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.
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Always see your healthcare provider for a diagnosis. Certain things can increase the risk for getting West Nile virus. You are more likely to get the virus if you are exposed to mosquito bites during the summer months. Most people who are infected have a minor illness and recover fully. But, older people and those with weak immune systems are more likely to get a serious illness from the infection.
There's no specific treatment for West Nile virus-related diseases. If a person gets the more severe form of the disease, West Nile encephalitis or meningitis, treatment may include intensive supportive therapy, such as:. Usually, the West Nile virus causes mild, flu-like symptoms. However, the virus can cause life-threatening illnesses, such as. At this time, there's no vaccine available to prevent West Nile virus. Repellents are effective only at short distances from the treated surface, so mosquitoes may still be flying nearby.
Always follow the directions on the insect repellent to determine how often you need to reapply repellent. To boost your protection from insect repellent, remember:. Repellents containing a higher concentration of active ingredient such as DEET provide longer-lasting protection. Read the directions to find out how long your product will last. Most people infected with the West Nile virus will have only mild symptoms.
However, if any of the following serious symptoms develop, seek medical attention right away:. Health Home Conditions and Diseases. But, the virus can cause life-threatening illnesses, such as: Encephalitis inflammation of the brain Meningitis inflammation of the lining of the brain and spinal cord Meningoencephalitis inflammation of the brain and its surrounding membrane What causes West Nile virus? What are the symptoms of West Nile virus?
These are the most common symptoms of West Nile fever: Fever Headache Body aches Skin rash on trunk of body Swollen lymph glands The more severe form of the West Nile virus affects mostly older adults. It occurs when the virus crosses the blood-brain barrier and can cause: Headache High fever Neck stiffness Stupor a state of impaired consciousness, extreme lethargy, and reduced reactivity to outside stimuli Disorientation Coma Tremors Convulsions Muscle weakness Paralysis The symptoms of West Nile virus may look like other conditions or health problems.
What are the risk factors for West Nile virus? How is West Nile virus diagnosed? Your doctor will order a blood test to check for antibodies to the West Nile virus.
He or she may also do a lumbar puncture to test cerebrospinal fluid for signs of infection. How is West Nile virus treated? Your healthcare provider will figure out the best treatment based on: How old you are Your overall health and medical history How sick you are How well you can handle specific medications, procedures, or therapies How long the condition is expected to last Your opinion or preference There's no specific treatment for West Nile virus-related diseases.
If a person gets the more severe form of the disease, West Nile encephalitis or meningitis, treatment may include intensive supportive therapy, such as: Hospitalization Intravenous IV fluids Breathing support ventilator Prevention of other infections such as pneumonia or urinary tract infections Nursing care What are the complications of West Nile virus? However, the virus can cause life-threatening illnesses, such as Encephalitis inflammation of the brain Meningitis inflammation of the lining of the brain and spinal cord Meningoencephalitis inflammation of the brain and its surrounding membrane Can West Nile virus be prevented?
If you spray your clothing, there's no need to spray repellent containing DEET on the skin under your clothing.
When possible, wear long-sleeved shirts and long pants treated with repellents containing permethrin or DEET since mosquitoes may bite through thin clothing. Don't directly apply repellents containing permethrin to exposed skin. Consider staying indoors at dawn, dusk, and in the early evening. These are peak hours for mosquito bites, especially those mosquitoes that carry the West Nile virus. Limit the number of places for mosquitoes to lay their eggs by getting rid of standing water sources from around your home.
To boost your protection from insect repellent, remember: Sweating, or water may call for reapplication of the product. If you aren't being bitten, you don't need to reapply repellent. Use enough repellent to cover exposed skin or clothing. Don't apply repellent to skin that's under clothing. Heavy application isn't needed for protection. Don't apply repellent to cuts, wounds, or irritated skin. After returning indoors, wash treated skin with soap and water. Don't spray aerosol or pump products in enclosed areas.
Don't apply aerosol or pump products directly to your face. Spray your hands and then rub them carefully over the face, avoiding your eyes and mouth.
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