the Imd pathway [33Carissimo G. et al.Antiviral immunity of Anopheles gambiae is highly compartmentalized, with distinct roles for RNA interference and gut microbiota.Proc. Natl. Acad. Sci. U.S.A. 2015; 112: E176-E185Crossref PubMed Scopus (106) Google Scholar]. In addition to the Imd-mediated immune response, the Toll pathway also activates antiviral responses to arboviral infection in mosquitoes [46Zambon R.A. et al.The Toll pathway is important for an antiviral response in Drosophila.Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 7257-7262Crossref PubMed Scopus (302) Google Scholar, 47Xi Z. et al.The Aedes aegypti Toll pathway controls dengue virus infection.PLoS Pathog. 2008; 4: e1000098Crossref PubMed Scopus (583) Google Scholar, 48Pan X. et al.Wolbachia induces reactive oxygen species (ROS)-dependent activation of the Toll pathway to control dengue virus in the mosquito Aedes aegypti.Proc. Natl. Acad. Sci. U.S.A. 2012; 109: E23-E31Crossref PubMed Scopus (364) Google Scholar]. Although the antibacterial and antifungal mechanisms of the Toll and Imd pathways have been well established, the pattern recognition receptors for viruses in Toll- and Imd-mediated antiviral immunity have not been elucidated. Additionally, the AMPs upregulated by the Toll and Imd pathways are potent antiviral effectors. However, their mechanisms of action are not yet understood. Notably, several studies indicated that the mosquito Toll pathway exerted its antiviral activity against specific virus species. For example, knockdown of a key component of the Toll pathway (Myd88) significantly enhanced DENV replication [47Xi Z. et al.The Aedes aegypti Toll pathway controls dengue virus infection.PLoS Pathog. 2008; 4: e1000098Crossref PubMed Scopus (583) Google Scholar]. Activation of the Toll pathway via Wolbachia-induced reactive oxygen species (ROS) stimulated AMPs to restrict DENV infection in A. aegypti, indicating a role for the Toll pathway against Flavivirus infection [48Pan X. et al.Wolbachia induces reactive oxygen species (ROS)-dependent activation of the Toll pathway to control dengue virus in the mosquito Aedes aegypti.Proc. Natl. Acad. Sci. U.S.A. 2012; 109: E23-E31Crossref PubMed Scopus (364) Google Scholar]. In contrast, the published literature to date indicates that Alphavirus infection is not controlled by the Toll pathway. In Aedes albopictus U4.4 cells, Semliki Forest virus (SFV) replication was not reduced by the expression of a constitutively active Toll protein [49Fragkoudis R. et al.Semliki Forest virus strongly reduces mosquito host defence signaling.Insect Mol. Biol. 2008; 17: 647-656Crossref PubMed Scopus (70) Google Scholar]. Silencing Cactus, a negative regulator of the Toll pathway in A. gambiae, resulted in an opposite phenotype during ONNV infection [50Waldock J. et al.Anopheles gambiae antiviral immune response to systemic O’nyong-nyong infection.PLoS Negl. Trop. Dis. 2012; 6: e1565Crossref PubMed Scopus (51) Google Scholar]. These results suggest that the Toll pathway may exhibit specificity in restricting Flavivirus but not Alphavirus replication in mosquitoes. The JAK–STAT pathway was originally identified as an immune signaling pathway that induced antiviral effectors in mammals [51Fu X.Y. et al.The proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction.Proc. Natl. Acad. Sci. U.S.A. 1992; 89: 7840-7843Crossref PubMed Scopus (452) Google Scholar, 52Schindler C. et al.Proteins of transcription factor ISGF-3: one gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha.Proc. Natl. Acad. Sci. U.S.A. 1992; 89: 7836-7839Crossref PubMed Scopus (543) Google Scholar]; interestingly, its core components are evolutionarily conserved between arthropods and mammals [53Dostert C. et al.The Jak–STAT signaling pathway is required but not sufficient for the antiviral response of Drosophila.Nat. Immunol. 2005; 6: 946-953Crossref PubMed Scopus (476) Google Scholar, 54Souza-Neto J.A. et al.An evolutionary conserved function of the JAK–STAT pathway in anti-dengue defense.Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 17841-17846Crossref PubMed Scopus (373) Google Scholar, 55Liu L. et al.Ixodes scapularis JAK–STAT pathway regulates tick antimicrobial peptides, thereby controlling the agent of human granulocytic anaplasmosis.J. Infect. Dis. 2012; 206: 1233-1241Crossref PubMed Scopus (57) Google Scholar]. The signaling cascade of the insect JAK–STAT pathway is briefly introduced in Figure 1. Similar to mammals, the JAK–STAT pathway in Drosophila and mosquitoes acts as a key antiviral player. In flies, the JAK–STAT pathway has been implicated in the control of DCV infection. A loss-of-function mutation in the Hop kinase in Drosophila resulted in impaired expression of antiviral effectors, enhanced DCV burden, and accelerated death due to infection [53Dostert C. et al.The Jak–STAT signaling pathway is required but not sufficient for the antiviral response of Drosophila.Nat. Immunol. 2005; 6: 946-953Crossref PubMed Scopus (476) Google Scholar]. In accordance with the finding in flies, knockdown of the Dome and Hop genes in A. aegypti enhanced the DENV burden, while silencing PIAS (a negative regulator of the JAK–STAT pathway) resulted in enhanced resistance to DENV infection [54Souza-Neto J.A. et al.An evolutionary conserved function of the JAK–STAT pathway in anti-dengue defense.Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 17841-17846Crossref PubMed Scopus (373) Google Scholar]. According to the JAK–STAT-regulated transcriptome, knockdown of PIAS resulted in the upregulation of four cecropin genes and one defensin gene, indicating that induction of AMPs might be a partial proxy for activation of the JAK–STAT pathway [54Souza-Neto J.A. et al.An evolutionary conserved function of the JAK–STAT pathway in anti-dengue defense.Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 17841-17846Crossref PubMed Scopus (373) Google Scholar]. Nonetheless, the activation and downstream effectors of the JAK–STAT pathway remain to be further understood in mosquitoes. Interferons are key agonists of the mammalian JAK–STAT pathway but no interferon orthologs have been identified in invertebrates [56Cheng G. et al.Identification of a putative invertebrate helical cytokine similar to the ciliary neurotrophic factor/leukemia inhibitory factor family by PSI–BLAST-based approach.J. Interferon Cytokine Res. 2009; 29: 461-468Crossref PubMed Scopus (7) Google Scholar]. A recent study found that the insect cytokine-like factor Vago acted in a manner similar to mammalian interferons [57Deddouche S. et al.The DExD/H-box helicase Dicer-2 mediates the induction of antiviral activity in Drosophila.Nat. Immunol. 2008; 9: 1425-1432Crossref PubMed Scopus (261) Google Scholar, 58Paradkar P.N. et al.Secreted Vago restricts West Nile virus infection in Culex mosquito cells by activating the Jak–STAT pathway.Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 18915-18920Crossref PubMed Scopus (205) Google Scholar]. Viral double-stranded RNA (dsRNA) sensed by the Dicer-2 DExD/H-box helicase domain resulted in robust Vago expression against DCV infection [57Deddou" @default.
• W2178554527 created "2016-06-24" @default.
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• W2178554527 date "2016-03-01" @default.
• W2178554527 modified "2023-10-16" @default.
• W2178554527 title "Mosquito Defense Strategies against Viral Infection" @default.
• W2178554527 cites W1523414017 @default.
• W2178554527 cites W1535231869 @default.
• W2178554527 cites W1601252917 @default.
• W2178554527 cites W1684286000 @default.
• W2178554527 cites W1810620314 @default.
• W2178554527 cites W1968552702 @default.
• W2178554527 cites W1969157447 @default.
• W2178554527 cites W1971395880 @default.
• W2178554527 cites W1981107494 @default.
• W2178554527 cites W1981591053 @default.
• W2178554527 cites W1983630074 @default.
• W2178554527 cites W1984299635 @default.
• W2178554527 cites W1986875579 @default.
• W2178554527 cites W1989759946 @default.
• W2178554527 cites W1990803929 @default.
• W2178554527 cites W1991533759 @default.
• W2178554527 cites W1999113367 @default.
• W2178554527 cites W2001419566 @default.
• W2178554527 cites W2002894499 @default.
• W2178554527 cites W2003694291 @default.
• W2178554527 cites W2003859935 @default.
• W2178554527 cites W2004818718 @default.
• W2178554527 cites W2007793421 @default.
• W2178554527 cites W2010970638 @default.
• W2178554527 cites W2012931223 @default.
• W2178554527 cites W2021618307 @default.
• W2178554527 cites W2022043924 @default.
• W2178554527 cites W2025476226 @default.
• W2178554527 cites W2028012273 @default.
• W2178554527 cites W2028543716 @default.
• W2178554527 cites W2028543950 @default.
• W2178554527 cites W2029433700 @default.
• W2178554527 cites W2030485536 @default.
• W2178554527 cites W2030551855 @default.
• W2178554527 cites W2033268647 @default.
• W2178554527 cites W2034771006 @default.
• W2178554527 cites W2036868716 @default.
• W2178554527 cites W2036933537 @default.
• W2178554527 cites W2039772376 @default.
• W2178554527 cites W2043283675 @default.
• W2178554527 cites W2045032544 @default.
• W2178554527 cites W2048030072 @default.
• W2178554527 cites W2052837081 @default.
• W2178554527 cites W2054682338 @default.
• W2178554527 cites W2055324984 @default.
• W2178554527 cites W2060611796 @default.
• W2178554527 cites W2064184998 @default.
• W2178554527 cites W2065140836 @default.
• W2178554527 cites W2065813900 @default.
• W2178554527 cites W2066268626 @default.
• W2178554527 cites W2066272313 @default.
• W2178554527 cites W2066905085 @default.
• W2178554527 cites W2067069163 @default.
• W2178554527 cites W2068955013 @default.
• W2178554527 cites W2070608209 @default.
• W2178554527 cites W2074173828 @default.
• W2178554527 cites W2074955153 @default.
• W2178554527 cites W2076414390 @default.
• W2178554527 cites W2079936712 @default.
• W2178554527 cites W2079955869 @default.
• W2178554527 cites W2083367400 @default.
• W2178554527 cites W2088335903 @default.
• W2178554527 cites W2090199520 @default.
• W2178554527 cites W2109389988 @default.
• W2178554527 cites W2111335255 @default.
• W2178554527 cites W2115324145 @default.
• W2178554527 cites W2119799069 @default.
• W2178554527 cites W2122657809 @default.
• W2178554527 cites W2124595898 @default.
• W2178554527 cites W2125912444 @default.
• W2178554527 cites W2127435093 @default.
• W2178554527 cites W2128322527 @default.
• W2178554527 cites W2130036534 @default.
• W2178554527 cites W2131222241 @default.
• W2178554527 cites W2133250947 @default.
• W2178554527 cites W2136104403 @default.
• W2178554527 cites W2141673119 @default.
• W2178554527 cites W2142296937 @default.
• W2178554527 cites W2149562859 @default.
• W2178554527 cites W2150034939 @default.
• W2178554527 cites W2150141855 @default.
• W2178554527 cites W2151648857 @default.
• W2178554527 cites W2156597566 @default.
• W2178554527 cites W2167488868 @default.
• W2178554527 cites W2171158206 @default.
• W2178554527 cites W2184815069 @default.
• W2178554527 cites W2201432318 @default.
• W2178554527 cites W2407765409 @default.
• W2178554527 cites W2419106857 @default.

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