West Nile virus infection and immunity

Key Points

  • West Nile virus (WNV) continues to pose a significant public health risk throughout most of the world. In the United States, WNV is endemic and the leading cause of mosquito-borne encephalitis.

  • Currently there is no approved vaccine or therapy to prevent or limit WNV infection in humans.

  • Mosquitoes have innate immune programmes, similar to those of mammalian hosts, that function to limit viral replication and spread. In addition, mosquito salivary factors enhance WNV replication, dissemination and virus-induced disease.

  • WNV can cross the blood–brain barrier by one of several routes, including passive transport through the endothelium, infection of the olfactory neurons, transport by infected immune cells, inflammation-induced disruption of blood–brain barrier integrity, and direct axonal retrograde transport from infected peripheral neurons.

  • Both innate and adaptive immune responses are required for controlling WNV replication and protection against a lethal disease outcome.

  • Type I interferons are crucial for eliciting cell-intrinsic immune defences and priming adaptive immune responses during WNV infection. In particular, the RIG-I-like receptor and Toll-like receptor signalling pathways are essential for triggering interferons and immune defences in response to WNV infection.


West Nile virus (WNV) is an emerging neurotropic flavivirus that is transmitted to humans through the bite of an infected mosquito. WNV has disseminated broadly in the Western hemisphere and now poses a significant public health risk. The continuing spread of WNV, combined with the lack of specific therapeutics or vaccines to combat or prevent infection, imparts a pressing need to identify the viral and host processes that control the outcome of and immunity to WNV infection. Here, we provide an overview of recent research that has revealed the virus–host interface controlling WNV infection and immunity.

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Figure 1: The West Nile virus life cycle.
Figure 2: Pathogenesis of West Nile virus in humans.
Figure 3: Cell-intrinsic innate immune response to West Nile virus infection.
Figure 4: Cell-mediated immunity to West Nile virus infection.


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Work from the Gale laboratory has been supported by the US National Institutes of Health (NIH) and Burroughs Wellcome. The Diamond laboratory has been supported by the US NIH. The authors thank B. Doehle and H. Ramos for comments and manuscript revisions, and apologize to the many authors whose work could not be cited owing to space constraints.

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Correspondence to Michael Gale Jr.

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Supplementary table 1

Innate immune response determinants of protection against WNV 1 infection in mice. (PDF 358 kb)



Pertaining to a pathogen: primarily targeting and infecting cells within the central nervous system.

Non-viraemic transmission

Viral transmission between two mosquitoes that are feeding on the same host which lacks detectable virus in the blood.

Regulatory T cells

A subset of CD4+ T cells that can suppress the responses of other T cells.

C-type lectins

Carbohydrate-binding protein domains that are involved in a wide range of functions.


A cellular process that occurs in plants and mammals to regulate gene expression by inhibiting translation of or degrading host cell mRNAs.

Oxidative stress

An accumulation of reactive oxygen species that can trigger apoptosis or necrosis.

Pathogen-associated molecular patterns

Molecular signatures that are found on pathogens and are identified by the host cell as non-self.

Humoral immunity

Immunity conferred through antibodies secreted by B cells.


A family of cysteine-aspartic proteases involved in apoptosis, necrosis and inflammasome activation.


A cytolytic protein that is released by T cells and natural killer cells and forms pores on target cells.


Pharmacological or biochemical agents that are often combined with vaccines to stimulate the immune response to an antigen.

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Suthar, M., Diamond, M. & Gale Jr, M. West Nile virus infection and immunity. Nat Rev Microbiol 11, 115–128 (2013). https://doi.org/10.1038/nrmicro2950

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