Research Article: Suppressor of Cytokine Signaling 4 (SOCS4) Protects against Severe Cytokine Storm and Enhances Viral Clearance during Influenza Infection

Date Published: May 8, 2014

Publisher: Public Library of Science

Author(s): 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, Kanta Subbarao.

http://doi.org/10.1371/journal.ppat.1004134

Abstract

Suppressor of cytokine signaling (SOCS) proteins are key regulators of innate and adaptive immunity. There is no described biological role for SOCS4, despite broad expression in the hematopoietic system. We demonstrate that mice lacking functional SOCS4 protein rapidly succumb to infection with a pathogenic H1N1 influenza virus (PR8) and are hypersusceptible to infection with the less virulent H3N2 (X31) strain. In SOCS4-deficient animals, this led to substantially greater weight loss, dysregulated pro-inflammatory cytokine and chemokine production in the lungs and delayed viral clearance. This was associated with impaired trafficking of influenza-specific CD8 T cells to the site of infection and linked to defects in T cell receptor activation. These results demonstrate that SOCS4 is a critical regulator of anti-viral immunity.

Partial Text

Influenza is a highly infectious, acute respiratory disease that causes profound morbidity and mortality. Annual seasonal influenza epidemics result in ∼500,000 deaths worldwide and substantial losses to global economies [1]. The development of a “cytokine storm” coupled with damage to pulmonary epithelium has been consistently observed in severe cases of influenza infection in humans. The mechanisms underlying this pathology, and an understanding of why some individuals respond excessively to virus, to an extent that results in hospitalisation or death, remains relatively unexplored.

Loss of functional SOCS4 protein led to a dramatic phenotype following influenza A infection. Socs4R108X/R108X mice were highly susceptible to primary infection with the virulent PR8 H1N1 strain exhibiting increased mortality associated with weight loss and delayed viral clearance. Similar results were observed following infection with the less virulent X31 H3N2 strain, however the anorexia was somewhat ameliorated, enabling us to dissect the underlying pathology in greater detail. The transient weight loss induced by influenza infection is known to reflect viral pathogenicity and as in this study, correlates with increased cytokine/chemokine levels in the lungs [2]. This is the first description of SOCS4-deficient mice and suggests that SOCS4 will play an important role in immune regulation during infection. Deletion of the C-terminal 328 amino acids removes the main functional domains, the SH2 domain and SOCS box, and the conserved SOCS4/5 N-terminal motif [7] is no longer intact. There is no described biological function for the remaining 108 amino acids of SOCS4. The long N-terminal regions of SOCS proteins are predicted to be largely disordered [7], and although such regions within a full-length molecule can play a role in multi-protein complex formation, it is unlikely that a short, disordered fragment will be functional. We have however, been able to express the truncated 108-residue fragment in 293T cells (data not shown). It is possible that, if expressed in vivo, the 108-residue fragment could retain binding to its endogenous target and compete off other signaling intermediates, acting as a dominant negative. It might be speculated that residues 1–108 are involved in binding to a receptor subunit in a similar fashion to SOCS5 binding to the IL-4Rα [31]but the identity of such a receptor complex is currently unknown. Regardless, given that expression of this putative fragment is under the control of the SOCS4 promoter, the observed phenotype indicates that normal SOCS4 function has been disrupted at the endogenous level and reflects a biological role for SOCS4 in regulating anti-viral immunity to influenza A.

 

Source:

http://doi.org/10.1371/journal.ppat.1004134

 

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