First evidence of a pro-inflammatory response to severe infection with influenza virus H1N1

The great majority of infections caused by the pandemic variant of the influenza virus (nvH1N1) are self-limited, but a small percentage of patients develop severe symptoms requiring hospitalization. Bermejo-Martin and colleagues have presented a pilot study describing the differences in the early immune response for patients both mildly and severely infected with nvH1N1. Patients who develop severe symptoms after nvH1N1 infection showed Th1 and Th17 'hypercytokinemia', compared to mildly infected patients and healthy controls. The mediators involved with the Th1 and Th17 profiles are known to be involved in antiviral, pro-inflammatory and autoimmune responses. This is the first work reporting the association of a pro-inflamatory immune response with a severe pandemic infection, although it is likely that more studies are needed to understand the detrimental or beneficial roles these cytokines play in the evolution of mild and severe nvH1N1 infection.

By analyzing 29 cytokines and chemokines and the hemagglutination inhibition activity, Bermejo-Martin and colleagues [1] assessed the early host innate and adaptive immune responses in patients both mildly and severely infected with nvH1N1. While infection with nvH1N1 induces a typical innate response in both mild and severe cases, severe infections with respiratory involvement are characterized by an early secretion of Th 17 and Th 1 cytokines. Th us, hospitalized patients tend to show high systemic levels of mediators that stimulate Th 17 (IL-8, IL-9, IL-17, IL-6) and Th 1 responses (IFN-γ, TNF-α, IL-15, IL-12p70) [1]. Based on this fi nding, this study was able to highlight similarities between the cytokine response to severe H1N1 infection and the pathogenesis of asthma and some autoimmune diseases.
Th e Th 1 response is primarily involved with host immune defense against intracellular pathogens by activating cellular immunity. Th is response is eff ective in eradicating infectious agents such as viruses [3]. Indeed, Th 1 cells produce IFN-γ and cytokines that are involved in monocyte/macrophage-mediated infl ammatory respon ses [4]. When the Th 1 response is exhaustively prolonged, it may result in host damage. Moreover, other authors have reported that Th 1-dominated responses may be implicated in the pathogenesis of autoimmune disorders and chronic infl ammatory diseases [5]. Bermejo-Martin and colleagues [1] found IL-15, IL-12p70, and IL-6 to be particularly elevated following severe nvH1N1 infection. Th ese three cytokines are known to mediate both antiviral and pro-infl ammatory responses. Th e authors [1] also found a signifi cant inverse relationship of IL-6 and IL-8 with the pressure of oxygen in arterial blood in severely infected patients. Interestingly, previous studies had already reported high levels of specifi c proinfl ammatory cytokines and chemokines in severe SARS coronavirus, H5N1 and respiratory syncytial virus infections [6][7][8][9][10][11].
Th 17 cells are required for host defense against intracellular pathogens [12]. Th 17 promotes infl ammation by inducing various pro-infl ammatory cytokines and chemo kines, recruiting neutrophils, enhancing antibody production, and activating T cells [12]. Th 17 cells secrete

Abstract
The great majority of infections caused by the pandemic variant of the infl uenza virus (nvH1N1) are self-limited, but a small percentage of patients develop severe symptoms requiring hospitalization. Bermejo-Martin and colleagues have presented a pilot study describing the diff erences in the early immune response for patients both mildly and severely infected with nvH1N1. Patients who develop severe symptoms after nvH1N1 infection showed Th1 and Th17 'hypercytokinemia' , compared to mildly infected patients and healthy controls. The mediators involved with the Th1 and Th17 profi les are known to be involved in antiviral, pro-infl ammatory and autoimmune responses. This is the fi rst work reporting the association of a pro-infl amatory immune response with a severe pandemic infection, although it is likely that more studies are needed to understand the detrimental or benefi cial roles these cytokines play in the evolution of mild and severe nvH1N1 infection.
IL-17, IL-17F, and IL-22, thereby inducing a massive tissue reaction. Also, these cells secrete IL-21 to communicate with the cells of the immune system [13]. However, uncontrolled production of these cytokines induces tissue damage in infected tissues [12]. In addition, Th 17 cells have a well-known role in clearing pathogens during infections and inducing tissue infl ammation in autoimmune disease [13]. Interestingly, the key role of IL-17 and its receptor in the immunopathology of infl uenza infection in a mouse model has just recently been reported [14].
Taken together, these fi ndings show that severe pandemic H1N1 infection is characterized by early elevation of key immune pro-infl ammatory mediators participating in both Th 1 and Th 17 infl ammatory responses. Th is pro-infl ammatory response may be the cause of the severe respiratory symptoms caused by nvH1N1 infection. However, the authors also provide an alternative version of the story: Th 1 and Th 17 cytokines may refl ect a vigorous antiviral host response necessary for viral clearance. Th is article [1] is the fi rst that describes an association between severe infl uenza infection and a Th 17 response in humans. Th e researchers correctly bring up the fact that a better understanding of the immune response to the new H1N1 virus could contribute to the design of more eff ective therapies. Similarly, the results of this study reinforce the importance of early treatment with antivirals in those patients with high risk factors, such as pregnancy, asthma, and obesity, among others, to avoid triggering unwanted infl ammatory phenomena, which could explain the appearance of pneumonia in these patients. Th e results of this work also support the study of drugs that modulate the immune response in the treatment of this disease [15]. Moreover, the study of genetic polymorphisms of relevant genes involved in the development of Th 1 and Th 17 immune responses in severely infected patients could be of interest, since these polymorphisms could strongly infl uence gene expression.
Further studies would help to understand the harmful or benefi cial roles that these cytokines play in the evolution of mild and severe nvH1N1 infection. But this report confi rms that Th 1 and Th 17 responses are distinctive hallmarks of severe respiratory compromise following nvH1N1 infection.