H1N1 Influenza Virus Infection Research Articles

Restricted Infection and Cytokine Expression in Primary Murine Astrocytes Induced by the H5N1 Influenza Virus

Central nervous system (CNS) dysfunction caused by infection with neurovirulent viruses is of interest, and may play an important role in many neurodegenerative diseases. Since neuronal functions are believed to be partly regulated by cytokines produced by astrocytes, neuroinflammation and neurodegeneration caused by H5N1 influenza virus infection could be due to abnormal cytokine production of those infected astrocytes. In the present study, cytokine responses of murine astrocytes following H5N1 virus infection were investigated. Primary astrocytes from neonatal outbred ICR mice were isolated and used to investigate cytopathology upon infection with the H5N1 virus (A/Chicken/Thailand/CUK2/04). Thereafter, cell lysates at 6, 24, 48, and 72 hours-post infection (hpi) were collected and subjected to quantification of cytokine gene expression, including TNF-α, IL-1β, IL-2, IL-6 and IL-12β, by quantitative RT-PCR. The results revealed that infection with the H5N1 virus in primary murine astrocytes was restricted, and resulted in abortive virus infection. However, this abortive infection in the astrocytes was found to result in significant upregulation of IL-1β mRNA expression at 72 hpi compared with the mock-infected group, while the mRNA expression of IL-2 and IL-12β was observed to have undergone significant down-regulation at 6-72 hpi and 24-48 hpi, respectively. The results of the present study could support the role of astrocytes in neuroinflammation and neurodegeneration.

High flow nasal oxygen therapy in a young pregnant patient with hypoxemic respiratory failure due to H1N1 influenza viral infection

Pregnant women are at high risk of infection with the novel H1N1 influenza A virus. A 30-year-old pregnant woman at 35 weeks of gestation was admitted with acute onset fever, cough and shortness of breath with hypoxaemic respiratory failure. Laboratory investigations confirmed influenza A infection. This case report illustrates how High Flow Nasal Oxygen device gave good results in hypoxemic respiratory failure especially in the setting of possible unexpected infections and ventilator associated pneumonia.

H1N1 influenza virus infection results in adverse pregnancy outcomes by disrupting tissue-specific hormonal regulation.

Increased susceptibility to influenza virus infection during pregnancy has been attributed to immunological changes occurring before and during gestation in order to “tolerate” the developing fetus. These systemic changes are most often characterized by a suppression of cell-mediated immunity and elevation of humoral immune responses referred to as the Th1-Th2 shift. However, the underlying mechanisms which increase pregnant mothers’ risk following influenza virus infection have not been fully elucidated. We used pregnant BALB/c mice during mid- to late gestation to determine the impact of a sub-lethal infection with A/Brisbane/59/07 H1N1 seasonal influenza virus on completion of gestation. Maternal and fetal health status was closely monitored and compared to infected non-pregnant mice. Severity of infection during pregnancy was correlated with premature rupture of amniotic membranes (PROM), fetal survival and body weight at birth, lung viral load and degree of systemic and tissue inflammation mediated by innate and adaptive immune responses. Here we report that influenza virus infection resulted in dysregulation of inflammatory responses that led to pre-term labor, impairment of fetal growth, increased fetal mortality and maternal morbidity. We observed significant compartment-specific immune responses correlated with changes in hormonal synthesis and regulation. Dysregulation of progesterone, COX-2, PGE2 and PGF2α expression in infected pregnant mice was accompanied by significant remodeling of placental architecture and upregulation of MMP-9 early after infection. Collectively these findings demonstrate the potential of a seasonal influenza virus to initiate a powerful pro-abortive mechanism with adverse outcomes in fetal health.

Food as a passible source af H5N1 influenza virus infection in mammals

The recent infections of humans and other mammals with die highly padiogenic H5N1 avian influenza virus have raised questions about the safety of the consumption of poultry products. The aim of this review is to collect and present information regarding the risk of infection in humans with H5N1 virus via the oral route. The presence of virus in edible poultry products and the chances for viral entry via the gastrointestinal (GI) tract, from a pathogenetic point of view, are the main focus points. The transmission of H5N1 from poultry to humans is a rare event which has been associated with very close contact with infected animals. It is generally accepted that the most likely candidate routes for the virus entry are the oropharygeal and/or respiratory tract tissues where virus replication may occur and leading to clinical symptoms. However, the low number of human cases, compared to the high number of humans that have been exposed to H5N1 virus infected animals, shows clearly that a readily accessible portal of entry does not exist. The possibility of virus entry through the GI tract has been proposed, but, so far, no proof that the virus can replicate in the human intestines has been shown. The presence of diarrhoea in several patients and the detection of viral RNA in the intestines and rectal swabs of 3 patients do not allow one to safely conclude that the GI tract can serve as a portal of entry or a target organ. Furthermore, the occurrence of disease has not clearly or definitely been associated with the consumption of poultry meat in any human case. Feline species, on the other hand, have been naturally and experimentally infected after the consumption of infected poultry. However, also in these mammals, it was not established that the intestine is the initial portal of entry of the virus. In conclusion, the possibility that the intestinal tract serves as a portal of entry in mammals remains unlikely, since there is no convincing evidence that the GI tract tissues can support virus replication. It can, however, not be excluded that food containing virus may be a source of infection when passing oropharyngeal tissues, which have been identified as target sites for virus replication.

MiR-194 Inhibits Innate Antiviral Immunity by Targeting FGF2 in Influenza H1N1 Virus Infection.

Fibroblast growth factor 2 (FGF2 or basic FGF) regulates a wide range of cell biological functions including proliferation, angiogenesis, migration, differentiation, and injury repair. However, the roles of FGF2 and the underlying mechanisms of action in influenza A virus (IAV)-induced lung injury remain largely unexplored. In this study, we report that microRNA-194-5p (miR-194) expression is significantly decreased in A549 alveolar epithelial cells (AECs) following infection with IAV/Beijing/501/2009 (BJ501). We found that miR-194 can directly target FGF2, a novel antiviral regulator, to suppress FGF2 expression at the mRNA and protein levels. Overexpression of miR-194 facilitated IAV replication by negatively regulating type I interferon (IFN) production, whereas reintroduction of FGF2 abrogated the miR-194-induced effects on IAV replication. Conversely, inhibition of miR-194 alleviated IAV-induced lung injury by promoting type I IFN antiviral activities in vivo. Importantly, FGF2 activated the retinoic acid-inducible gene I signaling pathway, whereas miR-194 suppressed the phosphorylation of tank binding kinase 1 and IFN regulatory factor 3. Our findings suggest that the miR-194-FGF2 axis plays a vital role in IAV-induced lung injury, and miR-194 antagonism might be a potential therapeutic target during IAV infection.

Mycophenolic mofetil, an alternative antiviral and immunomodulator for the highly pathogenic avian influenza H5N1 virus infection

Infection with the highly pathogenic avian influenza H5N1 virus results in a high incidence of mortality in humans. Severe complications from infection are often associated with hypercytokinemia. However, current neuraminidase inhibitors (NAIs) have several limitations including the appearance of oseltamivir-resistant H5N1 virus and the inability to completely ameliorate hyper-immune responses. To overcome these limitations, we evaluated the anti-viral activity of mycophenolic mofetil (MMF) against A/Vietnam/1194/2004 (H5N1) virus infection using MDCK cells and mice. The IC50 of MMF (0.94 μM) was comparable to that of zanamivir (0.87 μM) in H5N1 virus-infected MDCK cells based on ELISA. Time-course assays demonstrated that MMF completely inhibited H5N1 viral mRNA replication and protein expression for approximately 8 h after the initiation of treatment. In addition, MMF treatment protected 100% of mice, and lung viral titers were substantially reduced. The anti-viral mechanism of MMF against H5N1 virus infection was further confirmed to depend on the inhibition of cellular inosine monophosphate dehydrogenase (IMPDH) by exogenous guanosine, which inhibits viral mRNA and protein expression. Moreover, IL-1β, IFN-β, IL-6, and IP-10 mRNA expression levels were significantly downregulated in MDCK cells with MMF treatment. These results indicated that MMF could represent a novel inhibitor of viral replication and a potent immunomodulator for the treatment of H5N1 virus infection.

Antiviral activity of five Asian medicinal pant crude extracts against highly pathogenic H5N1 avian influenza virus.

To study the antiviral properties of the five Asian medicinal plants against invitro infection by the highly pathogenic avian influenza virus (H5N1). Crude extracts of Andrographis paniculata, Curcuma longa (C.longa), Gynostemma pentaphyllum, Kaempferia parviflora (K.parviflora), and Psidium guajava obtained by both water and ethanol extractions were investigated for their cytotoxicity in the Madin-Darby canine kidney cells. Thereafter, they were investigated invitro for antiviral activity and cytokine response upon H5N1 virus infection. The results revealed that both water and ethanol extracts of all the five studied plants showed significant antiviral activity against H5N1 virus. Among these plants, C.longa and K.parviflora showed strong anti-H5N1 activity. Thus, they were selected for further studies on their cytokine response upon virus infection. It was found that ethanol and water crude extracts of C.longa and K.parviflora induced significant upregulation of TNF-α and IFN-β mRNA expressions, suggesting their roles in the inhibition of H5N1 virus replication. To the best of the authors' knowledge, this study is among the earliest reports to illustrate the antiviral property of these Asian medicinal plants against the highly pathogenic avian H5N1 influenza virus. The results of this study shed light on alternative therapeutic sources for treatment of H5N1 influenza virus infection in the future.

Rapamycin adjuvant and exacerbation of severe influenza in an experimental mouse model

Influenza virus infection often causes severe disease and acute respiratory distress syndrome. It is a common belief that overwhelming immune response contributes to the severe illness. Physicians and researchers have put forth immune modulation as salvage therapy for better recovery. However, empiric corticosteroid failed in both humans and animal models. Reported success with Rapamycin in humans prompted a comprehensive animal study and mechanistic dissection. Here we report the effect of Rapamycin alone or in combination with Oseltamivir for severe influenza in BALB/c mice. We found that Rapamycin had no antiviral effect against H1N1, H3N2 and novel-H1N1 influenza viruses in vitro. Rapamycin alone aggravated the severe disease of PR8 H1N1 influenza virus infection in mice. Timely Oseltamivir anti-viral therapy abolished the disease. Delayed Oseltamivir treatment could not prevent severe illness and Rapamycin adjuvant was associated with exacerbated disease. Rapamycin adjuvant suppressed influenza hemagglutinin antigen-specific T cell immunity and impaired virus clearance from the lungs. It also resulted in intensified lung pathology with increased intra-alveolar edema and hyaline deposition. Rapamycin may work as the salvage therapy for severe influenza but it is very difficult to define the appropriate window for such treatment to take effect.

Live-attenuated auxotrophic mutant of Salmonella Typhimurium expressing immunogenic HA1 protein enhances immunity and protective efficacy against H1N1 influenza virus infection.

To evaluate the efficacy of attenuated Salmonella Typhimurium (JOL912) as a live bacterial vaccine vector. The JOL912 engineered to deliver HA1 protein from influenza A/Puerto Rico/8/1934 (H1N1; PR8) virus was coined as JOL1635 and further evaluated for immunogenicity and protective efficacy. The JOL1635 stably harbored the HA1 gene within pMMP65 plasmid with periplasmic expression and effective delivery of HA1 protein to RAW264.7 cells. The JOL1635 immunized chickens showed the significant increase in HA1-specific IgG, sIgA antibody, IFN-γ, IL-6 cytokine and cellular immune responses. The postoral challenge, the JOL1635-immunized chickens showed a faster clearance of PR8 virus cloacal shedding than the control group. Generated JOL1635 can establish specific immunogenicity and protection against the PR8 virus in chickens.

The changing landscape of A H7N9 influenza virus infections in China

The changing landscape of A H7N9 influenza virus infections in China

Linear DNA vaccine prepared by large-scale PCR provides protective immunity against H1N1 influenza virus infection in mice

Linear DNA vaccines provide effective vaccination. However, their application is limited by high cost and small scale of the conventional polymerase chain reaction (PCR) generally used to obtain sufficient amounts of DNA effective against epidemic diseases. In this study, a two-step, large-scale PCR was established using a low-cost DNA polymerase, RKOD, expressed in Pichia pastoris. Two linear DNA vaccines encoding influenza H1N1 hemagglutinin (HA) 1, LEC-HA, and PTO-LEC-HA (with phosphorothioate-modified primers), were produced by the two-step PCR. Protective effects of the vaccines were evaluated in a mouse model. BALB/c mice were immunized three times with the vaccines or a control DNA fragment. All immunized animals were challenged by intranasal administration of a lethal dose of influenza H1N1 virus 2 weeks after the last immunization. Sera of the immunized animals were tested for the presence of HA-specific antibodies, and the total IFN-γ responses induced by linear DNA vaccines were measured. The results showed that the DNA vaccines but not the control DNA induced strong antibody and IFN-γ responses. Additionally, the PTO-LEC-HA vaccine effectively protected the mice against the lethal homologous mouse-adapted virus, with a survival rate of 100% versus 70% in the LEC-HA-vaccinated group, showing that the PTO-LEC-HA vaccine was more effective than LEC-HA. In conclusion, the results indicated that the linear H1N1 HA-coding DNA vaccines induced significant immune responses and protected mice against a lethal virus challenge. Thus, the low-cost, two-step, large-scale PCR can be considered a potential tool for rapid manufacturing of linear DNA vaccines against emerging infectious diseases.

Natural H7N9 infection in humans boosts cross-group stalk-specific antibody responses broadly cross-reactive to heterosubtypic influenza hemagglutinins from both group 1 and group 2

Abstract Background The outbreak of novel avian H7N9 influenza virus infections in China in 2013 has demonstrated the continuing threat posed by zoonotic pathogens. To decipher the responses during natural infection will enlighten the vaccine development. Methods We assessed the induction of heterosubtypic cross-reactive antibodies induced by H7N9 infection against a large panel of recombinant hemagglutinins and neuraminidases by quantitative ELISA, and novel chimeric hemagglutinin constructs were employed to dissect the anti-stalk or head humoral response. Results H7N9 infection induced strong antibody responses against divergent H7 hemagglutinins. Interestingly, we also found the induction of antibodies against heterosubtypic hemagglutinins from both group 1 and group 2 and a boost in heterosubtypic neutralizing activity but not in hemagglutination inhibitory activity. Kinetic monitoring revealed that heterosubtypic binding/neutralizing antibody responses typically appeared and peaked earlier than intrasubtypic responses as stalk-specific memory responses. Conclusions Our results indicate cross-group binding and neutralizing antibody responses primarily targeting at stalk region could be elicited after influenza natural infection and probably with proper immunogen in the presence of preexisting responses. These data support our understanding of the breadth of the post-infection immune response that could inform the design of future, broadly protective influenza virus vaccines.

Hybrid inorganic-organic capsules for efficient intracellular delivery of novel siRNAs against influenza A (H1N1) virus infection

The implementation of RNAi technology into the clinical practice has been significantly postponing due to the issues regarding to the delivery of naked siRNA predominantly to target cells. Here we report the approach to enhance the efficiency of siRNA delivery by encapsulating the siRNA into new carrier systems which are obtained via the combination of widely used layer-by-layer technique and in situ modification by sol-gel chemistry. We used three types of siRNAs (NP-717, NP-1155 and NP-1496) in encapsulated form as new therapeutic agents against H1N1 influenza virus infection. By employing the hybrid microcontainers for the siRNA encapsulation we demonstrate the reduction of viral nucleoprotein (NP) level and inhibition of influenza virus production in infected cell lines (MDCK and A549). The obtained hybrid carriers based on assembled biodegradable polyelectrolytes and sol-gel coating possess several advantages such as a high cell uptake efficiency, low toxicity, efficient intracellular delivery of siRNAs and the protection of siRNAs from premature degradation before reaching the target cells. These findings underpin a great potential of versatile microencapsulation technology for the development of anti-viral RNAi delivery systems against influenza virus infection.

16S rDNA sequencing analysis of upper respiratory tract flora in patients with influenza H1N1 virus infection

BackgroundWe analyzed respiratory tract bacterial flora in patients with influenza H1N1 virus infection, and investigated the role of H1N1 virus in secondary bacterial infection. MethodA total of 12,766 operational taxonomic units (OTUs) were obtained, of which, 12,127 were identified to phylum level and 10,494 to genus level. We used next-generation sequencing technology to evaluate bacterial abundance in swab specimens from patients infected with influenza H1N1 virus or Non-H1N1 influenza and from healthy controls. Data analysis was carried out by using alpha analysis (Shannon-Wiener index and Rarefaction-Curve), beta analysis [UniFrac(abundance) and Metastats analysis], and Community-and-Phylogenesis analysis. ResultsAt phylum level, Proteobacteria in patients with H1N1 virus infection (99.928±0.008%) and common cold (89.019±1.845%) were significantly higher than in healthy controls (26.103±2.495%) (p<0.01). In contrast, proportions of Firmicutes, Bacteroidetes, Actinobacteria, Candidate division TM7, Fusobacteria and SR1 were down-regulated (p<0.01) in patients with H1N1 virus infection. At genus level, Pseudomonas increased >500-fold in patients with H1N1 virus infection compared with healthy controls. Ochrobactrum, Brevundimonas, Caulobacter, Aquabacterium and Serratia also increased significantly in H1N1 virus infection, while Neisseria, Prevotella, Veillonella, Actinomyces, Porphyromonas, Streptococcus, Haemophilus and Acinetobacter decreased. ConclusionOur data indicated that microbial abundance of the upper respiratory tract decreased in patients with H1N1 virus infection. Pseudomonas was the dominant genus among the upper respiratory tract bacterial flora in H1N1-infected patients. The changes in upper respiratory tract flora probably be closely related to the occurrence and progression of secondary bacterial infection.

Dynamic gene expression analysis in a H1N1 influenza virus mouse pneumonia model.

H1N1, a major pathogenic subtype of influenza A virus, causes a respiratory infection in humans and livestock that can range from a mild infection to more severe pneumonia associated with acute respiratory distress syndrome. Understanding the dynamic changes in the genome and the related functional changes induced by H1N1 influenza virus infection is essential to elucidating the pathogenesis of this virus and thereby determining strategies to prevent future outbreaks. In this study, we filtered the significantly expressed genes in mouse pneumonia using mRNA microarray analysis. Using STC analysis, seven significant gene clusters were revealed, and using STC-GO analysis, we explored the significant functions of these seven gene clusters. The results revealed GOs related to H1N1 virus-induced inflammatory and immune functions, including innate immune response, inflammatory response, specific immune response, and cellular response to interferon-beta. Furthermore, the dynamic regulation relationships of the key genes in mouse pneumonia were revealed by dynamic gene network analysis, and the most important genes were filtered, including Dhx58, Cxcl10, Cxcl11, Zbp1, Ifit1, Ifih1, Trim25, Mx2, Oas2, Cd274, Irgm1, and Irf7. These results suggested that during mouse pneumonia, changes in the expression of gene clusters and the complex interactions among genes lead to significant changes in function. Dynamic gene expression analysis revealed key genes that performed important functions. These results are a prelude to advancements in mouse H1N1 influenza virus infection biology, as well as the use of mice as a model organism for human H1N1 influenza virus infection studies.

Induction of Broadly Cross-Reactive Stalk-Specific Antibody Responses to Influenza Group 1 and Group 2 Hemagglutinins by Natural H7N9 Virus Infection in Humans

The outbreak of novel avian H7N9 influenza virus infections in China in 2013 has demonstrated the continuing threat posed by zoonotic pathogens. Deciphering the immune response during natural infection will guide future vaccine development. We assessed the induction of heterosubtypic cross-reactive antibodies induced by H7N9 infection against a large panel of recombinant hemagglutinins and neuraminidases by quantitative enzyme-linked immunosorbent assay, and novel chimeric hemagglutinin constructs were used to dissect the anti-stalk or -head humoral immune response. H7N9 infection induced strong antibody responses against divergent H7 hemagglutinins. Interestingly, we also found induction of antibodies against heterosubtypic hemagglutinins from both group 1 and group 2 and a boost in heterosubtypic neutralizing activity in the absence of hemagglutination inhibitory activity. Kinetic monitoring revealed that heterosubtypic binding/neutralizing antibody responses typically appeared and peaked earlier than intrasubtypic responses, likely mediated by memory recall responses. Our results indicate that cross-group binding and neutralizing antibody responses primarily targeting the stalk region can be elicited after natural influenza virus infection. These data support our understanding of the breadth of the postinfection immune response that could inform the design of future, broadly protective influenza virus vaccines.

Effects of calcitriol (1, 25-dihydroxy-vitamin D3) on the inflammatory response induced by H9N2 influenza virus infection in human lung A549 epithelial cells and in mice

BackgroundH9N2 influenza viruses circulate globally and are considered to have pandemic potential. The hyper-inflammatory response elicited by these viruses is thought to contribute to disease severity. Calcitriol plays an important role in modulating the immune response to viral infections. However, its unknown whether calcitriol can attenuate the inflammatory response elicited by H9N2 influenza virus infection.MethodsHuman lung A549 epithelial cells were treated with calcitriol (100 nM) and then infected with an H9N2 influenza virus, or infected and then treated with calcitriol (30 nM). Culture supernatants were collected every 24 h post infection and the viral growth kinetics and inflammatory response were evaluated. Calcitriol (5 mg/kg) was administered daily by intraperitoneal injection to BABL/c mice for 15 days following H9N2 influenza virus infection. Mice were monitored for clinical signs of disease, lung pathology and inflammatory responses.ResultsCalcitriol treatment prior to and post infection with H9N2 influenza significantly decreased expression of the influenza M gene, IL-6, and IFN-β in A549 cells, but did not affect virus replication. In vivo, we found that calcitriol treatment significantly downregulated pulmonary inflammation in mice 2 days post-infection, but increased the inflammatory response 4 to 6 days post-infection. In contrast, the antiviral cytokine IFN-β was significantly higher in calcitriol-treated mice than in the untreated infected mice at 2 days post-infection, but lower than in untreated infected mice on days 4 and 8 post-infection. The elevated levels of pro-inflammatory cytokines and the decreased levels of antiviral cytokine are consistent with the period of maximum body weight loss and the lung damage in calcitriol-treated mice.ConclusionsThese results suggest that calcitriol treatment might have a negative impact on the innate immune response elicited by H9N2 infection in mice, especially at the later stage of influenza virus infection. This study will provide some novel insights into the use of calcitriol to modulate the inflammatory response elicited by influenza virus infection in humans.

Proteome Response of Chicken Embryo Fibroblast Cells to Recombinant H5N1 Avian Influenza Viruses with Different Neuraminidase Stalk Lengths

The variation on neuraminidase (NA) stalk region of highly pathogenic avian influenza H5N1 virus results in virulence change in animals. In our previous studies, the special NA stalk-motif of H5N1 viruses has been demonstrated to play a significant role in the high virulence and pathogenicity in chickens. However, the molecular mechanisms underlying the pathogenicity of viruses with different NA stalk remain poorly understood. This study presents a comprehensive characterization of the proteome response of chicken cells to recombinant H5N1 virus with stalk-short NA (rNA-wt) and the stalkless NA mutant virus (rSD20). 208 proteins with differential abundance profiles were identified differentially expressed (DE), and these proteins were mainly related to stress response, transcription regulation, transport, metabolic process, cellular component and cytoskeleton. Through Ingenuity Pathways Analysis (IPA), the significant biological functions of DE proteins represented included Post-Translational Modification, Protein Folding, DNA Replication, Recombination and Repair. It was interesting to find that most DE proteins were involved in the TGF-β mediated functional network. Moreover, the specific DE proteins may play important roles in the innate immune responses and H5N1 virus replication. Our data provide important information regarding the comparable host response to H5N1 influenza virus infection with different NA stalk lengths.

Interleukin-1 receptor type 1 signaling induces excessive inflammatory responses in H1N1 influenza virus infection

Objective To investigate the role of interleukin-1 receptor type 1 (IL-1R1) signaling in H1N1 influenza virus infection. Methods IL-1R1 knockout (IL-1R1-/-) mice and wild type (WT) mice were infected intranasally with 2×104 TCID50 (50% tissue culture infective dose) of influenza virus H1N1 PR8. Changes in clinical signs, survivals and bodyweights of those mice were monitored daily for 14 consecutive days. Three mice from each group were sacrificed at 3, 7 and 14 days post infection (d.p.i), from which whole lungs were harvested. A part of the lobes was fixed in 4% paraformaldehyde for histopathological assessment and the rest were split and stored at -80 centigrade for further analysis. Real-time quantitative PCR and cytometric bead array (CBA) were performed to detect viral loads in lungs and inflammatory cytokines in supernatants of lung homogenates. Results The mice in both groups showed severe symptoms after the infection of PR8. The maximum bodyweight loss of IL-1R1-/- mice [(24.22±0.80) % at 8 d. p.i] was lower than that of WT mice [(28.03±1.51)% at 9 d. p.i] (P<0.05). The IL-1R1-/- mice with PR8 infection showed a higher survival rate (90%) as compared with that of the control group (40%) (P<0.05). No statistical differences in virus loads were observed between the two groups at 3, 7 and 14 d. p.i. The lung weight to body weight ratio of IL-1R1-/- mice [(1.42±0.03) %] was lower than that of WT mice [(1.79±0.08) %] at 3 d. p.i (P<0.05). Pathological changes in IL-1R1-/- mice were less severe than those in WT mice. CBA detection assay revealed that the proinflammatory cytokines in lungs of IL-1R1-/- mice were less than those in WT mice. Conclusion IL-1R1 signaling plays a pathogenic role in mice infected with 2×104 TCID50 of influenza virus PR8 by promoting inflammatory responses. Key words: IL-1R1; Influenza virus; Inflammatory responses

Cardiac complications associated with the influenza viruses A subtype H7N9 or pandemic H1N1 in critically ill patients under intensive care

Background and objectiveThe clinical presentations and disease courses of patients hospitalized with either influenza A virus subtype H7N9 (H7N9) or 2009 pandemic H1N1 influenza virus were compared in a recent report, but associated cardiac complications remain unclear. The present retrospective study investigated whether cardiac complications in critically ill patients with H7N9 infections differed from those infected with the pandemic H1N1 influenza virus strain. MethodsSuspect cases were confirmed by reverse transcription polymerase chain reaction assays with specific confirmation of the pandemic H1N1 strain at the Centers for Disease Control and Prevention. Comparisons were conducted at the individual-level data of critically ill patients hospitalized with H7N9 (n=24) or pandemic H1N1 influenza virus (n=22) infections in Suzhou, China. Changes in cardiac biochemical markers, echocardiography, and electrocardiography during hospitalization in the intensive care unit were considered signs of cardiac complications. ResultsThe following findings were more common among the H7N9 group relative to the pandemic H1N1 influenza virus group: greater tricuspid regurgitation pressure gradient, sinus tachycardia (heartbeat≥130bpm), ST segment depression, right ventricular dysfunction, and elevated cardiac biochemical markers. Pericardial effusion was more often found among pandemic H1N1 influenza virus patients than in the H7N9 group. In both groups, most of the cardiac complications were detected from day 6 to 14 after the onset of influenza symptoms. Those who developed cardiac complications were especially vulnerable during the first four days after initiation of mechanical ventilation. Cardiac complications were reversible in the vast majority of discharged H7N9 patients. ConclusionsCritically ill hospitalized H7N9 patients experienced a higher rate of cardiac complications than did patients with 2009 pandemic H1N1 influenza virus infections, with the exception of pericardial effusion. This study may help in the prevention, identification, and treatment of influenza-induced cardiac complications in both pandemic H1N1 influenza virus and H7N9 infections.