West Nile virus meningoencephalitis

DeBiasi, Roberta L.; Tyler, Kenneth L.

doi:10.1038/ncpneuro0176

Cited by 147 publications

(135 citation statements)

References 75 publications

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“…Two unique features are associated with WNV-induced acute flaccid paralysis: it can occur as an isolated disease in the absence of meningitis or encephalitis (34), and patients of all ages and immune status groups are at risk (12). Our experiments suggest that the route of WNV entry into the CNS in part determines pathological outcome.…”

Section: Discussionmentioning

confidence: 82%

“…Severe human cases of WNV disease most frequently manifest as encephalitis, meningitis, or acute flaccid paralysis. Interestingly, while increased susceptibility to encephalitis or meningitis correlates with depressed immunity and increased age, humans of all age and immune status groups are at risk for developing acute flaccid paralysis (12). Acute flaccid paralysis or associated muscle weakness may occur in 10-50% of patients with neuroinvasive WNV disease and is caused by viral infection and injury of anterior horn motor neurons in the spinal cord (12).…”

Section: W Est Nile Virus (Wnv) Is a Neurotropic Member Of Thementioning

confidence: 99%

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Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis

Samuel

Wang

Siddharthan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

192

176

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West Nile virus (WNV) has emerged as a significant cause of epidemic viral encephalitis and flaccid limb paralysis, yet the mechanism by which it enters the CNS remains uncertain. We used compartmentalized neuron cultures to demonstrate that WNV spreads in both retrograde and anterograde directions via axonal transport. Transneuronal spread of WNV required axonal release of viral particles and was blocked by addition of a therapeutic neutralizing antibody. To test the physiologic significance of axonal transport in vivo, we directly inoculated the sciatic nerve of hamsters with WNV. Intrasciatic infection resulted in paralysis of the hind limb ipsilateral but not contralateral to the injection site. Limb paralysis was blocked either by surgical transection of the sciatic nerve or treatment with the therapeutic neutralizing antibody. Collectively, these studies establish that WNV undergoes bidirectional spread in neurons and that axonal transport promotes viral entry into the CNS and acute limb paralysis. Moreover, antibody therapeutics directly inhibit transneuronal spread of WNV infection and prevent the development of paralysis in vivo.flavivirus ͉ neuron ͉ retrograde ͉ transneuronal spread W est Nile virus (WNV) is a neurotropic member of the Flaviviridae family of RNA viruses and is related to other important arthropod-borne human pathogens. WNV is maintained in an enzootic cycle between mosquitoes and birds and has become an important global cause of epidemic encephalitis. Since its emergence in the United States in 1999, Ϸ26,000 cases of symptomatic WNV infection have been confirmed (www.cdc. gov/ncidod/dvbid/westnile/surv&control.htm#maps), and seroprevalence studies suggest that several million people have been infected (1).Rodent models have provided insight into the mechanisms of WNV spread to the CNS. After s.c. inoculation, WNV-infected dendritic cells traffic to the draining lymph node, resulting in a primary viremia and infection of peripheral tissues. Within 6 days, WNV is cleared from the serum and peripheral organs and enters the CNS and induces neurological disease (reviewed in ref.2). Nonetheless, the specific mechanisms by which WNV or other neurotropic flaviviruses enter into the CNS are largely unknown. CNS infection may occur in part via hematogenous spread, as increased viremia in immunodeficient mice (2) and TNF-␣-mediated changes in blood-brain-barrier permeability correlate with earlier CNS entry (3).Axonal transport from infected peripheral neurons mediates CNS entry and pathogenesis of viruses in the Herpesviridae, Rhabdoviridae, and Picornaviridae families (4-6). Viral spread in neurons is generally mediated by fast axonal transport, a microtubule-associated, anterograde and retrograde transport system. In classical studies, CNS infection of rabies virus or poliovirus was prevented by axonal ligation or degeneration (7,8). Insights into the biology of axonal spread have been facilitated by the development of compartmentalized, or Campenot, chambers for culturing neurons (9). These s...

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Section: Discussionmentioning

confidence: 82%

Section: W Est Nile Virus (Wnv) Is a Neurotropic Member Of Thementioning

confidence: 99%

Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis

Samuel

Wang

Siddharthan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

192

176

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“…detectable or much lower viral load at T0. It is increasingly evident that the elderly are particularly susceptible to severe disease from viral infection, possibly through a dysregulation of their immune system (43,44), which may be failing to control viral replication.…”

Section: Discussionmentioning

confidence: 99%

Persistent Chronic Inflammation and Infection by Chikungunya Arthritogenic Alphavirus in Spite of a Robust Host Immune Response

Hoarau

Bandjee

Krejbich-Trotot

et al. 2010

The Journal of Immunology

503

671

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International audienceAlphaviruses, including Chikungunya virus (CHIKV), produce a transient illness in humans, but severe forms leading to chronic incapacitating arthralgia/arthritis have been reported by mechanisms largely ill-characterized. The pathogenesis of CHIKV was addressed in a prospective cohort study of 49 hospitalized patients from Reunion Island subsequently categorized into two distinct groups at 12 mo postinfection. Comprehensive analyses of the clinical and immunological parameters throughout the disease course were analyzed in either the “recovered” or the “chronic” groups to identify prognostic markers of arthritis-like pathology after CHIKV disease. We found that the chronic group consisted mainly of more elderly patients (\textgreater60 y) and with much higher viral loads (up to 1010 viruses per milliliter of blood) during the acute phase. Remarkably, a rapid innate immune antiviral response was demonstrated by robust dendritic/NK/CD4/CD8 cell activation and accompanied by a rather weak Th1/Th2 cytokine response in both groups. Interestingly, the antiviral immune response witnessed by high levels of IFN-α mRNA in PBMCs and circulating IL-12 persisted for months only in the chronic group. CHIKV (RNA and proteins) was found in perivascular synovial macrophages in one chronic patient 18 mo postinfection surrounded by infiltrating NK and T cells (CD4++ but rare cytotoxic CD8). Fibroblast hyperplasia, strong angiogenesis, tissue lesions given the high levels of matrix metalloproteinase 2, and acute cell death [high cleaved poly(ADP-ribose) polymerase staining] were observed in the injured synovial tissue. These observed cellular and molecular events may contribute to chronic arthralgia/arthritis targeted by methotrexate used empirically for effective treatment but with immunosuppressive function in a context of viral persistence

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“…First, infection with WNV causes neurological diseases such as encephalitis, meningitis, and acute flaccid paralysis (10). Second, while WNV infections in healthy humans are typically asymptomatic, death is more likely to occur with infection in elderly individuals (Ͼ55 years old) who develop encephalitis (10).…”

mentioning

confidence: 99%

Dysregulation of TLR3 Impairs the Innate Immune Response to West Nile Virus in the Elderly

Kong

Delroux

Wang

et al. 2008

J Virol

161

180

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West Nile virus (WNV), a mosquito-borne flavivirus, has recently emerged in North America, and the elderly are particularly susceptible to severe neurological disease and death from infection with this virus. We have investigated the innate immune response of primary human macrophages to WNV in vitro and have found significant differences between the responsiveness of macrophages derived from younger donors and that from older donors. Binding of the glycosylated WNV envelope protein to the C-type lectin dendritic cell-specific intercellular adhesion molecule 3 (ICAM3) grabbing nonintegrin (DC-SIGN) leads to a reduction in the expression of Toll-like receptor 3 (TLR3) in macrophages from young donors via the signal transducer and activator of transcription 1 (STAT1)-mediated pathway. This signaling is impaired in the elderly, and the elevated levels of TLR3 result in an elevation of cytokine levels. This alteration of the innate immune response with aging may contribute to the permeability of the blood-brain barrier and suggests a possible mechanism for the increased severity of WNV infection in older individuals.

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West Nile virus meningoencephalitis

Cited by 147 publications

References 75 publications

Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis

Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis

Persistent Chronic Inflammation and Infection by Chikungunya Arthritogenic Alphavirus in Spite of a Robust Host Immune Response

Dysregulation of TLR3 Impairs the Innate Immune Response to West Nile Virus in the Elderly

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