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  • Review Article
  • Published:

Innate immunity to influenza virus infection

Nature Reviews Immunology volume 14, pages 315–328 (2014)Cite this article

Subjects

Key Points

  • Influenza virus infection is detected by multiple pattern recognition receptors. Within the infected cells, retinoic acid-inducible gene I (RIG-I) detects the 5′-triphosphorylated RNA of replicating viral genomes, whereas in plasmacytoid dendritic cells and B cells Toll-like receptor 7 (TLR7) detects RNA that is associated with incoming virions. TLR3 is expressed in airway epithelial cells and macrophages and detects RNA that is associated with infected cells.

  • The activation of nucleic acid sensors leads to the expression of type I and type III interferons, which in turn stimulate the expression of hundreds of interferon-stimulated genes in neighbouring cells that induce antiviral state.

  • In myeloid cells, matrix 2 (M2) ion channel activity of influenza virus stimulates the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome, resulting in the activation of caspase 1 and the cleavage and release of interleukin-1β (IL-1β) and IL-18. Phagocytosis of influenza virus-infected cells containing PB1-F2 fibrils also triggers activation of the NLRP3 inflammasome. The NLRP3 inflammasome and IL-1β have an important role in host tolerance to influenza virus infection in response to high-dose viral challenge. IL-1β and IL-1R signalling promotes antiviral B cell and T cell responses after low-dose viral challenge.

  • Commensal bacteria provide signals that set the activation threshold for the induction of adaptive immune responses to influenza virus. Bacterial components drive the expression of the genes encoding pro-IL-1β and NLRP3, as well as interferon-stimulated genes, to promote the robust stimulation of B cell and T cell responses upon influenza virus infection.

  • Innate immune responses confer protection either by stimulating antiviral defence genes or by promoting disease tolerance of host tissues. Therapeutic approaches to combating influenza virus-initiated diseases should consider promoting both of these protective strategies.

Abstract

Influenza viruses are a major pathogen of both humans and animals. Recent studies using gene-knockout mice have led to an in-depth understanding of the innate sensors that detect influenza virus infection in a variety of cell types. Signalling downstream of these sensors induces distinct sets of effector mechanisms that block virus replication and promote viral clearance by inducing innate and adaptive immune responses. In this Review, we discuss the various ways in which the innate immune system uses pattern recognition receptors to detect and respond to influenza virus infection. We consider whether the outcome of innate sensor stimulation promotes antiviral resistance or disease tolerance, and propose rational treatment strategies for the acute respiratory disease that is caused by influenza virus infection.

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Figure 1: Antiviral resistance and disease tolerance.
Figure 2: Innate sensing of influenza virus infection.
Figure 3: Mechanisms of resistance, disease and tolerance.

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Acknowledgements

The authors would like to thank R. Medzhitov for critical discussion and the US National Institutes of Health (NIH) for its support of research in the laboratory (grant numbers AI081884, AI054359, AI062428 and AI064705). Research on influenza virus in the laboratory was supported in part by the National Institute of Allergy and Infectious Diseases, NIH, USA, under award number U54AI057160 to the Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research (MRCE), USA.

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  1. Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, New Haven, 06520, Connecticut, USA

    Akiko Iwasaki & Padmini S. Pillai

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  1. Akiko Iwasaki
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Correspondence to Akiko Iwasaki.

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PowerPoint slides

Glossary

Pattern recognition receptors

(PRRs). Germ-line encoded host receptors that are membrane bound (such as Toll-like receptors) or soluble and present in the cytoplasm (such as RIG-I, MDA5 and NLRs) and sense pathogen-associated molecular patterns and initiate signalling cascades that lead to innate immune responses.

Type I interferons

(Type I IFNs). Cytokines that are rapidly induced by virus infection, as well as by some bacterial infections. They act on the IFN receptor to limit viral replication and to enhance antigen-specific immune responses.

Antigenic drift

A process by which circulating influenza virus genomes are constantly changing, which allows the virus to cause annual epidemics. Antigenic drift occurs when mutations accumulate in the haemagglutinin and neuraminidase genes that alter the antigenicity of these proteins such that the 'drifted' strains are no longer neutralized by antibodies that were specific for previously circulating strains.

Antigenic shift

A process by which a new influenza A virus haemagglutinin subtype (with or without an accompanying new neuraminidase subtype) is introduced into the human population, which often lacks prior experience of and immunity to the subtype. Antigenic shift can occur as a result of the direct introduction of an influenza virus from an animal or avian host into humans or by the exchange or reassortment of gene segments between human and non-human influenza viruses when they co-infect animals or humans.

Eicosanoids

Fatty acid derivatives, mainly derived from arachidonic acid precursors, that have a wide variety of biological activities. There are four main classes of eicosanoid — the prostaglandins, prostacyclins, thromboxanes and leukotrienes — that are derived from the activities of cyclooxygenases and lipoxygenases on membrane-associated fatty acid precursors.

IFN-stimulated genes

(ISGs). These genes contain interferon (IFN)-responsive promoters and are responsible for the antiviral, antiproliferative and immunomodulatory properties of IFN. More than 400 such genes have been identified by microarray analysis. Some — such as protein kinase R, ribonuclease L, IFN-induced GTP-binding protein MX1 and ISG15 — have well-documented antiviral activities, but the precise biological function of the majority of these genes is unknown.

Antiviral resistance

A host strategy to reduce viral burden by recognizing and eliminating viruses and virus-infected cells.

Disease tolerance

A host strategy to reduce tissue damage inflicted by pathogens or the immune response to pathogens.

Antiviral stress granules

Dense cytoplasmic aggregates of RNA and proteins that appear when a cell is under stress. Stress granules contain stalled translation initiation complexes and processing bodies, and are a site for the storage of transiently repressed mRNA.

Inflammasome

A molecular complex of several proteins that upon assembly activates caspase 1, which in turn cleaves substrates including pro-interleukin-1 (pro-IL-1), thereby producing active IL-1.

Pyroptosis

A form of programmed cell death that requires caspase 1 downstream of inflammasome activation. Pyroptosis is accompanied by pore formation and cell swelling, and is an inflammatory form of death.

Mitofusin 2

A mitochondrial GTPase that is embedded in the outer membrane that participates in mitochondrial fusion.

Innate lymphoid cells

(ILCs). A group of innate immune cells that are lymphoid in morphology and developmental origin, but lack properties of adaptive B cells and T cells such as recombined antigen-specific receptors. They function in the regulation of immunity, tissue homeostasis and inflammation in response to cytokine stimulation.

Amphiregulin

An epidermal growth factor (EGF)-like growth factor that stimulates tissue remodelling and the growth of epithelial cells through binding to its receptor, EGFR. Amphiregulin has been shown to restore lung function after influenza virus infection.

Airway hyperresponsiveness

A hyperreactivity of the airways that is initiated by exposure to a defined stimulus and is usually tolerated by normal individuals but that causes bronchoconstriction and inflammatory cell infiltration in allergic individuals.

γδ T cells

T cells that express a T cell receptor that consists of a γ-chain and a δ-chain and that are involved in innate immune responses. γδ T cells are present in the skin, digestive tract and reproductive mucosa.

Viability-associated PAMPs

(Vita-PAMPs). Members of a special class of pathogen-associated molecular patterns (PAMPs) that are recognized by the innate immune system to signify microbial life. These patterns differentiate dead and living microorganisms to allow for the scaling of appropriate immune responses based on the level of threat that the microbial signals represents.

Cross-priming

The initiation of a CD8+ T cell response to an antigen that has been taken up by antigen-presenting cells and re-routed to the MHC class I presentation pathway.

NADPH oxidase

An enzyme system that consists of multiple cytosolic and membrane-bound subunits. The complex is assembled in activated neutrophils mainly on the phagolysosomal membrane. NADPH oxidase uses electrons from NADPH to reduce molecular oxygen to form superoxide anions. Superoxide anions are enzymatically converted into hydrogen peroxide, which is converted by myeloperoxidase to hypochloric acid, a highly toxic and microbicidal agent.

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Iwasaki, A., Pillai, P. Innate immunity to influenza virus infection. Nat Rev Immunol 14, 315–328 (2014). https://doi.org/10.1038/nri3665

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