Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza
- Jesus F Bermejo-Martin1, 2Email author,
- Raul Ortiz de Lejarazu1, 2,
- Tomas Pumarola3,
- Jordi Rello4,
- Raquel Almansa1, 2,
- Paula Ramírez5,
- Ignacio Martin-Loeches4,
- David Varillas1, 2,
- Maria C Gallegos6,
- Carlos Serón7,
- Dariela Micheloud8,
- JoseManuel Gomez8,
- Alberto Tenorio-Abreu9,
- María J Ramos9,
- MLourdes Molina10,
- Samantha Huidobro11,
- Elia Sanchez12,
- Mónica Gordón5,
- Victoria Fernández6,
- Alberto del Castillo13,
- MaÁngeles Marcos3,
- Beatriz Villanueva14,
- CarlosJavier López14,
- Mario Rodríguez-Domínguez15,
- Juan-Carlos Galan15,
- Rafael Cantón15,
- Aurora Lietor16,
- Silvia Rojo1, 2,
- Jose M Eiros1, 2,
- Carmen Hinojosa17,
- Isabel Gonzalez17,
- Nuria Torner18,
- David Banner19,
- Alberto Leon20,
- Pablo Cuesta21,
- Thomas Rowe19, 22 and
- David J Kelvin19, 20, 22
© Bermejo-Martin et al.; licensee BioMed Central Ltd. 2009
Received: 04 November 2009
Accepted: 11 December 2009
Published: 11 December 2009
Human 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.
We 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.
Increased 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.
While 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 emergence of the new pandemic variant of influenza virus (nvH1N1) has brought renewed attention to the strategies for prevention, treatment and minimization of the social and human costs of the influenza disease [1–5]. The great majority of nvH1N1 infections are mild and self-limiting in nature [6–8]. Nevertheless, a small percentage of the patients require hospitalization and specialized attention in Intensive Care Units (ICUs) [9–12]. Many severe cases occur in healthy young adults, an age group rarely seriously affected by seasonal influenza [9–14]. While pregnancy and metabolic conditions (including obesity and diabetes) have been identified as risk factors for severe nvH1N1 disease, 40 to 50% of fatal cases have no documented underlying medical condition [11, 12, 14]. The new virus causes more severe pathological lesions in the lungs of infected mice, ferrets and non-human primates than seasonal human H1N1 virus . The role of host immune responses in clearance of nvH1N1 or the role, if any, of host immune responses in contributing to severe respiratory pathogenesis of nvH1N1 infections is not known at this time. We have previously identified specific host immune response chemokine and cytokine signatures in severe and mild SARS CoV, H5N1 and Respiratory Syncytial Virus infections. In these studies, early host immune responses are characterized by the expression of systemic levels of chemokines, such as CXCL10, indicative of innate anti viral responses [16–19]. Severe and mild SARS and RSV illness could further be defined by chemokine and cytokine signatures involved in the development of adaptive immunity. Interestingly, de Jong et al. have demonstrated that hypercytokinemia of specific chemokines and cytokines is associated with severe and often fatal cases of human H5N1 infections . To determine if host immune responses play a potential role in the evolution of mild or severe nvH1N1 illness we performed an analysis of systemic chemokine and cytokine levels in serum from severe and mild nvH1N1 patients shortly following the onset of symptoms. Interestingly, we identified cytokine signatures unique to mild and severe patients.
Materials and methods
Patients and controls
Both hospitalized and outpatients were recruited during the first pandemic wave in the months of July and August 2009 in 10 different hospitals within the National Public Health System of Spain.
Exclusion criteria: Patients with signs of bacterial infection defined by the presence of purulent respiratory secretions, and/or positive results in respiratory cultures, blood cultures, and/or positive urinary antigen test to Legionella pneumophila or Streptococcus pneumoniae were excluded from the analysis (Figure 1). Children under 16 years old and one patient older than 80 years old were also excluded in order to make groups comparable by age. Pregnant women were also excluded to avoid confusion factors during the analysis of the immune response to the virus, since pregnancy induces physiological changes in the immune system (Figure 1). Informed consent was obtained directly from each patient or their legal representative and also from the healthy controls before enrollment. Approval of the study protocol in both the scientific and the ethical aspects was obtained from the Scientific Committee for Clinical Research of the coordinating center (Hospital Clinico Universitario de Valladolid, Spain).
Samples and laboratory studies
Sample collection and transport
Blood samples were collected by experienced nurses. A single serum sample was obtained from each patient or control. Serum samples were obtained after proper centrifugation and were sent refrigerated to the National Influenza Center of Valladolid (Spain), where they were stored at -70°C until immune mediator profiling, haemagglutination inhibition activity (HI) and viral load evaluation. Nasopharyngeal swabs preserved in virus transportation medium were sent to the World Health Organization (WHO) associated National Influenza Centers of Valladolid, Majadahonda and Barcelona, Spain for viral diagnosis purposes.
Viral RNA from nasopharyngeal swabs was obtained by using automatic extractors (Biomerieux® (Marcy l'Etoile, France), Roche® (Basel, Switzerland) and viral presence was assessed by real time PCR based methods using reagents provided free of charge by the Centers for Disease Control (CDC, Atlanta, USA) or purchased from Roche® (Basel, Switzerland) (H1N1 detection set) on 96-well plate termocyclers (Roche® LC480 (Basel, Switzerland) and Applied Biosystems® 7500 (Foster City, CA, USA)
Viral load measurement
Viral load was measured and compared between groups by real time reverse transcription PCR on RNA extracted from serum. Briefly, an external curve was obtained by using a serial dilution of human RNA extracted from cultured monocytic leukemia (THP-1) cells, and human gene GAPDH was employed as reporter gene. nvH1N1 neuraminidase gene was amplified by QRT-PCR in each serum sample, and crossing points were extrapolated to the external curve. Analysis of samples and standard curve was conducted by using the 7500 fast v2.0.3 software (Applied Biosystem™). Results were given as relative comparisons in (pg RNA/μl). 5'-3' sequences of primer pairs: GAPDH 5'-ACCCAGAAGACTGTGGATGG-3' (forward); 5'-TTCTAGACGGCAGGTCAGGT-3' (reverse); nvH1N1 neuraminidase: 5'-TCAGTCGAAATGAATGCCCTAA-3' (forward) and N1R 5'-CACGGTCGATTCGAGCCATG-3'(reverse).
Cytokines and chemokines quantification
Serum chemokine and cytokine levels were evaluated using the multiplex Biorad© 27 plex assay (Hercules, CA, USA). This system allows for quantitative measurement of 27 different chemokines, cytokines, growth-factors and immune mediators while consuming a small amount of biological material. Furthermore, this system has good representation of analytes for inflammatory cytokines, anti-inflammatory cytokines, Th1 cytokines, Th2 cytokines, Th17 cytokines and chemokines, allowing for the testing of differential levels of regulatory cytokines in the serum of severe and mild patients. Additionally, interferon α, adiponectin and leptin were measured by using an enzyme-linked inmuno adsorbant assay (ELISA) from R&D© Systems (Minneapolis, MN, USA).
Haemagglutination inhibition assay (HI)
HI assays were performed on a 100 μl aliquot of the samples at University Health Network (UHN), Toronto, Ontario, Canada. The sera was treated with Receptor-Destroying Enzyme (RDE) of V. cholerae by diluting one part serum with three parts enzyme and were incubated overnight in a 37°C water bath. The enzyme was inactivated by a 30-minute incubation at 56°C followed by the addition of six parts 0.85% physiological saline for a final dilution of 1/10. HI assays were performed in V-bottom 96-well microtiter plates (Corning Costar Co., Cambridge, MA, USA) with 0.5% turkey erythrocytes, as previously described , using inactivated pandemic influenza A/California/07/2009 (nvH1N1) antigens.
Data analysis was performed using SPSS 15.0. Comparisons between groups were performed using the non parametric U-Mann Whitney test. Data are displayed as (mean, standard deviation) for clinical and laboratory parameters and as (median, interquartile rank) for data on sample collection timing and the immune mediators levels. Association between variables was determined by calculating the Spearman correlation coefficient (r) and data shown as (r, P value). Significance was fixed at P value < 0.05
Clinical and laboratory characteristics of the patients
Hospitalized, critical illness(n = 10)
Hospitalized, non critical illness (n = 10)
Chronic disease conective tissue
Days at hospital
Days at ICU
O2 saturation (%)
Opacity in initial chest X-Ray
Treatment received at the time of sample collection
10/10 (75-150 mg/12 hs)
10/10 (75 mg/12 hs)
Renal replacement therapy
HI activity (A/California/07/2009) was present in serum from only two critically ill patients of 50 and 51 years old (titres 1/1280 and 1/160 respectively) and in one 25-year-old outpatient (titre 1/160). Serum from those three patients showing HI showed also the ability to block viral replication, as assessed by microneutralization assay against A/California/07/2009 (data not shown). This data supports the notion that at the time of sampling the vast majority of the patients had yet to produce antibodies against nvH1N1 and was in the early stages of disease.
Immune mediators profiling
In a first attempt to understand the role host immune responses play in the evolution of severe and mild nvH1N1 disease, we assessed systemic levels of chemokines and cytokines in the sera from hospitalized and outpatients. Consistent with our previous studies on early elevated expression of CXCL10, CCL2 and CCL4 in SARS CoV and RSV infected patients [16–19], we found in the present study elevated expression of these chemokines in severe patients (critical and non critical) and mild patients. The early expression of these chemokines in all patients likely is indicative of innate antiviral host responses.
Increase in IFN-γ IL-8, IL-9, IL-13 and IL-10 in both critical and non critical hospitalized patients compared to mild ones indicates that they constitute hallmarks of severe disease. IFN-γ and IL-8 promote antiviral immunity but also respiratory tract inflammation by recruiting neutrophils and mononuclear cells to the site of the infection [28–30]. IL-9 is a Th2 cytokine that induces differentiation of Th-17 cells . IL-10 and IL-13 show immunomodulatory properties. IL-13 attenuates Th-17 cytokine production . IL-10 is known to be an anti-inflammatory cytokine. In a murine model, McKinstry et al.revealed that IL-10 inhibits development of Th-17 responses during influenza infection, correlating with compromised protection . Increase of IL-17 and TNF-α in hospitalized patients over control indicated that they also parallel severe disease, but the significantly higher levels of IL-17 and TNF-α in severe non critical patients compared to mild (difference not found for critical ones), could reflect a beneficial role of these cytokines in this particular subset of patients. The patient who died five days after disease onset showed high viral load and undetectable IL-17 levels in serum. This could reflect a protective role of IL-17 in severe patients. IL-15, IL-12p70, IL-6 constituted a hallmark of critical illness in our study. These three cytokines also mediate both antiviral and pro-inflammatory responses. IL-6 is a potent regulator switching immune responses from the induction of Foxp3+ regulatory T cells to pathogenic Th17 cells in vivo . IL-15 promotes CD8 T cells homeostatic proliferation  in response to infection. IL-12 plays a key role in the switch from innate to adaptive immunity .
High levels of Th-1 and Th-17 related mediators could support the hypothesis of a Th-1+Th-17 inflammatory response in the origin of the severe respiratory disease caused by nvH1N1 infection. Alternatively, an increase in Th-1 and Th-17 cytokines may reflect a vigorous antiviral host response necessary for clearance of virus during severe lower respiratory infections. While the ability of influenza A virus to induce the production of chemotactic (RANTES, MIP-1α, MCP-1, MCP-3, and IP-10) and pro-inflammatory (IL-1β, IL-6, IL-18, and TNF-α) Th1 related mediators is well know from previous reports on seasonal influenza [29, 35], this is the first report evidencing Th17 response as a signature of severe influenza disease in humans [36, 37]. Since there are immunomodulatory drugs which have shown to down-modulate the activity of both Th1 and Th17 , the results obtained here supports the development of further studies on animal models aimed to clarify the role of these mediators in the pathogenesis of the acute respiratory disease showed by severe nvH1N1 infected patients.
Analysis of the immune mediators involved in host responses to the virus in mild and severe cases revealed Th1 and Th17 cytokine responses as early distinctive hallmarks of severe respiratory compromise following infection with nvH1N1. 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 influence of Th17-dominant conditions (autoimmune diseases) or Th1 deficient ones (HIV infection) on disease outcome should also be explored. Furthermore, the impact of other regulatory cytokines elevated in severe disease (IL-10, IL-13) on the evolution of host immune responses to nvH1N1 infections may represent alternative therapeutics for controlling severe illness.
The great majority of infections caused by the new influenza pandemic virus are mild and self-limiting in nature. Nevertheless, a small percentage of the patients develop severe respiratory disease. Analysis of the immune mediators involved in host responses to the virus along with the evaluation of the humoral responses in mild and severe cases may help understand the pathogenic events leading to poor outcomes.
Early response to the virus in both hospitalized and outpatients was characterized by expression of chemokines (CXCL10, CCL2 and CCL4), also observed in the response to SARS CoV, H5N1 and RSV, which previous literature describes to correspond to innate antiviral responses.
Patients who develop respiratory compromise in the first days following infection with nvH1N typically showed Th1 and Th17 hyper-cytokinemia, compared to mild patients and healthy controls. These cytokine profiles have been previously reported to participate in both antiviral and pro-inflammatory responses.
Increased systemic levels of IL-15, IL-12p70, IL-6 constituted a hallmark of critical illness. These mediators are known to promote the development of adaptive responses and also pro-inflammatory ones in other viral infections.
Our findings constitute a major avenue to guide the design of further works studying the beneficial or detrimental role of Th1 and Th17 responses in this disease.
Human Fibroblast Growth Factor-basic
granulocyte colony-stimulating factor
granulocyte macrophage colony-stimulating factor
Interleukin 1 receptor antagonist
monocyte chemoattractant protein-1
macrophage inflammatory protein-1α
macrophage inflammatory protein-1β
new variant of H1N1 influenza virus
platelet-derived growth factor
tumour necrosis factor α
vascular endothelial growth factor.
This work has been made by an international team pertaining to the Spanish-Canadian Consortium for the Study of Influenza Immuno-pathogenesis. The authors would like to thank Lucia Rico and Verónica Iglesias for their assistance in the technical development of the multiplex cytokine assays, to Begoña Nogueira for her technical support, and to Nikki Kelvin for language revision of this article. This work was possible thanks to the financial support obtained from the Ministry of Science of Spain and Consejería de Sanidad Junta de Castilla y León, Programa de investigación comisionada en gripe, GR09/0021, Programa para favorecer la incorporación de grupos de investigación en las Instituciones del Sistema Nacional de Salud, EMER07/050, and Proyectos en Investigación Sanitaria, PI081236. CIHR, NIH and LKSF-Canada support DJK. This sponsorship made possible reagent acquisition and sample transportation between participant groups.
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