Specifically, when mice were fed on by uninfected A. Even at a low dose of infection, mice that were previously fed on by mosquitoes had a lower survival rate after WNV infection Similar experiments with C.
Enhanced early infection was also observed when mice were inoculated with WNV mixed with mosquito salivary gland extract SGE. Importantly, enhanced viremia was not observed when SGE was inoculated in a distal site, supporting that mosquito saliva exerts its effect locally Due to the complex nature of mosquito saliva, multiple activities may lead to the enhancement of early virus infection.
Further, due to the intense selective pressures exerted on mosquito saliva proteins by the host immune systems, successful viruses likely coevolve with their mosquito vectors in order to coopt unique saliva protein activities. For example, A. The adaptation that has taken place between a virus and its vector's saliva proteins may contribute to vector competence, although these mechanisms remain poorly defined.
Multiple reports have suggested that immunomodulatory activities in mosquito saliva could result in enhanced early infection 45 , , , , These reports suggest that saliva modulates skin-resident immune cells. In one report, A. Recruitment of T cells was also reduced when WNV was inoculated during mosquito feeding, rather than by syringe, suggesting that saliva hinders infiltration of these cells into the inoculation site These effects correlated with enhanced expression of interleukin IL , which has anti-inflammatory activities, including the downregulation of Th1 cytokines, major histocompatibility complex MHC class II molecules, and costimulatory molecules on macrophages While this study is limited by the use of A.
It is unknown whether Culex sp. SGEs have similar immunomodulatory activities; however, C. Additionally, saliva from C. The fact that saliva from multiple species in both the Aedes and Culex genera was able to enhance virus infectivity would suggest either that the relevant saliva proteins are highly conserved or that a similar activity has convergently evolved in multiple mosquito vectors. If all Culex spp. In addition, differences in salivary gland protein activities could alter the ability of a mosquito species to enhance pathogen transmission.
Multiple activities that differ between Aedes and Culex mosquitoes have been noted , , , , Since such dramatically different saliva activities exist between Aedes and Culex spp. Though mosquito saliva has been shown to enhance WNV infection, the precise mechanisms as well as the specific saliva proteins involved remain to be investigated. In one example, hyaluronidase from sand fly saliva was found to be important for the enhancement of Leishmania infectivity in mice Saliva hyaluronidase may enlarge the feeding lesion and serve as a spreading factor for other pharmacologically active factors present in saliva This activity was also found in C.
In another example, Salp15 from tick saliva was able to directly interact with the surface of Borrelia burgdorferi and facilitated evasion from host B cell-mediated immunity , and immunization against Salp15 protected mice from Lyme disease Another study identified two tick saliva proteins that functioned to inhibit polymorphonuclear leukocyte recruitment during infection of mice with Borrelia burgdorferi , likely increasing the spirochete burden and enhancing infection Identification of proteins in mosquito saliva that are responsible for the enhancement of WNV transmission is under way, and these investigations may provide novel nonvirus targets for vaccine design.
Multiple negative salivary gland factors that limit flavivirus transmission have been identified 42 , In one example, microarray analysis of DENV-infected and uninfected salivary gland mRNAs showed an upregulation of a putative antibacterial, cecropin-like peptide i.
Genes downregulated by day 14 postinfection likely play a role in salivary gland invasion or virus transmission. Among those, a recombinant pupal cuticle protein was able to directly interact with WNV envelope protein and inhibit infection in vitro and prevent lethal WNV encephalitis in mice Although these proteins were expressed in salivary glands, they have yet to be formally identified in saliva.
Transgenic traits and introduced factors can also alter the transmission of vector-borne pathogens and may play a role in the future control of virus-infected mosquito populations. Transgenic mosquito populations that can be selected to either block transmission, block acquisition, decrease host seeking, decrease probing and biting, increase background mortality, or increase mosquito infection-induced mortality are in development 1 , 59 , 98 , , , To date, most studies have focused on producing transgenic mosquitoes that block transmission.
For example, experimental strains of A. Another gene that is responsible for host seeking behavior has been identified Many strategies that lead to increased background mortality have been implemented, and field trials have already begun to test the effectiveness of these transgenic mosquitoes in reducing wild mosquito populations 9 , 64 , 65 , Laboratory infection with Wolbachia bacteria also reduces the life span of mosquitoes This strategy has also been tested in field trials to reduce wild mosquito populations The release of insect-specific densoviruses also shows high mortality in mosquito populations and may be used as a control strategy The advantage of using Wolbachia or Densovirus infection as opposed to insecticide treatment is that these pathogens are expected to replicate and spread through the wild mosquito populations The emergence of WNV in North America was first documented in the fall of in New York City following an outbreak of mosquito-borne encephalitis responsible for the death of humans, birds, and horses 3 , 26 , , , As detailed above, in most cases the virus is transmitted by the Culex mosquito vector 4 , but transmission may occur through blood transfusion, organ transplantation, breast-feeding, or intrauterine exposure, and laboratory-acquired infection has also been reported 35a , 81 , 85 , , Infections in humans are predominantly subclinical, but reported infection manifestations may range from fever and myalgias to meningoencephalitis and death Encephalitis occurs in only a small subset of patients; progression to severe neurological illness may induce acute flaccid paralysis after meningitis or encephalitis, with rapidly progressing symptoms that may involve all four limbs Severe poliomyelitis-like syndrome can occur and has a poor long-term outcome Higher fatality is also seen in infected infants and immunocompromised patients Risk factors for encephalitis and death include being homeless, a history of cardiovascular disease or chronic renal disease, hepatitis C virus infection, and immunosuppression , In addition, in some cases convalescent patients may have persistent or chronic infection detected through PCR of the urine, which suggested ongoing viral replication in renal tissue , Although persistence of WNV has also been noted in several animal models , , , it has not been uniformly evident in assays of urine The diagnosis of WNV infection is based largely on clinical criteria and testing for antibody responses The incubation period for WNV infection is thought to range from about 2 to 14 days Cross-reactivity with related flaviviruses Japanese encephalitis virus, St.
Replication of WNV has been documented in human monocytes in vitro and with even higher efficiency in polymorphonuclear leukocytes; this could lead to transmission via transfusion of blood 10 , Thus, several rapid tests have been developed for blood donor screening using nucleic acid testing NAT , an amplification-based transcription technique, which identifies WNV-infected individuals before they become symptomatic and may be used to safeguard the blood supply Antibody testing in patients follows an expected timetable of median times of 3.
RNA generally became undetectable after Control of WNV infection by the human and murine hosts has been investigated for both innate and adaptive immune responses. Sensing WNV pathogen-associated molecular patterns through pathogen recognition receptors such as Toll-like receptors TLRs and cytoplasmic RNA helicases is critical for early detection and activation of innate immune pathways that facilitate early control of viral replication 48 , 61 , — , , , This early response is mediated largely by macrophages; WNV infection of macrophage-depleted mice results in increased mortality, higher and extended viremia, and substantially shortened survival.
Moreover, in mice, even a nonneurotrophic WNV strain may cross the blood-brain barrier BBB in the absence of macrophage clearance of virus Macrophages express TLRs, mediate clearance of opsonized viral particles, produce proinflammatory cytokines, and upregulate costimulatory proteins that link innate to adaptive immune responses a , Macrophages are also a major component in inflamed central nervous system CNS tissues and are considered protective against WNV infection.
Although cellular immune mechanisms remain incompletely explained, innate immunity and in particular interferon responses have been shown to be critical in resistance to WNV 7 , 9a , , b. Permeability of the blood-brain barrier BBB , which is enhanced by cytokine responses, has been shown in murine models to be critical to resistance to WNV infection , and elements which decrease the integrity of the BBB contribute to susceptibility to infection with WNV 7 , , Mice lacking TLR3 show improved survival over wild-type animals due to a lower cytokine response and protection from BBB permeability , Infection with flaviviruses leads to upregulation of MHC class I, MHC class II, and adhesion molecules, which may enhance infection through reducing NK cell activity, or enhance a transient autoimmunity in early infection The immunodominant T cell epitopes which elicited both highest-frequency and highest-magnitude responses included sequences from WNV M, E, NS3, and NS4 proteins and, furthermore, were equivalent between symptomatic and asymptomatic subjects in this cohort More cytolytic memory T cells were found in patients with neurological disease Tregs play an important role in protecting against severe disease, and it has been shown in both human patients and animal models that symptomatic patients show a lower frequency of Tregs despite having similar systemic T cell responses Complement has also been indicated as an important component of the host innate immune response to flavivirus infection.
However, while complement traditionally limits the spread of many pathogens, it appears to have both protective and pathogenic roles during flavivirus infection. Whether or not complement is protective or pathogenic depends on a variety of factors, including the specific virus, the phase of infection, and the underlying immune status of the host 40 , , Interestingly, studies with dendritic cells from human donors showed that type I IFN expression in response to WNV in vivo is lower in cells from older donors than in those from younger donors, which may contribute to older individuals being more susceptible to WNV disease These innate pathways are critical not only for immediate antiviral defense pathways such as the upregulation of type I interferons but also for the generation of an effective adaptive T and B cell-mediated sustained immune response 24 , 53a , , , , , Specific human genetic factors that influence the severity of infection with WNV and the antiviral innate immune response have been identified Table 2.
Single nucleotide polymorphism SNP studies have detected SNPs in key regulators of immune function, including interferon pathway elements. A dominant negative splice variant of RNase L, which functions in the antiproliferative roles of interferon, was detected more often in WNV patients than in control patients In addition, a deletion in CCR5, which is known to be protective in infection with HIV, while not associated with susceptibility to WNV, did correspond to severity of infection, presumably due to reduced function of CCR5 pathways in infected hosts 69 , , As more host factors are identified, there are sure to be a number of new determinants of WNV infection.
Current therapeutic options against WNV are mainly supportive; there are no FDA-approved vaccines or treatments available Investigations to identify individual susceptibility markers, recombinant antibodies, peptides, RNA interference, and small molecules with the ability to directly or indirectly neutralize WNV have been reported; however, an effective drug is still lacking 6 , 12 , 70 , 71 , 74 , , There are currently four USDA-licensed vaccines available for equines two are inactivated whole WNV, one is a nonreplicating live canary pox recombinant vector vaccine, and one is an inactivated flavivirus chimeric vaccine.
Though passive immunization has been used in a few cases, it has serious limitations, such as inadvertent transfer of blood-borne pathogens, inconsistent quality of the donor antisera, cost, and allergic reactions A case study of two WNV encephalitis patients treated with alpha interferon, the standard of care for infection with the related flavivirus hepatitis C virus, showed substantial improvement and an improved convalescence course Several approaches are being pursued for the development of a vaccine in humans that may prove valuable for use by targeted populations.
Investigations include live attenuated vaccines, recombinant subunit vaccines, vectorized vaccines, DNA vaccines with constructs that express the WNV E protein, live recombinant vaccines, and an attenuated strain based on nonglycosylated E and mutant NS1 proteins 15 , It was shown to be safe and immunogenic in phase II clinical trials, with high seroconversion rates, but it is no longer available WNV has now persisted and become established in North America.
Of particular significance is the expansion of the mosquito vectors harboring WNV to include Aedes albopictus , a common mammal-biting mosquito 2 , 73 , It is hoped that the increase in our knowledge of the interactions of WNV with the mosquito vector will lead to new avenues for therapeutics and preventative measures. Mosquito responses at the levels of protein and gene expression as well as a more complete understanding of viral pathogenesis in the vector, especially with regard to the immune response, may point to novel targets to focus our efforts to inhibit or block WNV infection in both mosquitoes and mammals.
For example, a single-chain human monoclonal antibody developed through phage display directed against the fusion loop of the envelope protein showed both pan-flaviviral protection and therapeutic efficacy when tested in the murine model 71 , Recent advances in nanoparticle technology have also been employed in vaccination studies of murine WNV infection and show promising efficacy of TLR9-targeted biodegradable nanoparticles, which produce a high number of circulating effector T cells and antigen-specific lymphocytes Potential relevant viral susceptibility mechanisms, including host antagonism of chemokine responses as has been noted in infection with the related flavivirus hepatitis C virus 35 , may reveal infectious mechanisms used by WNV and other mosquito-borne flaviviruses.
The pace of discovery of vector, virus, and host components of pathogenesis continues to provide critical insights for the successful development of controls and treatments for WNV. We are grateful to our long-standing colleague John F. C is supported by grant 5T32AI Tonya M. Colpitts received a B. Her research focuses on the exploration of the interactions between mosquitoes and flaviviruses, the identification of human host factors that bind flaviviral proteins, and the examination of how flavivirus infection affects proteins and pathways of human cells.
She is also researching the interactions of flavivirus capsid protein with nuclear and cytoplasmic proteins as well as the role of capsid in the nucleus of the cell during infection.
Michael J. Conway received a B. His current research interests involve vector-virus-host interactions that occur as disease vectors deposit salivary components and pathogens into the host. Ruth R. Montgomery received a B. After postdoctoral work on macrophage endocytosis with Ira Mellman, she remained at Yale, where she is now Associate Professor of Medicine. The focus of her lab is human innate immunity, specifically the interaction of macrophages, neutrophils, and dendritic cells with pathogens such as West Nile virus and the agent of Lyme disease, Borrelia burgdorferi , including elucidating effects of vector saliva on phagocyte function.
In studies of the pathogenesis of West Nile virus, the Montgomery lab has described inhibition of macrophage function, an unexpected biphasic role for PMNs in infection, and effects of aging on innate immunity, including dysregulation of TLR3 responses in macrophages and reduced responses of dendritic cells to infection with West Nile virus.
Erol Fikrig received a B. Fikrig did a residency in internal medicine at Vanderbilt University School of Medicine and was a fellow in infectious diseases and immunobiology at Yale University School of Medicine.
He currently leads a research group studying the immunopathogenesis of arthropod-borne diseases. Lyme disease, human granulocytic anaplasmosis, and West Nile encephalitis are areas of particular interest. Studies are directed at understanding the interactions between pathogen, host, and vector that result in virulence and transmission and the molecular basis of disease in animal models and patient populations. National Center for Biotechnology Information , U.
Journal List Clin Microbiol Rev v. Clin Microbiol Rev. Author information Copyright and License information Disclaimer. Corresponding author. Address correspondence to Erol Fikrig, ude. All Rights Reserved. This article has been cited by other articles in PMC.
Abstract Summary: West Nile Virus was introduced into the Western Hemisphere during the late summer of and has been causing significant and sometimes severe human diseases since that time. Life Cycle Entry of WNV is through receptor-mediated endocytosis after virus attachment to the cell surface. Open in a separate window. Fig 1. Vector Response to Infection There have been many recent studies aimed at elucidating the transcriptomic and proteomic response to flavivirus infection in the mosquito vector.
Transmission to Vertebrate Host WNV is transmitted to its vertebrate hosts by an infected mosquito vector during the probing process of blood feeding. Mosquito Saliva Factors Saliva from hematophagous insects has been shown to alter the transmissibility of many pathogens 1 , 50 , , , , , , Diagnostics The diagnosis of WNV infection is based largely on clinical criteria and testing for antibody responses Immune Response Control of WNV infection by the human and murine hosts has been investigated for both innate and adaptive immune responses.
Table 1 In vivo function of murine genes in WNV infection. Genetic Determinants of Disease Specific human genetic factors that influence the severity of infection with WNV and the antiviral innate immune response have been identified Table 2. Therapeutics Current therapeutic options against WNV are mainly supportive; there are no FDA-approved vaccines or treatments available Ader DB, et al.
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About 1 out of 10 people who develop severe illness affecting the central nervous system die. Diagnosis See your healthcare provider if you develop the symptoms described above. Your healthcare provider can order tests to look for West Nile virus infection. To learn more about testing, visit our Healthcare Providers page.
Treatment No vaccine or specific medicines are available for West Nile virus infection. Over-the-counter pain relievers can be used to reduce fever and relieve some symptoms In severe cases, patients often need to be hospitalized to receive supportive treatment, such as intravenous fluids, pain medication, and nursing care.
Cases of West Nile Virus occur during mosquito season, which starts in the summer and continues through fall. According to the Centers for Disease Control and Prevention CDC about 1 in 5 people who are infected develop a fever and other symptoms.
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Download PDF. Subjects Ecological epidemiology Viral infection. Results Evidence for West Nile virus circulation in Portugal The earliest evidence of WNV circulation in Portugal arose from serological surveys in the south of the country in —, reporting high titres of hemagglutination-inhibiting antibodies and neutralizing capacity against WNV in animal serum 32 , Full size image.
Discussion Recently, several European countries in the Mediterranean basin have progressed from sporadically reporting WNV infections to reporting yearly epidemic activity affecting both humans and equines e. Full size table. Table 2 Statistical output from the linear quantile mixed modelling.
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