Editors' ChoiceHost-Pathogen Interaction

Influenza: The New Great Imitator

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Science Translational Medicine  11 Apr 2012:
Vol. 4, Issue 129, pp. 129ec64
DOI: 10.1126/scitranslmed.3004094

The host response to microbial challenge is a double-edged sword: Microbial eradication requires immune activation, but severe organ damage results from an overexuberant inflammatory response. Influenza virus causes various degrees of disease severity that may be related to the frenzy of the host inflammatory response. For example, the pandemic H1N1 flu strain causes rapid pulmonary failure and death partly as a result of inflammatory lung injury. Now, new research by Marazzi et al. reveals how some flu strains trick the human immune system into silencing critical antiviral genes, resulting in prolonged pathogen survival and immune suppression.

The authors discovered that influenza A nonstructural protein 1 (NS1) shares sequence homology with the human histone H3 protein and hypothesized that NS1 mimics H3 by interacting directly with host transcriptional regulatory proteins. Indeed, NS1 positions itself at sites of active gene transcription by binding to a specific human transcription elongation factor complex, hPAF1C. This complex normally enhances RNA synthesis; however, binding of NS1 to hPAF1C renders the transcriptional machinery dysfunctional. Neither defective NS1 nor virus that expressed an aberrant version of NS1 bound the elongation complex or interfered with antiviral gene transcription. Interestingly, influenza virus without an H3-mimicking protein induced a profound antiviral response, characterized by robust host-gene transcription, thus demonstrating that influenza viruses are capable of manipulating the immune response at an epigenetic level.

This study demonstrates that influenza shuts down the antiviral response by mimicking a host histone and hijacking the cell’s transcription machinery. The ability to suppress immune function through mimicry is not likely shared by all influenza viruses as only certain strains produce the NS1 protein. Of note, the pandemic H1N1 strain does not produce the NS1 protein and caused severe respiratory failure and death, possibly owing to an uninhibited and robust immune response. Unraveling the mechanisms of post-influenza immune suppression will not only further our understanding of epidemic and pandemic outbreaks, but it also sheds light on why deadly secondary bacterial superinfections commonly occur after the flu.

I. Marazzi et al., Suppression of the antiviral response by an influenza histone mimic. Nature 483, 428–433 (2012). [Full text]

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