Impaired Hemostasis Leads To Alveolar Hemorrhages and Increased Mortality In Influenza A Infection

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1095-1095
Author(s):  
Silvio Antoniak ◽  
Kohei Tatsumi ◽  
Justin Milner ◽  
Melinda Beck ◽  
Nigel Mackman
Keyword(s):  
Influenza A ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Conflicts Of Interest ◽  
Littermate Control ◽  
Virus Challenge ◽  
Protein Levels ◽  
Increased Risk ◽  
Influenza A H1n1 ◽  
Body Weights

Abstract Objective Viral infections lead to activation of coagulation which enhances inflammatory responses. For instance, influenza A is associated with activation of coagulation and the increased risk for thrombotic events, such as myocardial infarction. Protease-activated receptor 4 (PAR-4) is the main functional receptor on mouse platelets. Here, we investigated the role of tissue factor (TF) and platelets in influenza A infection in mice. Methods We used male LowTF mice, which express 1% of normal TF levels, PAR-4 deficient mice and respective control mice. All mice were infected intranasal with influenza A H1N1/PR8. Changes in body weights and survival were analyzed up to 14 days after infection. In addition, bronchoalveolar lavage (BAL) was collected and analyzed 7 days after virus challenge. Results LowTF mice exhibited increased loss of body weights compared to littermate control mice between day 4 and 6 after infection (P<0.05). At day 7, BAL of LowTF had increased levels of free hemoglobin compared to infected control mice (2.60±0.39 g/dL vs. 0.05±0.02 g/dL, P<0.05). In addition, LowTF lungs exhibited increased protein levels in the BAL compared to controls (1.52±0.18 mg/mL vs. 0.70±0.26 mg/mL, P<0.05). Lung histology revealed that LowTF mice had extensive hemorrhages. The impaired hemostasis resulted in increased mortality in LowTF mice compared to control mice (90% vs 30%, P<0.004, N=9-10, Figure). Similarly, mice with defective thrombin signaling in platelets (PAR-4-/-) exhibited visible lung hemorrhages with increased hemoglobin levels in the BAL (P<0.05) at day 7 and increased mortality compared to controls (57% vs 10%, P<0.03, N=9-14, Figure). Conclusions TF mediated activation of coagulation and PAR-4 dependent platelet activation are essential for pulmonary hemostasis during influenza A infection. Disclosures: No relevant conflicts of interest to declare.

scholarly journals SP-A and SP-D: Dual Functioning Immune Molecules With Antiviral and Immunomodulatory Properties

2021 ◽  
Vol 11 ◽  
Author(s):  
Alastair Watson ◽  
Jens Madsen ◽  
Howard William Clark
Keyword(s):  
Viral Infection ◽  
Influenza A ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Chronic Obstructive ◽  
Cell Functions ◽  
Increased Risk ◽  
Syncytial Virus

Surfactant proteins A (SP-A) and D (SP-D) are soluble innate immune molecules which maintain lung homeostasis through their dual roles as anti-infectious and immunomodulatory agents. SP-A and SP-D bind numerous viruses including influenza A virus, respiratory syncytial virus (RSV) and human immunodeficiency virus (HIV), enhancing their clearance from mucosal points of entry and modulating the inflammatory response. They also have diverse roles in mediating innate and adaptive cell functions and in clearing apoptotic cells, allergens and other noxious particles. Here, we review how the properties of these first line defense molecules modulate inflammatory responses, as well as host-mediated immunopathology in response to viral infections. Since SP-A and SP-D are known to offer protection from viral and other infections, if their levels are decreased in some disease states as they are in severe asthma and chronic obstructive pulmonary disease (COPD), this may confer an increased risk of viral infection and exacerbations of disease. Recombinant molecules of SP-A and SP-D could be useful in both blocking respiratory viral infection while also modulating the immune system to prevent excessive inflammatory responses seen in, for example, RSV or coronavirus disease 2019 (COVID-19). Recombinant SP-A and SP-D could have therapeutic potential in neutralizing both current and future strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus as well as modulating the inflammation-mediated pathology associated with COVID-19. A recombinant fragment of human (rfh)SP-D has recently been shown to neutralize SARS-CoV-2. Further work investigating the potential therapeutic role of SP-A and SP-D in COVID-19 and other infectious and inflammatory diseases is indicated.

Mixed polysaccharides derived from shiitake mushroom, Poriacocos, Ginger and Tangerine peel prevent the H1N1 virus infections in mice

2021 ◽  
Author(s):  
Diqi Yang ◽  
Minghua Hu ◽  
Hongmei Zhu ◽  
Jianguo Chen ◽  
Dehai Wang ◽  
...  
Keyword(s):  
Influenza A ◽  
Clinical Symptoms ◽  
H1n1 Virus ◽  
Global Public Health ◽  
Virus Infections ◽  
Shiitake Mushroom ◽  
Virus Challenge ◽  
Influenza A H1n1 ◽  
Public Health Challenges ◽  
Cellular Immune

Abstract The pandemic influenza A (H1N1) virus spread globally and posed one of the most serious global public health challenges. The traditional Chinese medicine is served as a complementary treatment strategy with vaccine immunization. Here, we demonstrated the mixed polysaccharides (MPs) derived from shiitake mushroom, poriacocos, ginger and tyangerine peel prevent the H1N1 virus infections in mice. MPs pretreatment attenuated H1N1 virus-induced weight loss, clinical symptoms and death. The lymphocytes detection results showed the CD3+, CD19+ and CD25+ cell proportions were up-regulated in thymus under MPs pretreatment. Besides, MPs pretreatment reduced the inflammatory cell infiltration and increased the cell proportions of CD19+, CD25+ and CD278+ in lung. However, MPs treatment have no effective therapeutic effect after H1N1 virus challenge. The current study suggested that pretreatment with MPs could attenuate H1N1 virus-induced lung injury and up-regulate humoral and cellular immune responses in non- immunized mice.

scholarly journals Long-Lasting Mucosal and Systemic Immunity against Influenza A Virus Is Significantly Prolonged and Protective by Nasal Whole Influenza Immunization with Mucosal Adjuvant N3 and DNA-Plasmid Expressing Flagellin in Aging In- and Outbred Mice

Vaccines ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 64 ◽  
Author(s):  
Jorma Hinkula ◽  
Sanna Nyström ◽  
Claudia Devito ◽  
Andreas Bråve ◽  
Steven E. Applequist
Keyword(s):  
Immune Responses ◽  
Influenza A Virus ◽  
Influenza A ◽  
Influenza Infection ◽  
Inbred Mouse ◽  
Herd Immunity ◽  
Serum Antibody ◽  
Mouse Strains ◽  
Virus Challenge ◽  
Influenza A H1n1

Background: Vaccination is commonly used to prevent and control influenza infection in humans. However, improvements in the ease of delivery and strength of immunogenicity could markedly improve herd immunity. The aim of this pre-clinical study is to test the potential improvements to existing intranasal delivery of formalin-inactivated whole Influenza A vaccines (WIV) by formulation with a cationic lipid-based adjuvant (N3). Additionally, we combined WIV and N3 with a DNA-encoded TLR5 agonist secreted flagellin (pFliC(-gly)) as an adjuvant, as this adjuvant has previously been shown to improve the effectiveness of plasmid-encoded DNA antigens. Methods: Outbred and inbred mouse strains were intranasally immunized with unadjuvanted WIV A/H1N1/SI 2006 or WIV that was formulated with N3 alone. Additional groups were immunized with WIV and N3 adjuvant combined with pFliC(-gly). Homo and heterotypic humoral anti-WIV immune responses were assayed from serum and lung by ELISA and hemagglutination inhibition assay. Homo and heterotypic cellular immune responses to WIV and Influenza A NP were also determined. Results: WIV combined with N3 lipid adjuvant the pFliC(-gly) significantly increased homotypic influenza specific serum antibody responses (>200-fold), increased the IgG2 responses, indicating a mixed Th1/Th2-type immunity, and increased the HAI-titer (>100-fold). Enhanced cell-mediated IFNγ secreting influenza directed CD4+ and CD8+ T cell responses (>40-fold) to homotypic and heterosubtypic influenza A virus and peptides. Long-term and protective immunity was obtained. Conclusions: These results indicate that inactivated influenza virus that was formulated with N3 cationic adjuvant significantly enhanced broad systemic and mucosal influenza specific immune responses. These responses were broadened and further increased by incorporating DNA plasmids encoding FliC from S. typhimurum as an adjuvant providing long lasting protection against heterologous Influenza A/H1N1/CA09pdm virus challenge.

Pandemic 2009 Influenza A (H1N1) Virus among Japanese Healthcare Workers: Seroprevalence and Risk Factors

2012 ◽  
Vol 33 (1) ◽  
pp. 58-62 ◽  
Author(s):  
Yoko Nukui ◽  
Shuji Hatakeyama ◽  
Takatoshi Kitazawa ◽  
Tamami Mahira ◽  
Yoshizumi Shintani ◽  
...  
Keyword(s):  
Risk Factors ◽  
Healthcare Workers ◽  
Influenza A ◽  
H1n1 Virus ◽  
Healthcare Personnel ◽  
Care Hospital ◽  
Occupational Risk Factors ◽  
Increased Risk ◽  
Influenza A H1n1 ◽  
2009 H1n1

Objective.To evaluate the seroprevalence and risk factors for 2009 influenza A (H1N1) virus infection among healthcare personnel.Design.Observational cross-sectional study.Patients and Setting.Healthcare workers (HCWs) in an acute care hospital.Methods.Between September 14 and October 4, 2009, before 2009 H1N1 vaccination, we collected serological samples from 461 healthy HCWs. Hemagglutination-inhibition antibody assays were conducted. To evaluate the risk factors of seropositivity for 2009 H1N1 virus, gender, age, profession, work department, usage of personal protective equipment, and seasonal influenza vaccination status data were gathered via questionnaires.Results.Our survey showed that doctors and nurses were at highest risk of seropositivity for the 2009 H1N1 virus (odds ratio [OR], 5.25 [95% confidence interval {CI}, 1.21–22.7]). An increased risk of seropositivity was observed among pediatric, emergency room, and internal medicine staff (adjusted OR, 1.98 [95% CI, 1.07–3.65]). Risk was also higher among HCWs who had high titers of antibodies against the seasonal H1N1 virus (adjusted OR, 1.59 [95% CI, 1.02–2.48]).Conclusions.Seropositivity for the 2009 H1N1 virus was associated with occupational risk factors among HCWs.Infect Control Hosp Epidemiol 2012;33(1):58-62

A Mouse Model for XLP-2 Disease Uncovers a Critical Function for IL-1beta and TNF in Driving Hyper-Inflammation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1403-1403
Author(s):  
Philipp J. Jost ◽  
Monica Yabal ◽  
Heiko Adler ◽  
Nathalie Knies ◽  
Christina Groß ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Lymphocytes ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Conflicts Of Interest ◽  
Human Peripheral Blood ◽  
Critical Function ◽  
Deficient Mice

Abstract The hyper-inflammatory syndrome X-linked lymphoproliferative syndrome type 2 (XLP-2) is defined by mutations in BIRC4 (XIAP). XLP-2 is often diagnosed in paediatric patients and is characterized by hyper-inflammation triggered by common viral infections. Symptoms include splenomegaly, HLH, fevers, and chronic haemorrhagic colitis among others. Recent work has also shown that mutations in BIRC4 predispose to the development of early-onset IBD, which is not necessarily associated with symptoms of systemic hyper-inflammation. Symptoms of XLP-2 are mostly attributed to the aberrant activation of macrophages and dendritic cells (DC) and the subsequent accumulation of activated T-lymphocytes. We have characterized the inflammatory response of mice deficient for BIRC4 (XIAP) to viral infections with the murine herpes virus 68 (MHV-68) as the closest murine model for human EBV-driven mononucleosis. Xiap-/- mice were capable of clearing the virus normally during early infection (day 6, 16), but failed to do so during the course of the infection measured as elevated viral genomic loads during late (day 43) and very late (day 84) latency. Xiap-/- mice responded to intranasal application of the virus with systemic hyper-inflammation exemplified by elevated IL-1beta levels, splenomegaly and increased activation of peripheral T lymphocytes such as CD4+ effector T cells, regulatory T cells (Treg), and IFNg+ T cells. In previous work, we have shown that TNF is critically required to drive the hyper-inflammatory phenotype of macrophages and dendritic cells of XIAP-deficient mice. Indeed, genetic deletion of TNF in vivo or, alternatively, anti-TNF treatment in vivo using Eternacept (Enbrel) ameliorated the symptoms of XIAP-deficient mice in response to viral infection. Elevated IL-1beta levels were also observed in human peripheral blood-derived monocytes from XLP-2 patients (7 patients from 5 different families) when compared to healthy controls. In conclusion, this data supports the notion that anti-TNF treatment might be able to ameliorate the hyper-inflammatory responses in XLP-2 patients, when used early during an infection. Disclosures No relevant conflicts of interest to declare.

scholarly journals Heterosubtypic Protection Conferred by the Human Monoclonal Antibody PN-SIA28 against Influenza A Virus Lethal Infections in Mice

2015 ◽  
Vol 59 (5) ◽  
pp. 2647-2653 ◽  
Author(s):  
Miguel Retamal ◽  
Yacine Abed ◽  
Chantal Rhéaume ◽  
Francesca Cappelletti ◽  
Nicola Clementi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Body Weight ◽  
Influenza Virus ◽  
Influenza A ◽  
Human Monoclonal Antibody ◽  
Influenza A Viruses ◽  
Virus Challenge ◽  
Influenza A H1n1

ABSTRACTPN-SIA28 is a human monoclonal antibody (Hu-MAb) targeting highly conserved epitopes within the stem portion of the influenza virus hemagglutinin (HA) (N. Clementi, et al, PLoS One 6:e28001, 2011,http://dx.doi.org/10.1371/journal.pone.0028001). Previousin vitrostudies demonstrated PN-SIA28 neutralizing activities against phylogenetically divergent influenza A subtypes. In this study, the protective activity of PN-SIA28 was evaluated in mice inoculated with lethal influenza A/WSN/33 (H1N1), A/Quebec/144147/09 (H1N1)pdm09, and A/Victoria/3/75 (H3N2) viruses. At 24 h postinoculation (p.i.), animals received PN-SIA28 intraperitoneally (1 or 10 mg/kg of body weight) or 10 mg/kg of unrelated Hu-MAb (mock). Body weight loss and mortality rate (MR) were recorded for 14 days postinfection (p.i.). Lung viral titers (LVT) were determined at day 5 p.i. In A/WSN/33 (H1N1)-infected groups, all untreated and mock-receiving mice died, whereas MRs of 87.5% and 25% were observed in mice that received PN-SIA28 1 and 10 mg/kg, respectively. In influenza A(H1N1) pdm09-infected groups, an MR of 75% was recorded for untreated and mock-treated groups, whereas the PN-SIA28 1-mg/kg and 10-mg/kg groups had rates of 62.5% and 0%, respectively. In A/Victoria/3/75 (H3N2)-infected animals, untreated and mock-treated animals had MRs of 37.5% and 25%, respectively, and no mortalities were recorded after PN-SIA28 treatments. Accordingly, PN-SIA28 treatments significantly reduced weight losses and resulted in a ≥1-log reduction in LVT compared to the control in all infection groups. This study confirms that antibodies targeting highly conserved epitopes in the influenza HA stem region, like PN-SIA28, not only neutralize influenza A viruses of clinically relevant subtypesin vitrobut also, more importantly, protect from a lethal influenza virus challengein vivo.

Activation of the aryl hydrocarbon receptor increases pulmonary neutrophilia and diminishes host resistance to influenza A virus

2005 ◽  
Vol 289 (1) ◽  
pp. L111-L124 ◽  
Author(s):  
Sabine Teske ◽  
Andrea A. Bohn ◽  
Jean F. Regal ◽  
Joshua J. Neumiller ◽  
B. Paige Lawrence
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Influenza A Virus ◽  
Influenza A ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Neutrophil Function ◽  
Aryl Hydrocarbon ◽  
Potent Agonist

Unlike their role in bacterial infection, less is known about the role of neutrophils during pulmonary viral infection. Exposure to pollutant 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD, dioxin) results in excess neutrophils in the lungs of mice infected with influenza A virus. TCDD is the most potent agonist for the aryl hydrocarbon receptor (AhR), and exposure to AhR ligands has been correlated with exacerbated inflammatory lung diseases. However, knowledge of the effects of AhR agonists on neutrophils is limited. Likewise, the factors regulating neutrophil responses during respiratory viral infections are not well characterized. To address these knowledge gaps, we determined the in vivo levels of KC, MIP-1α, MIP-2, LIX, IL-6, and C5a in infected mouse lungs. Our data show that these neutrophil chemoattractants are generally produced transiently in the lung within 12–24 h of infection. We also report that expression of CD11a, CD11b, CD49d, CD31, and CD38 is increased on pulmonary neutrophils in response to influenza virus. Using AhR-deficient mice, we demonstrate that excess neutrophilia in the lung is mediated by activation of the AhR and that this enhanced neutrophilia correlates directly with decreased survival in TCDD-exposed mice. Although AhR activation results in more neutrophils in the lungs, we show that this is not mediated by deregulation in levels of common neutrophil chemoattractants, expression of adhesion molecules on pulmonary neutrophils, or delayed death of neutrophils. Likewise, exposure to TCDD did not enhance pulmonary neutrophil function. This study provides an important first step in elucidating the mechanisms by which AhR agonists exacerbate pulmonary inflammatory responses.

scholarly journals Concomitant Infections of Influenza A H1N1 and Disseminated Cryptococcosis in an HIV Seropositive Patient

2015 ◽  
Vol 7 (02) ◽  
pp. 134-136 ◽  
Author(s):  
Ankit Gupta ◽  
Malini R Capoor ◽  
Sonal Gupta ◽  
Harish Chand Sachdeva
Keyword(s):  
Pandemic Influenza ◽  
Influenza A ◽  
Unusual Case ◽  
Viral Infections ◽  
Dual Infection ◽  
Seropositive Patient ◽  
Seropositive Individual ◽  
Influenza A H1n1 ◽  
Respiratory Viral Infections ◽  
Hiv Seropositive

ABSTRACTRespiratory viral infections, especially influenza have a potential to form a fatal association with cryptococcosis in the setting of compromised immunity. Considering the lethality of these two infections, we report an unusual case of dual infection of pandemic influenza A H1N1 and disseminated cryptococcosis in an HIV seropositive individual.

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