Acute Influenza Infection Research Articles

Correlation of C-reactive protein to severity of symptoms in acute influenza A infection

Background:Currently there is no objective measure to determine disease severity in patients with acute influenza infection. During acute viral infections, C-reactive protein (CRP) has been shown to be elevated.Aim:To study the relationship between the symptoms of acute influenza A infection and correlate them with the level of inflammation as measured by serum CRP levels.Settings and Design:Prospective study.Materials and Methods:We enrolled a convenience sample of adults presenting to an urban academic emergency department (ED), who had positive Enzyme-linked immunosorbent assay detection of the influenza A antigen. The subjects were excluded if they had immunosuppression, liver disease or were currently taking antiviral medication. A previously validated severity of symptom (SOS) score was calculated by asking the participants to record the severity of seven symptoms associated with influenza infection. The subjects had the serum C-reactive protein (CRP) levels tested during their ED visit.Statistical Analysis:A linear regression model was used with CRP as a predictor of the SOS score. Pearson's product-moment coefficient was used to measure the dependence between the two quantities.Results:Thirty-two subjects were enrolled from January through March 2009, and of those, eight patients were excluded from the analysis, leaving 24 study subjects: 58% were women, of ages 18 to 63 years, with a mean age of 31 years (95% CI 25, 37). The mean SOS score was 14.1 ranging from 6 to 21 (95% CI 12.6, 26.4). The mean CRP score was 24.6 ranging from 0 to 64.7 (95% CI 15.8, 33.4). The correlation coefficient between the SOS score and CRP levels was r = 0.65 (P=0.00056).Conclusion:The severity of symptoms associated with acute influenza A infection correlateswith the serum CRP levels.

Influenza A facilitates sensitization to house dust mite in infant mice leading to an asthma phenotype in adulthood

AbstractThe origins of allergic asthma, particularly in infancy, remain obscure. Respiratory viral infections and allergen sensitization in early life have been associated with asthma in young children. However, a causal link has not been established. We investigated whether an influenza A infection in early life alters immune responses to house dust mite (HDM) and promotes an asthmatic phenotype later in life. Neonatal (8-day-old) mice were infected with influenza virus and 7 days later, exposed to HDM for 3 weeks. Unlike adults, neonatal mice exposed to HDM exhibited negligible immune responsiveness to HDM, but not to influenza A. HDM responsiveness in adults was associated with distinct Ly6c+ CD11b+ inflammatory dendritic cell and CD8α+ plasmacytoid (pDC) populations that were absent in HDM-exposed infant mice, suggesting an important role in HDM-mediated inflammation. Remarkably, HDM hyporesponsiveness was overcome when exposure occurred concurrently with an acute influenza infection; young mice now displayed robust allergen-specific immunity, allergic inflammation, and lung remodeling. Remodeling persisted into early adulthood, even after prolonged discontinuation of allergen exposure and was associated with marked impairment of lung function. Our data demonstrate that allergen exposure coincident with acute viral infection in early life subverts constitutive allergen hyporesponsiveness and imprints an asthmatic phenotype in adulthood.

Control of Pathogenic CD4 T Cells and Lethal Immunopathology by Signaling Immunoadaptor DAP12 during Influenza Infection

Immunopathology is a major cause of influenza-associated morbidity and mortality worldwide. However, the role and regulatory mechanisms of CD4 T cells in severe lung immunopathology following acute influenza infection are poorly understood. In this paper, we report that the emergence of immunopathogenic CD4 T cells is under the control of a transmembrane immunoadaptor DAP12 pathway during influenza infection. We find that the mice lacking DAP12 have unaltered viral clearance but easily succumb to influenza infection as a result of uncontrolled immunopathology. Such immunopathology is associated with markedly increased CD4 T cells displaying markedly increased cytotoxicity and Fas ligand expression. Furthermore, the immunopathogenic property of these CD4 T cells is transferrable. Thus, depletion of CD4 T cells or abrogation of Fas/Fas ligand signaling pathway improves survival and immunopathology. We further find that DAP12 expressed by dendritic cells plays an important role in controlling the immunopathogenic CD4 T cells during influenza infection. Our findings identify a novel pathway that controls the level of immune-pathogenic CD4 T cells during acute influenza infection.

Negative Regulation of Lung Inflammation and Immunopathology by TNF-α during Acute Influenza Infection

Lung immunopathology is the main cause of influenza-mediated morbidity and death, and much of its molecular mechanisms remain unclear. Whereas tumor necrosis factor-α (TNF-α) is traditionally considered a proinflammatory cytokine, its role in influenza immunopathology is unresolved. We have investigated this issue by using a model of acute H1N1 influenza infection established in wild-type and TNF-α-deficient mice and evaluated lung viral clearance, inflammatory responses, and immunopathology. Whereas TNF-α was up-regulated in the lung after influenza infection, it was not required for normal influenza viral clearance. However, TNF-α deficiency led not only to a greater extent of illness but also to heightened lung immunopathology and tissue remodeling. The severe lung immunopathology was associated with increased inflammatory cell infiltration, anti-influenza adaptive immune responses, and expression of cytokines such as monocyte chemoattractant protein-1 (MCP-1) and fibrotic growth factor, TGF-β1. Thus, in vivo neutralization of MCP-1 markedly attenuated lung immunopathology and blunted TGF-β1 production following influenza infection in these hosts. On the other hand, in vivo transgenic expression of MCP-1 worsened lung immunopathology following influenza infection in wild-type hosts. Thus, TNF-α is dispensable for influenza clearance; however, different from the traditional belief, this cytokine is critically required for negatively regulating the extent of lung immunopathology during acute influenza infection.

Changes in Cytokine Levels and NK Cell Activation Associated with Influenza

Several studies have highlighted the important role played by murine natural killer (NK) cells in the control of influenza infection. However, human NK cell responses in acute influenza infection, including infection with the 2009 pandemic H1N1 influenza virus, are poorly documented. Here, we examined changes in NK cell phenotype and function and plasma cytokine levels associated with influenza infection and vaccination. We show that absolute numbers of peripheral blood NK cells, and particularly those of CD56bright NK cells, decreased upon acute influenza infection while this NK cell subset expanded following intramuscular influenza vaccination. NK cells exposed to influenza antigens were activated, with higher proportions of NK cells expressing CD69 in study subjects infected with seasonal influenza strains. Vaccination led to increased levels of CD25+ NK cells, and notably CD56bright CD25+ NK cells, whereas decreased amounts of this subset were present in the peripheral blood of influenza infected individuals, and predominantly in study subjects infected with the 2009 pandemic H1N1 influenza virus. Finally, acute influenza infection was associated with low plasma concentrations of inflammatory cytokines, including IFN-γ, MIP-1β, IL-2 and IL-15, and high levels of the anti-inflammatory cytokines IL-10 and IL-1ra. Altogether, these data suggest a role for the CD56bright NK cell subset in the response to influenza, potentially involving their recruitment to infected tissues and a local production and/or uptake of inflammatory cytokines.

Memory precursor phenotype of CD8+ T cells reflects early antigenic experience rather than memory numbers in a model of localized acute influenza infection

The mechanistic basis of memory T-cell development is poorly defined. Phenotypic markers that define precursors at effector stages have been characterized for acute systemic infections with high antigen load. We asked whether such markers can identify memory precursors from early effectors (d6) to late memory (>d500) for two immunodominant CD8(+) responses during the course of a localized low-load influenza infection in mice. CD8(+) T cells stained with the D(b) NP(366) and D(b) PA(224) tetramers were characterized as IL-7Rα(hi) , IL-7Rα(hi) CD62L(hi) or IL-7Rα(hi) KLRG1(lo) . While the D(b) NP(366) - and D(b) PA(224) -specific responses were comparable in size, decay kinetics and memory precursor frequency, their expansion characteristics differed. This correlated with a divergence in the IL-7Rα(hi) , IL-7Rα(hi) CD62L(hi) and IL-7Rα(hi) KLRG1(lo) phenotypes on effector, but not naïve, CD8(+) populations. That effect was abrogated by priming with viruses engineered to present equivalent levels of NP(366) and PA(224) peptides, indicating that memory phenotypes reflect early antigenic experience rather than memory potential. Thus, the IL-7Rα(hi) KLRG1(lo) phenotype had a poor predictive value in identifying memory precursors in the spleen and at the site of infection. Greater consistency in influenza-specific IL-7Rα(hi) KLRG1(lo) CD8(+) T-cell numbers was found in draining lymph nodes, suggesting that this may be the preferential site for memory establishment and maintenance following localized virus infections.

Two cases of H1N1 influenza infection as the initial presentation of acute leukemia

Pandemic 2009 influenza A virus (H1N1) is a new influenza virus causing illness in human populations. Immunocompromised patients are at high risk for the acquisition of influenza and serious influenza-associated complications. However, there are no reports about patients with both newly diagnosed acute leukemia and H1N1 influenza infection. We reported 2 cases of previously healthy patients with H1N1 influenza infection as the initial presentation of acute leukemia.

In this issue

In this issue

No role for neutrophil elastase in influenza-induced cellular recruitment, cytokine production or airway hyperresponsiveness in mice

Previous studies have suggested that in vitro modulation of neutrophil chemokines and inflammatory cytokines by neutrophil elastase (NE) does not translate to the in vivo setting. We aimed to test the role of NE in the recruitment of neutrophils, cytokine production and lung function responses to respiratory viral infection. To address this, we inoculated neutrophil elastase (NE(-/-)) deficient and wild-type (WT) 129Sv mice with 50μL of 10(4.5)pfu Influenza A/Mem71 (H3N1) or a control preparation. Mice were subjected to methacholine (MCh) challenge at 3-4 days post-infection during the peak of cellular inflammation. Inflammation, protein content and cytokines (TNF-α and MIP-2) were assessed in bronchoalveolar lavage fluid. Influenza-infected mice had a heightened responsiveness to MCh, increased cellular inflammation, increased protein leak and altered cytokine production, none of which were influenced by the absence of NE. These data demonstrate that NE does not modulate neutrophil recruitment, cytokine production, epithelial permeability or responsiveness to bronchoconstricting agents during acute influenza infection in mice.

Obstetric Outcomes of Influenza A H1N1 (2009) Infection in Pregnancy – Experience of a Singapore Tertiary Hospital

Influenza A H1N1 (2009) pandemic has affected countries worldwide including Singapore. Data on obstetric outcomes of women with H1N1 (2009) in pregnancy are lacking. This was an observational study analysing the obstetric outcomes of pregnant women with influenza A H1N1 (2009) infection who had delivered at a viable gestation (24 weeks or more) in our centre. Between 23 June 2009 and 30 September 2009, 235 pregnant women were diagnosed with influenza A H1N1 (2009) at our centre, with 42 having delivered and comprising the study cohort. Median age was 27.5 years (range, 16 to 42). Multiparous women comprised 59.5% (25/42) whilst 40.5% (17/42) were primiparous. In terms of ethnicity, 61.9% were Malays, 26.2% Chinese, 4.8% Indians and 7.1% Others. All women received oseltamivir. All had shown recovery from the acute influenza infection. There were no respiratory complications. Twenty-nine women (69.0%) delivered at term. Twenty-fi ve women (59.5%) had spontaneous labour whilst 15 (35.7%) had labour induction. Two women (4.8%) did not labour. Thirty-six women (85.7%) had vaginal delivery, of whom 3 were instrumental deliveries. Apgar scores of greater than 8 at 1 min and 5 min were documented in babies of 95.2% (40/42) women, respectively. Thirty-two women (76.2%) delivered babies with birthweights greater than 2500 g. Compared with historical data from 2008, the H1N1 cohort had comparable mean birthweight and average gestational age at delivery of 38 weeks. Our study suggested that obstetric outcomes were not adversely affected by influenza A H1N1 (2009) infection.

Cytokines and acute phase proteins associated with acute swine influenza infection in pigs.

This study set out to investigate the cytokines and acute phase proteins (APPs) associated with the acute stages of experimentally-induced swine influenza virus (SIV) infection in 3-week-old, colostrum-deprived, caesarean-derived piglets. The piglets were inoculated intratracheally with 107.5 50% egg infective dose [EID50] Swine/Belgium/1/98 (H1N1) SIV and were euthanased at time-points between 0 and 120 h post-inoculation (PI). Broncho-alveolar lavage fluid (BALF), lung homogenates and sera were examined for inflammatory mediators by bioassay or ELISA. Interferon (IFN)-α, interleukin (IL)-6, IL-1 and tumour necrosis factor (TNF)-α peaked in BALF 24–30 h PI, when virus titres and the severity of clinical signs were maximal.Whereas IFN-γ and IL-12, but not IL-18, increased in tandem in BALF, serum cytokine concentrations were either undetectable or were up to 100-fold lower. The APP C-reactive protein (CRP) and haptoglobin peaked 24 h later than the cytokines and reached higher levels in serum than in BALF. In contrast, lipopolysaccharide (LPS)-binding protein (LBP) only increased in BALF. Lung virus titres tightly correlated with BALF IFN-α, IL-6, IL-1, TNF-α, IFN-γ and IL-12, as well as with serum IL-6, IFN-α and IFN-γ. Signs of disease correlated with the same cytokines in BALF and serum, as well as with BALF LBP and serum CRP. The findings suggest that IFN-γ and IL-12 play a role in the pathogenesis of SIV and that APPs are induced by cytokines. This influenza infection model may have value in assessing the therapeutic potential of cytokine antagonists.

A Quantitative Assessment of the Efficacy of Surgical and N95 Masks to Filter Influenza Virus in Patients with Acute Influenza Infection

We assessed the in vivo efficacy of surgical and N95 (respirator) masks to filter reverse transcription-polymerase chain reaction (RT-PCR)-detectable virus when worn correctly by patients with laboratory-confirmed acute influenza. Of 26 patients with a clinical diagnosis of influenza, 19 had the diagnosis confirmed by RT-PCR, and 9 went on to complete the study. Surgical and N95 masks were equally effective in preventing the spread of PCR-detectable influenza.

Effector T-cells control lung inflammation during acute respiratory virus infection by producing interleukin-10 (43.7)

Abstract Activated antigen-specific T cells produce a variety of effector molecules for clearing infection, but also contribute significantly to inflammation and tissue injury. Here we report an anti-inflammatory property of anti-viral CD8+ and CD4+ effector T cells (Te) in the infected periphery during acute pulmonary virus infection. We find that, during acute influenza and other respiratory virus infection, IL-10 is produced in the infected lungs at high levels -- exclusively by infiltrating virus-specific Te, with CD8+ Te contributing a larger fraction of the IL-10 produced. These Te in the periphery simultaneously produce IL-10 and proinflammatory cytokines, and express lineage markers characteristic of conventional Th/c1 cells. Importantly, blocking the action of the Te-derived IL-10 results in enhanced pulmonary inflammation and injury associated with the viral infection. Our results demonstrate that anti-viral Te exert regulatory functions -- that is, fine-tune the extent of lung inflammation/injury associated with respiratory virus infection by the production of an anti-inflammatory cytokine.

Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10

Activated antigen-specific T cells produce a variety of effector molecules for clearing infection, but also contribute significantly to inflammation and tissue injury. Here we report an anti-inflammatory property of anti-viral CD8+ and CD4+ effector T cells (Te) in the infected periphery during acute virus infection. We find that, during acute influenza infection, IL-10 is produced in the infected lungs at high levels -- exclusively by infiltrating virus-specific Te, with CD8+ Te contributing a larger fraction of the IL-10 produced. These Te in the periphery simultaneously produce IL-10 and proinflammatory cytokines, and express lineage markers characteristic of conventional Th/c1 cells. Importantly, blocking the action of the Te-derived IL-10 results in enhanced pulmonary inflammation and lethal injury. Our results demonstrate that anti-viral Te exert regulatory functions -- that is, fine-tune the extent of lung inflammation and injury associated with influenza infection by the production of an anti-inflammatory cytokine. The potential implications of these findings for infection with highly pathogenic influenza viruses are discussed.

Low-dose supplementation with active hexose correlated compound improves the immune response to acute influenza infection in C57BL/6 mice

Supplementation with mushroom-derived active hexose correlated compound (AHCC) modulates immunity and increases survival in response to a broad spectrum of acute infections, including influenza virus infection. However, dose-response data are nonexistent. Therefore, the aims of this study were to evaluate AHCC supplementation at various doses and determine the effects of low-dose supplementation on the immune response in a mouse model of influenza virus infection. We hypothesized that AHCC supplementation would influence the immune response to influenza infection in a dose-dependent manner. Male C57BL/6 mice were supplemented with AHCC at daily doses of 0.05, 0.1, 0.5, and 1 g/kg and infected intranasally with influenza A virus (H1N1, PR8). Supplemented mice demonstrated a dose-dependent increase in survival and reduction in the loss of body weight. To further evaluate the effects of low-dose AHCC supplementation on the immune response to influenza infection, mice were supplemented with 0.1 g/kg per day and infected with a sublethal dose of influenza virus. Supplemented mice exhibited enhanced virus clearance and decreased weight loss compared to controls. Low-dose supplementation did not influence total natural killer (NK) cell cytotoxicity, although lytic efficiency was increased in the spleens of AHCC-supplemented mice, indicating enhanced NK cell function per cell. In conclusion, these data suggest that the effects of AHCC on the immune response to influenza infection are dose dependent and that low-dose AHCC supplementation improves the response to influenza infection despite no effect on total NK cell cytotoxicity.

A Key Role for CC Chemokine Receptor 1 in T-Cell-Mediated Respiratory Inflammation

CC chemokine receptor 1 (CCR1) is found on a variety of cells in the immune system and has been shown to play an important role in the host response to pathogens. These studies used a murine model of virus-induced exacerbation of allergic airway disease to examine the role of CCR1 on T cells associated with immune responses taking place in the lung. Lungs of virally exacerbated allergic animals contained elevated levels of interferon-gamma and interleukin-13 and increased levels of CCR1 ligands CCL3 and CCL5. CCR1 expression on T cells was increased in virally exacerbated allergic animals over the level observed in mice sensitized to allergen or exposed to viral infection alone. Using mice deficient for CCR1, we observed decreased airway hyperreactivity and Th2 cytokine production from CD4(+) T cells when this receptor was absent. Transfer studies demonstrated that neither CD4(+) nor CD8(+) T cells from CCR1(-/-) mice migrated to the lymph node as efficiently as wild-type T cells. Intracellular cytokine staining in wild-type mice revealed that CCR1(+) CD4(+) and CD8(+) T cells are associated with interleukin-13 production. Thus, these studies identify CCR1 as a potential target for alleviating T-cell accumulation during exacerbation of asthmatic disease.

T Cell Memory Generation in the Face of Persistent Antigen Presentation

In the face of emerging infectious diseases, we are challenged to develop innovative vaccine strategies that can protect against rapidly evolving and highly virulent pathogens. Since CD4 T cells are needed to generate and maintain protective B cell and CD8 T cell immunity, new vaccines should ideally elicit both T and B cell memory. In order to generate long-lived immune memory in both T and B cell compartments, such vaccines will need to induce cross-reactive memory against highly conserved antigens within a given pathogen. Acute influenza infection provides a model system whereby the generation of T cell memory is influenced by residual antigen depots. These antigen depots persist for months after live virus clearance, and provide continued, low level T cell stimulation. Here we discuss the impact and implications of residual pathogen-derived antigen depots on the generation and maintenance of T cell immunity. We propose that effective vaccines may need to include persistent depots of conserved proteins to generate a functionally flexible memory T cell pool that can confer protection against rapidly evolving pathogens.

Influenza A and B Infection in Children in Urban Slum, Bangladesh

Influenza A and B Infection in Children in Urban Slum, Bangladesh

CD8+ T Cell Dysfunction and Increase in Murine Gammaherpesvirus Latent Viral Burden in the Absence of 4-1BB Ligand

Studies of costimulatory receptors belonging to the TNFR family have revealed their diverse roles in affecting different stages of the T cell response. The 4-1BB ligand (4-1BBL)/4-1BB pathway has emerged as a receptor-ligand pair that impacts not the initial priming, but later phases of the T cell response, such as sustaining clonal expansion and survival, maintaining memory CD8(+) T cells, and supporting secondary expansion upon Ag challenge. Although the role of this costimulatory pathway in CD8(+) T cell responses to acute viral infections has been well-studied, its role in controlling chronic viral infections in vivo is not known to date. Using the murine gammaherpesvirus-68 (MHV-68) model, we show that 4-1BBL-deficient mice lack control of MHV-68 during latency and show significantly increased latent viral loads. In contrast to acute influenza infection, the numbers of MHV-68-specific memory CD8(+) T cells were maintained during latency. However, the virus-specific CD8(+) T cells showed defects in function, including decreased cytolytic function and impaired secondary expansion. Thus, 4-1BBL deficiency significantly affects the function, but not the number, of virus-specific CD8(+) T cells during gammaherpesvirus latency, and its absence results in an increased viral burden. Our study suggests that the 4-1BB costimulatory pathway plays an important role in controlling chronic viral infections.

Acute Hepatitis and Liver Failure Associated With Influenza A Infection in Children

Acute Hepatitis and Liver Failure Associated With Influenza A Infection in Children