The function of caspase in viral immunity has not received much attention. Previously, it was shown that caspase plays a role in endoplasmic reticulum stress-induced apoptosis in response to amyloid toxicity [ 92 ]. Wang et al. In vitro studies of primary neurons and mouse embryonic fibroblasts further demonstrated that caspase positively modulated the production of type I interferon by regulating E3 ubiquitin ligase TRIMmediated ubiquitination of RIG-1, which is a critical signaling event for the type I interferon response to WNV and other viral pathogens.

Alternatively, high levels of WNV non-structural e. How much cell injury can be attributed to viral cytopathology and how much to the inflammatory response is not known. Infection of neurons with WNV leads to the induction of several cytokines and chemokines, which promote leukocyte invasion into the CNS and neuroinflammation [ 95 , 96 ].

However, the extent to which this inflammation contributes to disease pathology remains unclear. In particular, the relative contribution of neurons to inflammation is a subject of intensive research.

These results suggest that neurons are one of the potential sources of pro-inflammatory cytokines in WNV-infected brain, and that pro-inflammatory mediators are one of the main factors driving WNV-induced neurotoxicity. In animal models of JEV there is some evidence that activation of microglial cells plays a role in pathogenesis of encephalitis through the action of pro-inflammatory mediators, which induce neuronal cell death [ 99 ].

Although reactive gliosis activation of astrocytes and microglia has been reported in WNV neuroinvasive disease and is considered a key pathogenic feature [ — ], the extent to which infection of glial cells contributes to WNV-induced neurological disease has never been fully investigated.

It is believed that collateral damage is mediated by inflammatory factors that are either neurotoxic or attract leukocytes into the affected area, which results in a detrimental inflammatory milieu. Recent evidence is provided by observational studies suggesting that macrophages from young individuals can down regulate TLR3 following infection with WNV, whereas macrophages of the elderly cannot.

Therefore, it has been hypothesized that failure to down regulate TLR3 in infected cells results in production of high levels of pro-inflammatory and vasculogenic cytokines [ ]. Furthermore, a study conducted by van Marle et al.

This study also showed an induction of neuroinflammatory genes, where a subset of these genes was specifically induced by the capsid protein of WNV. Interestingly, production of CXCL10 by astrocytes has also been implicated in the neuropathogenesis of other viral infections, such as human immunodeficiency virus [ — ].

Nonetheless, further studies are needed to define the genetic programs associated with neuroprotection or the neurotoxic action of glial cells during WNV infection. Recently, a paradoxical role for neutrophils in WNV pathogenesis has been described.

When Bai et al. In addition, neutrophils were found to be the most abundant cell type in the peritoneal cavity as early as 12 hours after WNV inoculation. These results suggest that neutrophils are the predominant immune cells that are initially and rapidly recruited to sites of infection with WNV.

Interestingly, however, mice depleted of neutrophils had significantly lower WNV in their blood on day 2 or 3 after infection, and increased survival rates were seen.

In contrast, when mice were infected with WNV before the depletion of neutrophils on days 1 and 2 after infection, they showed higher levels of viral load as well as reduced survival rates. The authors concluded that WNV may replicate in neutrophils and increase WNV load in blood early in infection, but that in the later course of infection these cells contribute to the control of infection.

Eventhough these results should be confirmed, it is tempting to speculate that neutrophils play a critical role in WNV replication and dissemination in vivo , especially in humans where neutrophils are the predominant cell type in blood. Most studies conducted have elucidated a protective role of the immune system in WNV infection. Most of our knowledge regarding the immune response and pathogenesis has been derived from mouse studies. How the responses in birds differ from mammals and how it influences the course of disease has not been completely elucidated.

Some studies suggest that differences in host response between different bird species may influence the outcome of WNV infection [ ].

So far, only few studies have been able to demonstrate a pathogenic role for the immune system in inbred mice. Direct infection of neurons may result in apoptosis via caspase-3 and The role of the immune system in pathogenesis of WNV remains speculative. More studies need to be done to uncover further evidence for this hypothesis. However, it is plausible that after infection, WNV enters the brain of significantly more patients, but that certain host factors, such as an overactive inflammatory response, lead to excessive permeability of the BBB, as well as excessive neuronal death, eventually overruling the protective effects of the immune system.

Conflict of Interest. The authors declare no conflict of interest apart from Albert Osterhaus, who is a part time employee of Viroclinics BV [ ]. National Center for Biotechnology Information , U. Journal List Viruses v. Published online Jun Stephanie M. Lim , Penelope Koraka , Albert D. Osterhaus , and Byron E. Author information Article notes Copyright and License information Disclaimer.

This article has been cited by other articles in PMC. Abstract West Nile virus WNV is a neurotropic, arthropod-borne flavivirus that is maintained in an enzootic cycle between mosquitoes and birds, but can also infect and cause disease in horses and humans.

Keywords: West Nile virus, pathogenesis, central nervous system, neuroinvasion. Tropism It is believed that after a mosquito bite WNV infects keratinocytes [ 26 ] and Langerhans cells, which migrate to regional lymph nodes where initial replication occurs [ 27 — 31 ]. Open in a separate window. Figure 1. Crossing the Blood-Brain-Barrier BBB Inflammation has been functionally defined as the host response to injury, meant to eliminate the cause of damage and promote tissue healing.

Figure 2. Mechanisms of Cell Death Programmed cell death can be considered as a defense mechanism of the host in response to pathogenic insults. Immunopathology How much cell injury can be attributed to viral cytopathology and how much to the inflammatory response is not known. Concluding Remarks Most studies conducted have elucidated a protective role of the immune system in WNV infection.

Footnotes Conflict of Interest The authors declare no conflict of interest apart from Albert Osterhaus, who is a part time employee of Viroclinics BV [ ]. References and Notes 1. West Nile: Worldwide current situation in animals and humans. Introductions of West Nile virus strains to Mexico. Komar N, Clark GG. West Nile virus activity in Latin America and the Caribbean. Salud Public. Complete genome sequences and phylogenetic analysis of West Nile virus strains isolated from the United States, Europe, and the Middle East.

New Engl. West Nile encephalitis epidemic in southeastern Romania. Epidemic West Nile encephalitis, New York, Results of a household-based seroepidemiological survey. West Nile virus: A primer for the clinician. Clinical characteristics and functional outcomes of West Nile Fever. West Nile virus. Lancet Infect. The natural history of West Nile Fever. Clinical observations during an epidemic in Israel. Hubalek Z. Comparative symptomatology of West Nile fever. Induced virus infections in man by the Egypt isolates of West Nile virus.

Clinical manifestations in the West Nile virus outbreak. West Nile virus infection in Morbidity and mortality among patients admitted to hospital in southcentral Ontario. Acute flaccid paralysis and West Nile virus infection. Long-term prognosis for clinical West Nile virus infection. Risk factors for encephalitis and death from West Nile virus infection. Mouse neuroinvasive phenotype of West Nile virus strains varies depending upon virus genotype.

Dengue virus pathogenesis: An integrated view. Encephalitis and myelitis associated with dengue viral infection clinical and neuroimaging features. Dengue encephalopathy in children in Northern India: Clinical features and comparison with non dengue.

Sequence signatures in envelope protein may determine whether flaviviruses produce hemorrhagic or encephalitic syndromes.

Virus Genes. Keratinocytes are cell targets of west nile virus in vivo. Infection of human dendritic cells by dengue virus causes cell maturation and cytokine production. Phenotypic changes in Langerhans' cells after infection with arboviruses: A role in the immune response to epidermally acquired viral infection? Human dendritic cells are activated by dengue virus infection: Enhancement by gamma interferon and implications for disease pathogenesis.

Human dendritic cells as targets of dengue virus infection. Human skin Langerhans cells are targets of dengue virus infection. Monocytes-macrophages are a potential target in human infection with West Nile virus through blood transfusion. Nathanson N. Slow viruses and chronic disease: The contribution of epidemiology. Health Rep. Identification of neutralizing epitopes within structural domain III of the West Nile virus envelope protein.

Very rarely, the virus can spread in transfused blood, a transplanted organ, or through the placenta to a fetus. West Nile virus occurs in late summer and early fall in mild zones. It can also occur year-round in southern climates. Most often, the West Nile virus causes mild, flu-like symptoms. But, the virus can cause life-threatening illnesses, such as:.

West Nile virus is spread to humans through the bite of an infected female mosquito. The mosquitoes get the virus when they bite an infected bird. Crows and jays are the most common birds linked to the virus.

But at least other bird species also have the virus. West Nile virus isn't spread between humans. However, in a few cases it has spread through organ transplant. Health officials think the organ donor acquired the virus through a blood transfusion. All blood is screened for the virus. The risk for getting West Nile virus from blood is much lower than the risk of not having any procedure that would call for a blood transfusion.

Most people infected with West Nile virus have only mild, flu-like symptoms that last a few days. Symptoms usually appear within 3 to 14 days of infection. These are the most common symptoms of West Nile fever:. 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:.

The symptoms of West Nile virus may look like other conditions or health problems. 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. ScienceDaily, 5 October UT Southwestern Medical Center. Retrieved January 12, from www. Featured Content.

The researchers demonstrated that mammalian insulin activated an antiviral immunity pathway The innovative approach reduced the virus in the brain, allowing the immune But because these human strains frequently mutate to adapt to their new Print Email Share.

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