scholarly journals Protective Cellular Immunity Against Influenza Virus Induced by Plasmid Inoculation of Newborn Mice

1998 ◽  
Vol 5 (3) ◽  
pp. 197-210 ◽  
Author(s):  
Adrian Bot ◽  
Simona Bot ◽  
Adolfo García-Sastre ◽  
Constantin Bona
Keyword(s):  
Influenza Virus ◽  
Cellular Immunity ◽  
Early Period ◽  
Tolerance Induction ◽  
Vaccination Strategy ◽  
Influenza Viruses ◽  
Lethal Challenge ◽  
Newborn Mice ◽  
Adult Mice ◽  
Multiple Strains

Neonate organisms display an intrinsic disability to mount effective immune responses to infectious agents or conventional vaccines. Whereas low. doses of antigens trigger a suboptimal response, higher doses are frequently associated with tolerance induction. We investigated the ability of a plasmid-expressing nucleoprotein of influenza virus to prime a specific cellular immune response when administered to newborn mice. We found that persistent exposure to antigen following plasmid inoculation of neonates leads to a vigorous priming of specific CTLs rather than tolerance induction. The CTLs were cross-reactive against multiple strains of type A influenza viruses and produced IFNγbut no IL-4. The immunity triggered by plasmid inoculation of neonates was protective in terms of pulmonary virus clearance as well as survival rate following lethal challenge with influenza virus. Whereas the persistence of the plasmid at the site of injection was readily demonstrable in adult mice at 3 months after inoculation, mice immunized as newborns displayed no plasmid at 3 months and very little at 1 month after injection. Thus, DNA-based immunization of neonates may prove an effective and safe vaccination strategy for induction of cellular immunity against microbes that cause serious infectious diseases in the early period of life.

scholarly journals Virus-specific interferon action. Protection of newborn Mx carriers against lethal infection with influenza virus.

1981 ◽  
Vol 154 (1) ◽  
pp. 199-203 ◽  
Author(s):  
O Haller ◽  
H Arnheiter ◽  
I Gresser ◽  
J Lindenmann
Keyword(s):  
Influenza Virus ◽  
Influenza Virus Infection ◽  
Specific Effect ◽  
Influenza Viruses ◽  
Encephalomyocarditis Virus ◽  
Lethal Challenge ◽  
Newborn Mice ◽  
Adult Mice ◽  
High Degree

The efficacy of interferon in antiviral protection of newborn mice differing at the Mx locus was investigated. Adult mice bearing the allele Mx exhibit a high degree of specific resistance toward lethal challenge with influenza viruses. In contrast, newborn Mx carriers are virtually as susceptible to influenza viruses as newborn mice devoid of Mx. Resistance can be abrogated by treating adult animals with anti-interferon serum. Here, we provide direct evidence of a virus-specific effect of interferon in vivo: newborn mice carrying the resistance gene Mx could be protected against lethal influenza virus infection with doses of interferon that were not protective in the absence of Mx. The efficacy of interferon towards a picornavirus (encephalomyocarditis virus) and a rhabdovirus (vesicular stomatitis virus) was independent of Mx.

scholarly journals Cross-Reactive, Cell-Mediated Immunity and Protection of Chickens from Lethal H5N1 Influenza Virus Infection in Hong Kong Poultry Markets

2001 ◽  
Vol 75 (6) ◽  
pp. 2516-2525 ◽  
Author(s):  
Sang Heui Seo ◽  
Robert G. Webster
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
Hong Kong ◽  
Virus Infection ◽  
Cellular Immunity ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
H5n1 Influenza Virus ◽  
H9n2 Influenza Virus ◽  
H5n1 Influenza

ABSTRACT In 1997, avian H5N1 influenza virus transmitted from chickens to humans resulted in 18 confirmed infections. Despite harboring lethal H5N1 influenza viruses, most chickens in the Hong Kong poultry markets showed no disease signs. At this time, H9N2 influenza viruses were cocirculating in the markets. We investigated the role of H9N2 influenza viruses in protecting chickens from lethal H5N1 influenza virus infections. Sera from chickens infected with an H9N2 influenza virus did not cross-react with an H5N1 influenza virus in neutralization or hemagglutination inhibition assays. Most chickens primed with an H9N2 influenza virus 3 to 70 days earlier survived the lethal challenge of an H5N1 influenza virus, but infected birds shed H5N1 influenza virus in their feces. Adoptive transfer of T lymphocytes or CD8+ T cells from inbred chickens (B2/B2) infected with an H9N2 influenza virus to naive inbred chickens (B2/B2) protected them from lethal H5N1 influenza virus. In vitro cytotoxicity assays showed that T lymphocytes or CD8+ T cells from chickens infected with an H9N2 influenza virus recognized target cells infected with either an H5N1 or H9N2 influenza virus in a dose-dependent manner. Our findings indicate that cross-reactive cellular immunity induced by H9N2 influenza viruses protected chickens from lethal infection with H5N1 influenza viruses in the Hong Kong markets in 1997 but permitted virus shedding in the feces. Our findings are the first to suggest that cross-reactive cellular immunity can change the outcome of avian influenza virus infection in birds in live markets and create a situation for the perpetuation of H5N1 influenza viruses.

scholarly journals Role of interferon in the pathogenesis of virus diseases in mice as demonstrated by the use of anti-interferon serum. II. Studies with herpes simplex, Moloney sarcoma, vesicular stomatitis, Newcastle disease, and influenza viruses.

1976 ◽  
Vol 144 (5) ◽  
pp. 1316-1323 ◽  
Author(s):  
I Gresser ◽  
M G Tovey ◽  
C Maury ◽  
M T Bandu
Keyword(s):  
Herpes Simplex ◽  
Influenza Virus Infection ◽  
Rapid Onset ◽  
Subsequent Treatment ◽  
Influenza Viruses ◽  
Type I ◽  
Virus Diseases ◽  
Newborn Mice ◽  
Infected Control ◽  
Adult Mice

The effect of potent sheep anti-mouse interferon globulin was investigated in several different experimental virus diseases of mice. In anti-interferon globulin-treated mice infected intraperitoneally with herpes simplex virus (HSV) type I, the latent period was shortened, and the overall LD50 was increased several hundredfold compared to virus-infected control mice. When HSV was inoculated subcutaneously all anti-interferon globulin-treated mice died, whereas only 5% of virus-infected control mice died. Subsequent treatment with anti-interferon globulin of previously HSV-infected mice did not result in reactivation of HSV. Treatment of adult mice with anti-interferon globulin resulted in an earlier appearance of MSV-induced tumors, a greater number of mice bearing tumors, an increase in tumor size, and an increase in the duration of tumors. All tumors eventually regressed despite reinjection of anti-interferon globulin. Anti-interferon globulin treatment resulted in a rapid onset of disease and death in adult mice inoculated (intranasal) with VSV and in newborn mice infected with NDV. Anti-interferon globulin exerted no effect on the course of influenza virus infection of mice. We conclude that the early production of interferon is an importane element in the response of the mouse to several viruses exhibiting different pathogeneses.

scholarly journals Broadly Reactive Human Monoclonal Antibodies Elicited following Pandemic H1N1 Influenza Virus Exposure Protect Mice against Highly Pathogenic H5N1 Challenge

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Raffael Nachbagauer ◽  
David Shore ◽  
Hua Yang ◽  
Scott K. Johnson ◽  
Jon D. Gabbard ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Monoclonal Antibodies ◽  
Influenza Viruses ◽  
Health Concern ◽  
Human Monoclonal Antibodies ◽  
Lethal Challenge ◽  
Highly Pathogenic ◽  
Zoonotic Infections ◽  
Stalk Domain ◽  
Group 1

ABSTRACT Broadly cross-reactive antibodies (Abs) that recognize conserved epitopes within the influenza virus hemagglutinin (HA) stalk domain are of particular interest for their potential use as therapeutic and prophylactic agents against multiple influenza virus subtypes, including zoonotic virus strains. Here, we characterized four human HA stalk-reactive monoclonal antibodies (MAbs) for their binding breadth and affinity, in vitro neutralization capacity, and in vivo protective potential against an highly pathogenic avian influenza virus. The monoclonal antibodies were isolated from individuals shortly following infection with (70-1F02 and 1009-3B05) or vaccination against (05-2G02 and 09-3A01) A(H1N1)pdm09. Three of the MAbs bound HAs from multiple strains of group 1 viruses, and one MAb, 05-2G02, bound to both group 1 and group 2 influenza A virus HAs. All four antibodies prophylactically protected mice against a lethal challenge with the highly pathogenic A/Vietnam/1203/04 (H5N1) strain. Two MAbs, 70-1F02 and 09-3A01, were further tested for their therapeutic efficacy against the same strain and showed good efficacy in this setting as well. One MAb, 70-1F02, cocrystallized with H5 HA and showed heavy-chain-only interactions similar to those seen with the previously described CR6261 anti-stalk antibody. Finally, we show that antibodies that compete with these MAbs are prevalent in serum from an individual recently infected with the A(H1N1)pdm09 virus. The antibodies described here can be developed into broad-spectrum antiviral therapeutics that could be used to combat infections by zoonotic or emerging pandemic influenza viruses. IMPORTANCE The rise in zoonotic infections of humans by emerging influenza viruses is a worldwide public health concern. The majority of recent zoonotic human influenza cases were caused by H7N9 and H5Nx viruses and were associated with high morbidity and mortality. In addition, seasonal influenza viruses are estimated to cause up to 650,000 deaths annually worldwide. Currently available antiviral treatment options include only neuraminidase inhibitors, but some influenza viruses are naturally resistant to these drugs, and others quickly develop resistance-conferring mutations. Alternative therapeutics are urgently needed. Broadly protective antibodies that target the conserved “stalk” domain of the hemagglutinin represent potential potent antiviral prophylactic and therapeutic agents that can assist pandemic preparedness. Here, we describe four human monoclonal antibodies that target conserved regions of influenza HA and characterize their binding spectrum as well as their protective capacity in prophylactic and therapeutic settings against a lethal challenge with a zoonotic influenza virus.

MDCK cell-cultured influenza virus vaccine protects mice from lethal challenge with different influenza viruses

2012 ◽  
Vol 94 (5) ◽  
pp. 1173-1179 ◽  
Author(s):  
Kun Liu ◽  
Zhidong Yao ◽  
Liangyan Zhang ◽  
Junli Li ◽  
Li Xing ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Mdck Cell ◽  
Influenza Virus Vaccine ◽  
Influenza Viruses ◽  
Lethal Challenge

scholarly journals Sialic Acid-Binding ProteinSp2CBMTD Protects Mice against Lethal Challenge with Emerging Influenza A (H7N9) Virus

2014 ◽  
Vol 59 (3) ◽  
pp. 1495-1504 ◽  
Author(s):  
Elena A. Govorkova ◽  
Tatiana Baranovich ◽  
Bindumadhav M. Marathe ◽  
Lei Yang ◽  
Margaret A. Taylor ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Sialic Acid ◽  
Influenza A ◽  
Adaptive Immune Response ◽  
Genetically Engineered ◽  
Influenza Viruses ◽  
H7n9 Virus ◽  
Lethal Challenge ◽  
Proinflammatory Mediators

ABSTRACTCompounds that target the cellular factors essential for influenza virus replication represent an innovative approach to antiviral therapy.Sp2CBMTD is a genetically engineered multivalent protein that masks sialic acid-containing cellular receptors on the respiratory epithelium, which are recognized by influenza viruses. Here, we evaluated the antiviral potential ofSp2CBMTD against lethal infection in mice with an emerging A/Anhui/1/2013 (H7N9) influenza virus and addressed the mechanistic basis of its activityin vivo. Sp2CBMTD was administered to mice intranasally as a single or repeated dose (0.1, 1, 10, or 100 μg) before (day −7, −3, and/or −1) or after (6 or 24 h) H7N9 virus inoculation. A singleSp2CBMTD dose (10 or 100 μg) protected 80% to 100% of the mice when administered 7 days before the H7N9 lethal challenge. RepeatedSp2CBMTD administration conferred the highest protection, resulting in 100% survival of the mice even at the lowest dose tested (0.1 μg). When treatment began 24 h after exposure to the H7N9 virus, a single administration of 100 μg ofSp2CBMTD protected 40% of the mice from death. The administration ofSp2CBMTD induced the pulmonary expression of proinflammatory mediators (interleukin-6 [IL-6], IL-1β, RANTES, monocyte chemotactic protein-1 [MCP-1], macrophage inflammatory protein-1α [MIP-1α], and inducible protein [IP-10]) and recruited neutrophils to the respiratory tract before H7N9 virus infection, which resulted in less pronounced inflammation and rapid virus clearance from mouse lungs.Sp2CBMTD administration did not affect the virus-specific adaptive immune response, which was sufficient to protect against reinfection with a higher dose of homologous H7N9 virus or heterologous H5N1 virus. Thus,Sp2CBMTD was effective in preventing H7N9 infections in a lethal mouse model and holds promise as a prophylaxis option against zoonotic influenza viruses.

scholarly journals Cross-Protection of Chicken Immunoglobulin Y Antibodies against H5N1 and H1N1 Viruses Passively Administered in Mice

2011 ◽  
Vol 18 (7) ◽  
pp. 1083-1090 ◽  
Author(s):  
Michael G. Wallach ◽  
Richard J. Webby ◽  
Fakhrul Islam ◽  
Stephen Walkden-Brown ◽  
Eva Emmoth ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza Pandemic ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Antigenic Drift ◽  
Virus Infectivity ◽  
Lethal Challenge ◽  
H5n1 Influenza

ABSTRACTInfluenza viruses remain a major threat to global health due to their ability to undergo change through antigenic drift and antigenic shift. We postulated that avian IgY antibodies represent a low-cost, effective, and well-tolerated approach that can easily be scaled up to produce enormous quantities of protective antibodies. These IgY antibodies can be administered passively in humans (orally and intranasally) and can be used quickly and safely to help in the fight against an influenza pandemic. In this study, we raised IgY antibodies against H1N1, H3N2, and H5N1 influenza viruses. We demonstrated that, using whole inactivated viruses alone and in combination to immunize hens, we were able to induce a high level of anti-influenza virus IgY in the sera and eggs, which lasted for at least 2 months after two immunizations. Furthermore, we found that by use ofin vitroassays to test for the ability of IgY to inhibit hemagglutination (HI test) and virus infectivity (serum neutralization test), IgYs inhibited the homologous as well as in some cases heterologous clades and strains of viruses. Using anin vivomouse model system, we found that, when administered intranasally 1 h prior to infection, IgY to H5N1 protected 100% of the mice against lethal challenge with H5N1. Of particular interest was the finding that IgY to H5N1 cross-protected against A/Puerto Rico/8/34 (H1N1) bothin vitroandin vivo. Based on our results, we conclude that anti-influenza virus IgY can be used to help prevent influenza virus infection.

The cap-binding site of influenza virus protein PB2 as a drug target

2016 ◽  
Vol 72 (2) ◽  
pp. 245-253 ◽  
Author(s):  
Chelsea Severin ◽  
Tales Rocha de Moura ◽  
Yong Liu ◽  
Keqin Li ◽  
Xiaofeng Zheng ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Binding Site ◽  
Structural Changes ◽  
Hydrophobic Interactions ◽  
Influenza Viruses ◽  
Virus Protein ◽  
Mrna Transcription ◽  
Viral Mrnas ◽  
Multiple Strains ◽  
Virus Strains

The RNA polymerase of influenza virus consists of three subunits: PA, PB1 and PB2. It uses a unique `cap-snatching' mechanism for the transcription of viral mRNAs. The cap-binding domain of the PB2 subunit (PB2cap) in the viral polymerase binds the cap of a host pre-mRNA molecule, while the endonuclease of the PA subunit cleaves the RNA 10–13 nucleotides downstream from the cap. The capped RNA fragment is then used as the primer for viral mRNA transcription. The structure of PB2cap from influenza virus H1N1 A/California/07/2009 and of its complex with the cap analog m7GTP were solved at high resolution. Structural changes are observed in the cap-binding site of this new pandemic influenza virus strain, especially the hydrophobic interactions between the ligand and the target protein. m7GTP binds deeper in the pocket than some other virus strains, much deeper than the host cap-binding proteins. Analysis of the new H1N1 structures and comparisons with other structures provide new insights into the design of small-molecule inhibitors that will be effective against multiple strains of both type A and type B influenza viruses.

scholarly journals Drug repositioning of Clopidogrel or Triamterene to inhibit influenza virus replication in vitro

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0259129
Author(s):  
Nichole Orr-Burks ◽  
Jackelyn Murray ◽  
Kyle V. Todd ◽  
Abhijeet Bakre ◽  
Ralph A. Tripp
Keyword(s):  
Influenza Virus ◽  
Virus Replication ◽  
Drug Repositioning ◽  
Antiviral Drug ◽  
Influenza Viruses ◽  
Influenza Virus Replication ◽  
Approved Drugs ◽  
Multiple Strains ◽  
Tract Infections

Influenza viruses cause respiratory tract infections and substantial health concerns. Infection may result in mild to severe respiratory disease associated with morbidity and some mortality. Several anti-influenza drugs are available, but these agents target viral components and are susceptible to drug resistance. There is a need for new antiviral drug strategies that include repurposing of clinically approved drugs. Drugs that target cellular machinery necessary for influenza virus replication can provide a means for inhibiting influenza virus replication. We used RNA interference screening to identify key host cell genes required for influenza replication, and then FDA-approved drugs that could be repurposed for targeting host genes. We examined the effects of Clopidogrel and Triamterene to inhibit A/WSN/33 (EC50 5.84 uM and 31.48 uM, respectively), A/CA/04/09 (EC50 6.432 uM and 3.32 uM, respectively), and B/Yamagata/16/1988 (EC50 0.28 uM and 0.11 uM, respectively) replication. Clopidogrel and Triamterene provide a druggable approach to influenza treatment across multiple strains and subtypes.

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