Journal Articles

Differential evolution of peripheral cytokine levels in symptomatic and asymptomatic responses to experimental influenza virus challenge

October 28, 2015

Differential evolution of peripheral cytokine levels in symptomatic and asymptomatic responses to experimental influenza virus challengeClin Exp Immunol. 2015 Oct 28, McClain MT1,2,3, Henao R1,4, Williams J2, Nicholson B2, Veldman T1, Hudson L1, Tsalik EL1,2,3, Lambkin-Williams R5, Gilbert A5, Mann A5, Ginsburg GS1,Woods CW1,2,3.

  • 1Center for Applied Genomics and Precision Medicine, , Duke University, Durham, NC.
  • 2Durham Veterans Affairs Medical Center, Durham, NC.
  • 3Division of Infectious Diseases, Duke University Medical Center, Durham, NC.
  • 4Department of Electrical Engineering, Duke University, Durham, NC.
  • 5hVIVO, London, UK.

Abstract

Exposure to influenza virus triggers a complex cascade of events in the human host. In order to better understand the evolution of this intricate response over time, human volunteers were inoculated with influenza A/Wisconsin/67/2005 (H3N2), and then had serial peripheral blood samples drawn and tested for the presence of 25 major human cytokines. Nine out of 17 (53%) inoculated subjects developed symptomatic influenzainfection. Individuals who will go on to become symptomatic demonstrate increased circulating levels of IL-6, IL-8, IL-15, MCP-1, and IP-10 as early as 12-29 hours post-inoculation (during the pre-symptomatic phase), whereas challenged patients who remain asymptomatic do not. Overall the immunologic pathways of leukocyte recruitment, TLR-signaling, innate antiviral immunity and fever production are all overrepresented in symptomaticindividuals very early in disease, but are also dynamic and continuously evolve over time. Comparison with simultaneous peripheral blood genomics demonstrates that some inflammatory mediators (MCP-1, IP-10, IL-15) are being actively expressed in circulating cells while others (IL-6, IL-8, IFN-α and IFN-γ) are likely effectors produced locally at the site of infection. Interestingly, asymptomatic exposed subjects are not quiescent either immunologically or genomically but instead exhibit early and persistent downregulation of important inflammatory mediators in the periphery. The host inflammatory response to influenza infection is variable but robust and evolves over time. These results offer critical insight into pathways driving influenza-related symptomatology and offer the potential to contribute to early detection and differentiation of infected hosts. This article is protected by copyright. All rights reserved.

© 2015 British Society for Immunology.

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