Current Understanding of West Nile Virus Clinical Manifestations, Immune Responses, Neuroinvasion, and Immunotherapeutic Implications

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Abstract

West Nile virus (WNV) is the most common mosquito-borne virus in North America. WNV-associated neuroinvasive disease affects all ages, although elderly and immunocompromised individuals are particularly at risk. WNV neuroinvasive disease has killed over 2300 Americans since WNV entered into the United States in the New York City outbreak of 1999. Despite 20 years of intensive laboratory and clinical research, there are still no approved vaccines or antivirals available for human use. However, rapid progress has been made in both understanding the pathogenesis of WNV and treatment in clinical practices. This review summarizes our current understanding of WNV infection in terms of human clinical manifestations, host immune responses, neuroinvasion, and therapeutic interventions.

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Most cited references 149

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The outbreak of West Nile virus infection in the New York City area in 1999.

Denis Nash, Farzad Mostashari, Annie Fine … (2001)

In late August 1999, an unusual cluster of cases of meningoencephalitis associated with muscle weakness was reported to the New York City Department of Health. The initial epidemiologic and environmental investigations suggested an arboviral cause. Active surveillance was implemented to identify patients hospitalized with viral encephalitis and meningitis. Cerebrospinal fluid, serum, and tissue specimens from patients with suspected cases underwent serologic and viral testing for evidence of arboviral infection. Outbreak surveillance identified 59 patients who were hospitalized with West Nile virus infection in the New York City area during August and September of 1999. The median age of these patients was 71 years (range, 5 to 95). The overall attack rate of clinical West Nile virus infection was at least 6.5 cases per million population, and it increased sharply with age. Most of the patients (63 percent) had clinical signs of encephalitis; seven patients died (12 percent). Muscle weakness was documented in 27 percent of the patients and flaccid paralysis in 10 percent; in all of the latter, nerve conduction studies indicated an axonal polyneuropathy in 14 percent. An age of 75 years or older was an independent risk factor for death (relative risk adjusted for the presence or absence of diabetes mellitus, 8.5; 95 percent confidence interval, 1.2 to 59.1), as was the presence of diabetes mellitus (age-adjusted relative risk, 5.1; 95 percent confidence interval, 1.5 to 17.3). This outbreak of West Nile meningoencephalitis in the New York City metropolitan area represents the first time this virus has been detected in the Western Hemisphere. Given the subsequent rapid spread of the virus, physicians along the eastern seaboard of the United States should consider West Nile virus infection in the differential diagnosis of encephalitis and viral meningitis during the summer months, especially in older patients and in those with muscle weakness.

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Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2.

Takeshi Saito, Reiko Hirai, Yueh-Ming Loo … (2007)

RIG-I is an RNA helicase containing caspase activation and recruitment domains (CARDs). RNA binding and signaling by RIG-I are implicated in pathogen recognition and triggering of IFN-alpha/beta immune defenses that impact cell permissiveness for hepatitis C virus (HCV). Here we evaluated the processes that control RIG-I signaling. RNA binding studies and analysis of cells lacking RIG-I, or the related MDA5 protein, demonstrated that RIG-I, but not MDA5, efficiently binds to secondary structured HCV RNA to confer induction of IFN-beta expression. We also found that LGP2, a helicase related to RIG-I and MDA5 but lacking CARDs and functioning as a negative regulator of host defense, binds HCV RNA. In resting cells, RIG-I is maintained as a monomer in an autoinhibited state, but during virus infection and RNA binding it undergoes a conformation shift that promotes self-association and CARD interactions with the IPS-1 adaptor protein to signal IFN regulatory factor 3- and NF-kappaB-responsive genes. This reaction is governed by an internal repressor domain (RD) that controls RIG-I multimerization and IPS-1 interaction. Deletion of the RIG-I RD resulted in constitutive signaling to the IFN-beta promoter, whereas RD expression alone prevented signaling and increased cellular permissiveness to HCV. We identified an analogous RD within LGP2 that interacts in trans with RIG-I to ablate self-association and signaling. Thus, RIG-I is a cytoplasmic sensor of HCV and is governed by RD interactions that are shared with LGP2 as an on/off switch controlling innate defenses. Modulation of RIG-I/LGP2 interaction dynamics may have therapeutic implications for immune regulation.

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LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses.

Takashi Satoh, Hiroki Kato, Yutaro Kumagai … (2010)

RNA virus infection is recognized by retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), RIG-I, and melanoma differentiation-associated gene 5 (MDA5) in the cytoplasm. RLRs are comprised of N-terminal caspase-recruitment domains (CARDs) and a DExD/H-box helicase domain. The third member of the RLR family, LGP2, lacks any CARDs and was originally identified as a negative regulator of RLR signaling. In the present study, we generated mice lacking LGP2 and found that LGP2 was required for RIG-I- and MDA5-mediated antiviral responses. In particular, LGP2 was essential for type I IFN production in response to picornaviridae infection. Overexpression of the CARDs from RIG-I and MDA5 in Lgp2(-/-) fibroblasts activated the IFN-beta promoter, suggesting that LGP2 acts upstream of RIG-I and MDA5. We further examined the role of the LGP2 helicase domain by generating mice harboring a point mutation of Lys-30 to Ala (Lgp2 (K30A/K30A)) that abrogated the LGP2 ATPase activity. Lgp2 (K30A/K30A) dendritic cells showed impaired IFN-beta productions in response to various RNA viruses to extents similar to those of Lgp2(-/-) cells. Lgp2(-/-) and Lgp2 (K30A/K30A) mice were highly susceptible to encephalomyocarditis virus infection. Nevertheless, LGP2 and its ATPase activity were dispensable for the responses to synthetic RNA ligands for MDA5 and RIG-I. Taken together, the present data suggest that LGP2 facilitates viral RNA recognition by RIG-I and MDA5 through its ATPase domain.

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Author and article information

Journal

Journal ID (nlm-ta): Pathogens

Journal ID (iso-abbrev): Pathogens

Journal ID (publisher-id): pathogens

Title: Pathogens

Publisher: MDPI

ISSN (Electronic): 2076-0817

Publication date (Electronic): 16 October 2019

Publication date Collection: December 2019

Volume: 8

Issue: 4

Electronic Location Identifier: 193

Affiliations

[1 ]Department of Cell and Molecular Biology, University of Southern Mississippi, Hattiesburg, MS 39406, USA; elizabeth.a.thompson@ 123456usm.edu

[2 ]Departments of Neurology, University of Mississippi Medical Center, Jackson, MS 39216, USA; pvig@ 123456umc.edu

[3 ]Methodist Rehabilitation Center, Jackson, MS 39216, USA; aleis@ 123456mmrcrehab.org

Author notes

[* ]Correspondence: fengwei.bai@ 123456usm.edu ; Tel.: +1-601-266-4748; Fax: +1-601-266-5797

Article

Publisher ID: pathogens-08-00193

DOI: 10.3390/pathogens8040193

PMC ID: 6963678

PubMed ID: 31623175

SO-VID: 3ab03b46-9c4b-48f2-a3c0-1d71e19d83ff

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Current Understanding of West Nile Virus Clinical Manifestations, Immune Responses, Neuroinvasion, and Immunotherapeutic Implications

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European Journal of Microbiology and Immunology

Most cited references 149

The outbreak of West Nile virus infection in the New York City area in 1999.

Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2.

LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses.

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