Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza

Abstract

IntroductionHuman host immune response following infection with the new variant of A/H1N1 pandemic influenza virus (nvH1N1) is poorly understood. We utilize here systemic cytokine and antibody levels in evaluating differences in early immune response in both mild and severe patients infected with nvH1N1.MethodsWe profiled 29 cytokines and chemokines and evaluated the haemagglutination inhibition activity as quantitative and qualitative measurements of host immune responses in serum obtained during the first five days after symptoms onset, in two cohorts of nvH1N1 infected patients. Severe patients required hospitalization (n = 20), due to respiratory insufficiency (10 of them were admitted to the intensive care unit), while mild patients had exclusively flu-like symptoms (n = 15). A group of healthy donors was included as control (n = 15). Differences in levels of mediators between groups were assessed by using the non parametric U-Mann Whitney test. Association between variables was determined by calculating the Spearman correlation coefficient. Viral load was performed in serum by using real-time PCR targeting the neuraminidase gene.ResultsIncreased levels of innate-immunity mediators (IP-10, MCP-1, MIP-1β), and the absence of anti-nvH1N1 antibodies, characterized the early response to nvH1N1 infection in both hospitalized and mild patients. High systemic levels of type-II interferon (IFN-γ) and also of a group of mediators involved in the development of T-helper 17 (IL-8, IL-9, IL-17, IL-6) and T-helper 1 (TNF-α, IL-15, IL-12p70) responses were exclusively found in hospitalized patients. IL-15, IL-12p70, IL-6 constituted a hallmark of critical illness in our study. A significant inverse association was found between IL-6, IL-8 and PaO2 in critical patients.ConclusionsWhile infection with the nvH1N1 induces a typical innate response in both mild and severe patients, severe disease with respiratory involvement is characterized by early secretion of Th17 and Th1 cytokines usually associated with cell mediated immunity but also commonly linked to the pathogenesis of autoimmune/inflammatory diseases. The exact role of Th1 and Th17 mediators in the evolution of nvH1N1 mild and severe disease merits further investigation as to the detrimental or beneficial role these cytokines play in severe illness.

The mucosal and systemic immune responses elicited by a chitosan‐adjuvanted intranasal influenza H5N1 vaccine

“…Both intranasal vaccination 43 and influenza virus challenge 44 , 45 have previously been shown to induce a strong IL‐17 response in mice; however, the exact role of IL‐17 in the pathogenesis of influenza is not yet clear. Recent reports suggest a role for IL‐17 in inducing a protective immune response against influenza viral challenge in mice 45 , 46 and also in patients with severe pandemic H1N1 influenza 47 . In contrast, Crowe et al.…”

Microcirculatory abnormalities in patients with severe influenza A (H1N1) infection

“…Compared with outpatients, the inflammatory response to severe influenza A (H1N1) is more pronounced in patients with severe disease who require hospitalization, and the response can be observed even in patients who do not have bacterial superinfection. 12 The ability of the influenza and other acute respiratory viruses to provoke microvascular alterationscharacterized by sludge of capillary flow associated with hypercoagulability and increased blood viscosity-has been suggested by others. 28 Therefore, significant microcirculatory perfusion deficits could be an important pathophysiological mechanism in severe influenza A (H1N1) infections.…”

“…11 This proinflammatory response is not restricted to the lungs. Recently, Bermejo-Martin et al 12 reported that systemic levels of several pro-inflammatory cytokines were increased in patients hospitalized with H1N1 infection, especially in those who were critically ill. Remote organ dysfunction may also be observed, including elevated liver enzymes, rhabdomyolysis, renal failure, and shock.…”

IL-17 response mediates acute lung injury induced by the 2009 Pandemic Influenza A (H1N1) Virus

“…Previous clinical reports analyzing sera obtained from 29 patients in Spain and 57 patients in Hong Kong showed that Th-1 and Th-17 hypercytokinemia is an early host response signature in severe cases of 2009 pandemic influenza [6,8]. However, controversy regarding the role of the Th-17 response was raised by a npg recent study from a Romanian group reporting cytokine responses in 32 patients with severe H1N1 influenza A virus infection [7].…”

“…Altogether, these data suggest that the 2009 H1N1 strain is still circulating in the world. Previous clinical reports indicated that hypercytokinemia is involved in the pathology of severe 2009 pandemic influenza [6][7][8]. However, the underlying molecular mechanism is unclear.…”