scholarly journals Kallistatin Ameliorates Influenza Virus Pathogenesis by Inhibition of Kallikrein-Related Peptidase 1-Mediated Cleavage of Viral Hemagglutinin

2015 ◽  
Vol 59 (9) ◽  
pp. 5619-5630 ◽  
Author(s):  
Chia-Hsing Leu ◽  
Mei-Lin Yang ◽  
Nai-Hui Chung ◽  
Yen-Jang Huang ◽  
Yu-Chu Su ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Serine Protease ◽  
Serine Proteases ◽  
Inflammatory Responses ◽  
Antiviral Agents ◽  
Influenza Virus Infection ◽  
Viral Production ◽  
Proteolytic Activation ◽  
Virus Challenge

ABSTRACTProteolytic cleavage of the hemagglutinin (HA) of influenza virus by host trypsin-like proteases is required for viral infectivity. Some serine proteases are capable of cleaving influenza virus HA, whereas some serine protease inhibitors (serpins) inhibit the HA cleavage in various cell types. Kallikrein-related peptidase 1 (KLK1, also known as tissue kallikrein) is a widely distributed serine protease. Kallistatin, a serpin synthesized mainly in the liver and rapidly secreted into the circulation, forms complexes with KLK1 and inhibits its activity. Here, we investigated the roles of KLK1 and kallistatin in influenza virus infection. We show that the levels of KLK1 increased, whereas those of kallistatin decreased, in the lungs of mice during influenza virus infection. KLK1 cleaved H1, H2, and H3 HA molecules and consequently enhanced viral production. In contrast, kallistatin inhibited KLK1-mediated HA cleavage and reduced viral production. Cells transduced with the kallistatin gene secreted kallistatin extracellularly, which rendered them more resistant to influenza virus infection. Furthermore, lentivirus-mediated kallistatin gene delivery protected mice against lethal influenza virus challenge by reducing the viral load, inflammation, and injury in the lung. Taking the data together, we determined that KLK1 and kallistatin contribute to the pathogenesis of influenza virus by affecting the cleavage of the HA peptide and inflammatory responses. This study provides a proof of principle for the potential therapeutic application of kallistatin or other KLK1 inhibitors for influenza. Since proteolytic activation also enhances the infectivity of some other viruses, kallistatin and other kallikrein inhibitors may be explored as antiviral agents against these viruses.

scholarly journals Diverse and Unexpected Roles of Human Monocytes/Macrophages in the Immune Response to Influenza Virus

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 379 ◽  
Author(s):  
Norbert J. Roberts
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Virus Infection ◽  
Immune Cell ◽  
Influenza Virus Infection ◽  
Human Monocytes ◽  
Human Influenza Virus ◽  
Virus Challenge ◽  
The Common ◽  
Antigen Presenting

Human monocytes/macrophages play a central role in the immune response and defense of the host from influenza virus infection. They classically act as antigen-presenting cells for lymphocytes in the context of an immune cell cluster. In that setting, however, monocytes/macrophages exhibit additional, unexpected, roles. They are required for influenza virus infection of the lymphocytes in the cluster, and they are responsible for lymphocyte apoptosis via their synthesis and expression of the viral neuraminidase. Surprisingly, human alveolar macrophages, expected to be among the first cells to encounter the virus, are not susceptible to direct infection by a human influenza virus but can be infected when the virus is complexed with an antibody. Such monocyte/macrophage responses to influenza virus challenge should be considered part of a very complex but quite effective defense, since the common outcome is recovery of the host with development of immunity to the challenging strain of virus.

scholarly journals EXPERIMENTAL TRANSMISSION OF INFLUENZA VIRUS INFECTION IN MICE

1967 ◽  
Vol 125 (3) ◽  
pp. 467-478 ◽  
Author(s):  
Jerome L. Schulman
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Virus Vaccine ◽  
Intraperitoneal Injection ◽  
Influenza Virus Infection ◽  
Transmitted Infection ◽  
Experimental Transmission ◽  
Virus Challenge

Immunization of mice by infection or intraperitoneal injection with homotypic A2, heterotypic A0, or recombinant A0A2 virus have differing effects on transmission of influenza A2 virus infection. Immunization by infection with A2 virus resulted in refractoriness to reinfection either by artificial aerosols or by exposure to infected cage-mates. Immunization by inoculation with inactivated A2 virus vaccine resulted in a decreased susceptibility to transmitted infection in immunized contacts, but following A2 virus challenge, transmission of infection by immunized infectors was not altered. Immunization by infection with influenza A0 virus or recombinant A0A2 virus resulted in a decreased susceptibility to transmitted A2 virus infection in immunized contacts, and to decreased transmission after A2 virus infection in immunized infector mice. These differing effects on transmission of infection are attributed to differences in specific local immunologic responses following the various immunization procedures.

scholarly journals A unique nanoparticulate TLR9 agonist enables a HA split vaccine to confer FcγR-mediated protection against heterologous lethal influenza virus infection

2018 ◽  
Vol 31 (2) ◽  
pp. 81-90 ◽  
Author(s):  
Takuya Yamamoto ◽  
Yuji Masuta ◽  
Masatoshi Momota ◽  
Masaru Kanekiyo ◽  
Tomohiro Kanuma ◽  
...  
Keyword(s):  
Influenza Virus ◽  
T Cell ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
Cd8 T Cell ◽  
Influenza Vaccines ◽  
Global Public Health ◽  
Virus Challenge ◽  
Tlr9 Agonist ◽  
Heterologous Virus

Abstract The development of a universal influenza vaccine that can provide a robust and long-lasting protection against a broader range of influenza virus strains is a global public health priority. One approach to improve vaccine efficacy is to use an adjuvant to boost immune responses to the target antigens; nevertheless, the role of adjuvants in the context of influenza vaccines is not fully understood. We have previously developed the K3-schizophyllan (SPG) adjuvant, which is composed of nanoparticulated oligodeoxynucleotides K3, a TLR9 agonist, with SPG, a non-agonistic β-glucan ligand of Dectin-1. In this study, K3-SPG given with conventional influenza hemagglutinin (HA) split vaccine (K3-SPG HA) conferred protection against antigenically mismatched heterologous virus challenge. While K3-SPG HA elicited robust cross-reactive HA-specific IgG2c and CD8 T-cell responses, CD8 T-cell depletion had no impact on this cross-protection. In contrast, K3-SPG HA was not able to confer protection against heterologous virus challenge in FcRγ-deficient mice. Our results indicated that FcγR-mediated antibody responses induced by the HA antigen and K3-SPG adjuvant were important for potent protection against antigenically mismatched influenza virus infection. Thus, we demonstrated that the K3-SPG-adjuvanted vaccine strategy broadens protective immunity against influenza and provides a basis for the development of next-generation influenza vaccines.

scholarly journals Nanodisc-Incorporated Hemagglutinin Provides Protective Immunity against Influenza Virus Infection

2009 ◽  
Vol 84 (1) ◽  
pp. 361-371 ◽  
Author(s):  
Palash Bhattacharya ◽  
Steve Grimme ◽  
Balaji Ganesh ◽  
Anupama Gopisetty ◽  
Jian Rong Sheng ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Virus Strain ◽  
New Caledonia ◽  
Influenza Virus Infection ◽  
Soluble Form ◽  
Correct Prediction ◽  
Human Populations ◽  
Virus Challenge ◽  
Influenza Virus Strain

ABSTRACT Every year, influenza virus infection causes significant mortality and morbidity in human populations. Although egg-based inactivated viral vaccines are available, their effectiveness depends on the correct prediction of the circulating viral strains and is limited by the time constraint of the manufacturing process. Recombinant subunit vaccines are easier to manufacture with a relatively short lead time but are limited in their efficacy partly because the purified recombinant membrane proteins in the soluble form most likely do not retain their native membrane-bound structure. Nanodisc (ND) particles are soluble, stable, and reproducibly prepared discoid shaped nanoscale structures that contain a discrete lipid bilayer bound by two amphipathic scaffold proteins. Because ND particles permit the functional reconstitution of membrane/envelope proteins, we incorporated recombinant hemagglutinin (HA) from influenza virus strain A/New Caledonia/20/99 (H1N1) into NDs and investigated their potential to elicit an immune response to HA and confer immunity to influenza virus challenge relative to the commercial vaccines Fluzone and FluMist. HA-ND vaccination induced a robust anti-HA antibody response consisting of predominantly the immunoglobulin G1 (IgG1) subclass and a high hemagglutination inhibition titer. Intranasal immunization with HA-ND induced an anti-HA IgA response in nasal passages. HA-ND vaccination conferred protection that was comparable to that of Fluzone and FluMist against challenge with influenza virus strain A/Puerto Rico/8/1934 (H1N1).

scholarly journals Mapping the innate signaling cascade essential for cytokine storm during influenza virus infection

2014 ◽  
Vol 111 (10) ◽  
pp. 3799-3804 ◽  
Author(s):  
John R. Teijaro ◽  
Kevin B. Walsh ◽  
Stephanie Rice ◽  
Hugh Rosen ◽  
Michael B. A. Oldstone
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Immune Cell ◽  
Influenza Virus Infection ◽  
Primary Response ◽  
Cytokine Storm ◽  
Tissue Destruction ◽  
Chemokine Production ◽  
Virus Challenge ◽  
Pathway Inhibition

During pathogenic influenza virus infection, robust cytokine production (cytokine storm), excessive inflammatory infiltrates, and virus-induced tissue destruction all contribute to morbidity and mortality. Earlier we reported that modulation of sphingosine-1-phosphate-1 receptor (S1P1R) signaling provided a chemically tractable approach for the effective blunting of cytokine storm, leading to the improvement of clinical and survival outcomes. Here, we show that S1P1R agonist treatment suppresses global cytokine amplification. Importantly, S1P1R agonist treatment was able to blunt cytokine/chemokine production and innate immune cell recruitment in the lung independently of endosomal and cytosolic innate sensing pathways. S1P1R signaling suppression of cytokine amplification was independent of multiple innate signaling adaptor pathways for myeloid differentiation primary response gene 88 (MyD88) and IFN-β promoter stimulator-1 signaling, indicating a common pathway inhibition of cytokine storm. We identify the MyD88 adaptor molecule as responsible for the majority of cytokine amplification observed following influenza virus challenge.

scholarly journals A novel family of peptides with potent activity against influenza A viruses

2012 ◽  
Vol 93 (5) ◽  
pp. 980-986 ◽  
Author(s):  
Marlynne Q. Nicol ◽  
Yvonne Ligertwood ◽  
Matthew N. Bacon ◽  
Bernadette M. Dutia ◽  
Anthony A. Nash
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Influenza A ◽  
Antiviral Agents ◽  
Influenza Virus Infection ◽  
Influenza A Viruses ◽  
Potent Inhibition ◽  
Human Immunodeficiency Virus Entry ◽  
Drug Resistant Strains

The emergence of drug-resistant strains of influenza virus has catalysed a search for new antiviral agents to supplement or replace existing drugs. Following the success of the human immunodeficiency virus entry blocker Enfuvirtide, there has been a resurgence of interest in peptide-based antivirals. In this paper, we report on the discovery of a novel family of peptides (FluPep, FP) that function as inhibitors of influenza A virus infection. The prototype peptide (FP1, also known as Tkip) interacts with haemagglutinin and inhibits the binding of the virus to cell membranes. Using a plaque-reduction assay, we have demonstrated that a variety of influenza A virus subtypes (including H1N1, H3N2 and H5N1) are inhibited by FluPep and its derivatives at nanomolar concentrations. By truncating FluPep we have identified a minimal sequence of 6 aa that binds to haemagglutinin and inhibits infection. Using a mouse model of intranasal influenza virus infection, we observed potent inhibition of virus infection when peptide is given at the time of virus administration. These data indicate that FluPep is a highly effective anti-influenza agent with the potential to translate to the clinic.

scholarly journals Complexes of Oligoribonucleotides with d-Mannitol Modulate the Innate Immune Response to Influenza A Virus H1N1 (A/FM/1/47) In Vivo

2018 ◽  
Vol 11 (3) ◽  
pp. 73 ◽  
Author(s):  
Nataliia Melnichuk ◽  
Vladimir Kashuba ◽  
Svitlana Rybalko ◽  
Zenoviy Tkachuk
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Virus Infection ◽  
Signaling Pathways ◽  
Influenza A Virus ◽  
Innate Immune Response ◽  
Influenza A ◽  
Inflammatory Responses ◽  
Influenza Virus Infection ◽  
Innate Immune

Rapid replication of the influenza A virus and lung tissue damage caused by exaggerated pro-inflammatory host immune responses lead to numerous deaths. Therefore, novel therapeutic agents that have anti-influenza activities and attenuate excessive pro-inflammatory responses that are induced by an influenza virus infection are needed. Oligoribonucleotides-d-mannitol (ORNs-d-M) complexes possess both antiviral and anti-inflammatory activities. The current research was aimed at studying the ORNs-d-M effects on expression of innate immune genes in mice lungs during an influenza virus infection. Expression of genes was determined by RT-qPCR and Western blot assays. In the present studies, we found that the ORNs-d-M reduced the influenza-induced up-expression of Toll-like receptors (TLRs) (tlr3, tlr7, tlr8), nuclear factor NF-kB (nfkbia, nfnb1), cytokines (ifnε, ifnk, ifna2, ifnb1, ifnγ, il6, il1b, il12a, tnf), chemokines (ccl3, ccl4, сcl5, cxcl9, cxcl10, cxcl11), interferon-stimulated genes (ISGs) (oas1a, oas2, oas3, mx1), and pro-oxidation (nos2, xdh) genes. The ORNs-d-M inhibited the mRNA overexpression of tlr3, tlr7, and tlr8 induced by the influenza virus, which suggests that they impair the upregulation of NF-kB, cytokines, chemokines, ISGs, and pro-oxidation genes induced by the influenza virus by inhibiting activation of the TLR-3, TLR-7, and TLR-8 signaling pathways. By impairing activation of the TLR-3, TLR-7, and TLR-8 signaling pathways, the ORNs-d-M can modulate the innate immune response to an influenza virus infection.

scholarly journals Influenza Virus Infection of Human Lymphocytes Occurs in the Immune Cell Cluster of the Developing Antiviral Response

Viruses ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 420 ◽  
Author(s):  
David Mock ◽  
Mark Frampton ◽  
Joan Nichols ◽  
Frank Domurat ◽  
Denise Signs ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Immune Cell ◽  
Human Lymphocytes ◽  
Influenza Virus Infection ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Virus Challenge ◽  
Cd8 T Lymphocytes ◽  
Cell Clustering

Monocytes-macrophages and lymphocytes are recruited to the respiratory tract in response to influenza virus challenge and are exposed to the virus during the establishment of immune defenses. The susceptibility of human lymphocytes to infection was assessed. The presence of monocytes-macrophages was required to attain infection of both resting and proliferating lymphocytes. Lymphocyte infection occurred in the context of immune cell clusters and was blocked by the addition of anti-intercellular adhesion molecule-1 (ICAM-1) antibody to prevent cell clustering. Both peripheral blood-derived and bronchoalveolar lymphocytes were susceptible to infection. Both CD4+ and CD8+ T lymphocytes were susceptible to influenza virus infection, and the infected CD4+ and CD8+ lymphocytes served as infectious foci for other nonpermissive or even virus-permissive cells. These data show that monocytes-macrophages and both CD4+ and CD8+ lymphocytes can become infected during the course of an immune response to influenza virus challenge. The described leukocyte interactions during infection may play an important role in the development of effective anti-influenza responses.

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