Review Article | Published:

Host and viral determinants of influenza A virus species specificity

Nature Reviews Microbiologyvolume 17pages6781 (2019) | Download Citation


Influenza A viruses cause pandemics when they cross between species and an antigenically novel virus acquires the ability to infect and transmit between these new hosts. The timing of pandemics is currently unpredictable but depends on ecological and virological factors. The host range of an influenza A virus is determined by species-specific interactions between virus and host cell factors. These include the ability to bind and enter cells, to replicate the viral RNA genome within the host cell nucleus, to evade host restriction factors and innate immune responses and to transmit between individuals. In this Review, we examine the host barriers that influenza A viruses of animals, especially birds, must overcome to initiate a pandemic in humans and describe how, on crossing the species barrier, the virus mutates to establish new interactions with the human host. This knowledge is used to inform risk assessments for future pandemics and to identify virus–host interactions that could be targeted by novel intervention strategies.

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Change history

  • 18 December 2018

    In Figure 4, seasonal influenza virus was erroneously indicated as having “HA α2-3 SA preference” instead of “HA drift from population immunity” to represent ongoing evolution of seasonal influenza virus. This has now been corrected in all versions of the Review. The publisher apologizes to the authors and to readers for this error.


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S.M.H. acknowledges grant 082098 from the Wellcome Trust and grants BB/K016164/1 and BB/F008309/1 from the Biotechnology and Biological Sciences Research Council. W.S.B. acknowledges grants 200187 and 205100 from the Wellcome Trust and grant BB/K002465/1 from the Biotechnology and Biological Sciences Research Council.

Reviewer information

Nature Reviews Microbiology thanks R. Fouchier, A. Mehle and other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Department of Medicine, Imperial College London, London, UK

    • Jason S. Long
    • , Bhakti Mistry
    •  & Wendy S. Barclay
  2. Department of Life Sciences, Imperial College London, London, UK

    • Stuart M. Haslam


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The authors contributed equally to all aspects of the article.

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The authors declare no competing interests.

Corresponding author

Correspondence to Wendy S. Barclay.



Diseases transmitted from animals to humans, such as H5N1 Avian influenza virus.


Disease circulating in a non-human animal population.


The worldwide spread of a novel pathogen. Influenza pandemics occur when a new influenza virus emerges owing to a lack of immunity in the human population.

Seasonal influenza virus

Human-adapted influenza viruses that regularly circulate and cause epidemics in the human population.


Carbohydrates or assemblies of carbohydrates that are attached to proteins or lipids.

Antigenic shift

Where two antigenically distinct influenza viruses co-infect a cell and reassort their genome segments, generating a novel virus with the surface antigens of one and the internal genes of the other, whereby the novel virus is of a different subtype than the virus that previously circulated in that specific host.

Antigenic drift

The continual evolution of the antigenic sites present on surface antigens of influenza virus, driven by the need to evade the host antibody response.


Proteins that recognize and bind to specific carbohydrates.

Apical surface

The apical surface of a polarized epithelial cell faces the lumen or external environment.


The addition of a sulfo group to another organic molecule by a sulfotransferase enzyme.

Sda epitope

A histo-blood group antigen of structure NeuAcα2-3(GalNAcβ1–4)Galβ1–4GlcNAc.

Haemadsorption (Hd) site

A sialic acid binding site that is present in neuraminidase and separate from the catalytic site.


The biological process of carbohydrates (glycans) being attached to proteins or lipids.

Interferon-stimulated genes

(ISGs). A set of genes for which transcription is stimulated following engagement of the soluble cytokine interferon with its receptor. ISGs exert antiviral effects within the cell.

Primary transcription

mRNA synthesized by transcription of vRNA from incoming influenza virus genomes.

Minigenome reporter

A single-stranded viral-like RNA flanked by the viral promoter sequences of the influenza virus genome encoding a reporter gene such as firefly luciferase or GFP.

SUMO interacting motif

(SIM). The amino acid sequence found on cellular proteins recognized by small ubiquitin-like modifier (SUMO) proteins.


Birds including the ostrich, emu, rhea and kiwi belonging to the Palaeognathae.

Pathogen-associated molecular patterns

(PAMPs). Stimulatory molecules generated by pathogens that are recognized by cellular pattern recognition receptors, leading to the induction of an antiviral response.


(Cleavage and polyadenylation specificity factor 30 kDa subunit). A component of the 3′ end processing machinery of cellular precursor mRNAs.


The complex and diverse physiological process of intracellular degradation

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