Editors' ChoiceInfluenza

From Contagion to Outbreak: Host Susceptibility in Viral Pneumonia

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Science Translational Medicine  04 Apr 2012:
Vol. 4, Issue 128, pp. 128ec59
DOI: 10.1126/scitranslmed.3004066

The famed “Spanish flu” pandemic of 1918 killed more people than did World War I—and more people in a single year than did 4 years of the bubonic plague in medieval Europe. Even now, fear of a viral pandemic is widespread, fueling recent disaster movies such as Contagion and the ongoing controversy over publication of experiments on enhancing influenza virulence. One consistent puzzle has been why some people develop much more severe disease than others when infected with the same strain of virus. Everitt and colleagues bring us one step closer to the answer with their study of interferon-inducible transmembrane (IFITM) protein 3 in mice and humans with influenza.

Starting with the observation that IFITM3 may mediate resistance to viral infection in vitro, the authors used a mouse in which IFITM3 was knocked out to test the protein’s role in influenza infection. When infected with a relatively mild strain of influenza, the mice lacking IFITM3 came down with much more severe infections than did their wild-type counterparts (as measured by body weight, lung pathology, and survival). In addition, the IFITM3 knockout mice had higher lung concentrations of inflammatory cytokines that are associated with more severe clinical disease in humans. Most notably, viral replication was poorly controlled in embryonic fibroblasts from IFITM3 knockout mice, whereas administration of IFITM3 restored replication to wild-type levels.

The authors demonstrated the clinical relevance of their work by evaluating the IFITM3 genotypes of patients hospitalized for seasonal or pandemic influenza. Compared with population-based controls, the hospitalized flu patients were more likely to carry a particular allele (SNP-rs12252-C) of the IFITM3 gene. The authors then showed that lymphoblastoid cells with this genotype were more susceptible to influenza infection and had lower levels of IFITM3 expression in vitro. Although more work is needed before we fully understand how IFITM3 functions in humans with influenza and can plan potential therapeutic interventions, this study partially explains why people vary so much in their susceptibility to severe viral infection—perhaps making those scary pandemic movies a little less frightening.

A. R. Everitt et al., IFITM3 restricts the morbidity and mortality associated with influenza. Nature 25 March 2012 (10.1038/nature10921). [PubMed]

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