Certain influenza strains are highly virulent – they cause more serious disease and kill more people. Some of the damage is caused by the stronger immune response such strains elicit, especially in the lung. A study published in PLOS Pathogens identifies SOCS4 as a key regulator of the immune response against influenza virus.
Lukasz Kedzierski, Sandra Nicholson, and colleagues from the Walter and Eliza Hall Institute of Medical Research and the University of Melbourne, Australia, studied mice with a mutation in the Socs4 gene, a member of a gene family whose other members are known to be involved in regulating immune responses.
To investigate the role of the SOCS4 protein (the product of the Socs4 gene), the researchers first tested how the mutant mice responded to infection with a virulent influenza strain. Compared with normal mice, the mutants were more sensitive to the virus; they got much sicker and many more died. When the researchers used a weaker virus, the Socs4 mutants survived but again showed more severe symptoms than mice with intact SOCS4.
When the researchers analyzed the immune response in the Socs4 mutants they found that the mutant mice responded to influenza virus with production of abnormally high levels of cytokines and chemokines–both small molecules that promote inflammation. The observed response resembled the so-called “cytokine storm” situation that is thought to cause the lung tissue damage associated with virulent influenza strains.
In addition to the aberrant cytokine production, the mutant mice also appeared defective in mobilization of virus-specific killer T cells to the lungs. Presumably as a result of the latter problem, the mutants needed more time than their normal counterparts to clear the virus from their lungs and fully recover.
According to the researchers, this first description of SOCS4-deficient mice “suggests that SOCS4 will play an important role in immune regulation during infection.”
This work was supported in part by the National Health and Medical Research Council (NHMRC), Australia (Program grant #487922, Project grant #1023559), as well as an NHMRC IRIISS grant 361646 and a Victorian State Government Operational Infrastructure Scheme grant. KK is a recipient of an NHMRC CDA2 Fellowship, SEN, BTK and NAN are supported by NHMRC fellowships, GTB is a recipient of an Australian Research Council Fellowship, BTK is supported by a fellowship from the Sylvia and Charles Viertel Foundation, and EML is the recipient of an Australian Postgraduate Award. This work was also supported in part by the National Institutes of Health (RO1 CA22556-26). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Suppressor of Cytokine Signaling 4 (SOCS4) Protects against Severe Cytokine Storm and Enhances Viral Clearance during Influenza Infection, Lukasz Kedzierski, Edmond M. Linossi, Tatiana B. Kolesnik, E. Bridie Day, Nicola L. Bird, Benjamin T. Kile, Gabrielle T. Belz, Donald Metcalf, Nicos A. Nicola, Katherine Kedzierska, Sandra E. Nicholson, PLOS Pathogens, DOI:10.1371/journal.ppat.1004134, published online 8 May 2014.