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

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.

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

Clinical and Vaccine Immunology ◽

10.1128/cvi.05075-11 ◽

2011 ◽

Vol 18 (7) ◽

pp. 1083-1090 ◽

Cited By ~ 19

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.

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

Developmental Immunology ◽

10.1155/1998/50472 ◽

1998 ◽

Vol 5 (3) ◽

pp. 197-210 ◽

Cited By ~ 17

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.

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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.

Journal of Experimental Medicine ◽

10.1084/jem.144.5.1316 ◽

1976 ◽

Vol 144 (5) ◽

pp. 1316-1323 ◽

Cited By ~ 151

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.

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Perforin and Fas Cytolytic Pathways Coordinately Shape the Selection and Diversity of CD8+-T-Cell Escape Variants of Influenza Virus

Journal of Virology ◽

10.1128/jvi.79.13.8545-8559.2005 ◽

2005 ◽

Vol 79 (13) ◽

pp. 8545-8559 ◽

Cited By ~ 18

Author(s):

Graeme E. Price ◽

Lei Huang ◽

Rong Ou ◽

Menghua Zhang ◽

Demetrius Moskophidis

Keyword(s):

Influenza Virus ◽

T Cell ◽

Vaccine Development ◽

Influenza Virus Infection ◽

Influenza Viruses ◽

Viral Escape ◽

Viral Control ◽

Ctl Escape ◽

Selection Of

ABSTRACT Antigenic variation is a viral strategy exploited to promote survival in the face of the host immune response and represents a major challenge for efficient vaccine development. Influenza viruses are pathogens with high transmissibility and mutation rates, enabling viral escape from immunity induced by prior infection or vaccination. Intense selection from neutralizing antibody drives antigenic changes in the surface glycoproteins, resulting in emergence of new strains able to reinfect hosts immune to previously circulating viruses. CD8+ cytotoxic T cells (CTLs) also provide protective immunity from influenza virus infection and may contribute to the antigenic evolution of influenza viruses. Utilizing mice transgenic for an influenza virus NP366-374 peptide-specific T-cell receptor, we demonstrated that the respiratory tract is a suitable site for generation of escape variants of influenza virus selected by CTL in vivo. In this report the contributions of the perforin and Fas pathways utilized by influenza virus-specific CTLs in viral clearance and selection of CTL escape variants have been evaluated. While transgenic CTLs deficient in either perforin- or Fas-mediated pathways are efficient in initial pulmonary viral control, variant virus emergence was observed in all the mice studied, although the spectrum of viral CTL escape variants selected varied profoundly. Thus, a less-restricted repertoire of escape variants was observed in mice with an intact perforin cytotoxic pathway compared with a limited variant diversity in perforin pathway-deficient mice, although maximal variant diversity was observed in mice having both Fas and perforin pathways intact. We conclude that selection of viral CTL escape variants reflects coordinate action between the tightly controlled perforin/granzyme pathway and the more promiscuous Fas/FasL pathway.

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Ethanol Extract of Caesalpinia decapetala Inhibits Influenza Virus Infection In Vitro and In Vivo

Viruses ◽

10.3390/v12050557 ◽

2020 ◽

Vol 12 (5) ◽

pp. 557 ◽

Cited By ~ 1

Author(s):

Li Zhang ◽

Jungang Chen ◽

Chang Ke ◽

Haiwei Zhang ◽

Shoujun Zhang ◽

...

Keyword(s):

Influenza Virus ◽

Influenza A ◽

Antiviral Agents ◽

Influenza Virus Infection ◽

Virus Titer ◽

Ethanol Extract ◽

Influenza Viruses ◽

Virus Infections

Influenza virus infections can lead to viral pneumonia and acute respiratory distress syndrome in severe cases, causing significant morbidity and mortality and posing a great threat to human health. Because of the diversity of influenza virus strains and drug resistance to the current direct antiviral agents, there have been no effective drugs as yet to cure all patients infected by influenza viruses. Natural products from plants contain compounds with diverse structures that have the potential to interact with multiple host and virus factors. In this study, we identified the ethanol extract of Caesalpinia decapetala (Roth) Alston (EEC) as an inhibitor against the replication of a panel of influenza A and B viruses both on human pulmonary epithelial A549 and human monocytic U937 cells. The animal study revealed that EEC administration reduces the weight loss and improves the survival rate of mice infected with lethal influenza virus. Also, EEC treatment attenuated lung injury and reduced virus titer significantly. In conclusion, we showed that EEC has antiviral activity both in vitro and in vivo, suggesting that the plant C. decapetala has the potential to be further developed as a resource of new anti-influenza drugs.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04431-14 ◽

2014 ◽

Vol 59 (3) ◽

pp. 1495-1504 ◽

Cited By ~ 6

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.

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Oseltamivir-Ribavirin Combination Therapy for Highly Pathogenic H5N1 Influenza Virus Infection in Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01579-07 ◽

2008 ◽

Vol 52 (11) ◽

pp. 3889-3897 ◽

Cited By ~ 90

Author(s):

Natalia A. Ilyushina ◽

Alan Hay ◽

Neziha Yilmaz ◽

Adrianus C. M. Boon ◽

Robert G. Webster ◽

...

Keyword(s):

Influenza Virus ◽

Influenza Virus Infection ◽

Antiviral Effect ◽

Influenza Viruses ◽

Oseltamivir Carboxylate ◽

Highly Pathogenic ◽

H5n1 Influenza ◽

Pathogenic H5n1

ABSTRACT We studied the effects of a neuraminidase inhibitor (oseltamivir) and an inhibitor of influenza virus polymerases (ribavirin) against two highly pathogenic H5N1 influenza viruses. In vitro, A/Vietnam/1203/04 virus (clade 1) was highly susceptible to oseltamivir carboxylate (50% inhibitory concentration [IC50] = 0.3 nM), whereas A/Turkey/15/06 virus (clade 2.2) had reduced susceptibility (IC50 = 5.5 nM). In vivo, BALB/c mice were treated with oseltamivir (1, 10, 50, or 100 mg/kg of body weight/day), ribavirin (37.5, 55, or 75 mg/kg/day), or the combination of both drugs for 8 days, starting 4 h before virus inoculation. Monotherapy produced a dose-dependent antiviral effect against the two H5N1 viruses in vivo. Three-dimensional analysis of the drug-drug interactions revealed that oseltamivir and ribavirin interacted principally in an additive manner, with several exceptions of marginal synergy or marginal antagonism at some concentrations. The combination of ribavirin at 37.5 mg/kg/day and oseltamivir at 1 mg/kg/day and the combination of ribavirin at 37.5 mg/kg/day and oseltamivir at 10 mg/kg/day were synergistic against A/Vietnam/1203/04 and A/Turkey/15/06 viruses, respectively. These optimal oseltamivir-ribavirin combinations significantly inhibited virus replication in mouse organs, prevented the spread of H5N1 viruses beyond the respiratory tract, and abrogated the cytokine response (P < 0.01). Importantly, we observed clear differences between the efficacies of the drug combinations against two H5N1 viruses: higher doses were required for the protection of mice against A/Turkey/15/06 virus than for the protection of mice against A/Vietnam/1203/04 virus. Our preliminary results suggest that oseltamivir-ribavirin combinations can have a greater or lesser antiviral effect than monotherapy, depending on the H5N1 virus and the concentrations used.

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TRM Integrins CD103 and CD49a Differentially Support Adherence and Motility After Resolution of Influenza Virus Infection

10.1101/2020.02.14.947986 ◽

2020 ◽

Author(s):

Emma C Reilly ◽

Kris Lambert Emo ◽

Patrick M Buckley ◽

Nicholas S Reilly ◽

Francisco A Chaves ◽

...

Keyword(s):

T Cells ◽

Influenza Virus ◽

T Cell ◽

Virus Infection ◽

Cell Surface ◽

Cell Motility ◽

Influenza Virus Infection ◽

Influenza Viruses ◽

Peripheral Tissues

AbstractTissue resident memory CD8 T (TRM) cells are a unique immune memory subset that develops and remains in peripheral tissues at the site of infection, providing future host resistance upon re-exposure to that pathogen. In the pulmonary system, TRM are identified through S1P antagonist CD69 and expression of integrins CD103/β7 and CD49a/CD29(β1). Contrary to the established role of CD69 on CD8 T cells, the functions of CD103 and CD49a on this population are not well defined. This study examines the expression patterns and functions of CD103 and CD49a with a specific focus on their impact on T cell motility during influenza virus infection. We show that the TRM cell surface phenotype develops by two-weeks post-infection and that each integrin contributes a distinct function regulating CD8 T cell motility both in vitro and in vivo, with CD49a facilitating migration and CD103 limiting motility through tethering. These results demonstrate for the first time how CD103 and CD49a differentially impact adherence and migration in the tissue, likely affecting overall retention, maintenance of TRM, and host protection.Significance StatementCurrent influenza vaccination strategies require annual immunizations, with fairly low efficacy rates. One technique to improve protection against a greater breadth of influenza viruses is to elicit broadly cross-reactive cell-mediated immunity and generate a local population of cytotoxic T cells to respond to conserved regions of circulating viruses. However, this approach requires improved understanding of how these cells migrate within and attach to the tissue, in order to persist and offer long-term immunity. This study investigates how receptors on the T cell surface impact the cell’s ability to interact with the tissue and provide evidence for which of these receptors are essential for protection. Furthermore, these studies reveal functional in vivo mechanisms of cellular markers used to characterize TRM.

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Co-infection between influenza virus and flagellated bacteria

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652005000500007 ◽

2005 ◽

Vol 47 (5) ◽

pp. 275-280 ◽

Cited By ~ 16

Author(s):

Dalva Assunção Portari Mancini ◽

Rita Maria Zucatelli Mendonça ◽

Andrea Luppi Fernandes Dias ◽

Ronaldo Zucatelli Mendonça ◽

José Ricardo Pinto

Keyword(s):

Influenza Virus ◽

Respiratory Tract ◽

Stenotrophomonas Maltophilia ◽

Viral Infections ◽

Influenza Virus Infection ◽

Influenza Viruses ◽

Cell Entry ◽

Upper Respiratory Tract

Trypsin is required in the hemagglutinin (HA) cleavage to in vitro influenza viruses activation. This HA cleavage is necessary for virus cell entry by receptor-mediated endocytosis. Bacteria in the respiratory tract are potential sources of proteases that could contribute to the cleavage of influenza virus in vivo. From 47 samples collected from horses, pigs, and from humans, influenza presence was confirmed in 13 and these samples demonstrated co-infection of influenza with flagellated bacteria, Stenotrophomonas maltophilia from the beginning of the experiments. Despite treatment with antibiotics, the bacteria remained resistant in several of the co-infected samples (48.39%). These bacteria, considered opportunistic invaders from environmental sources, are associated with viral infections in upper respiratory tract of hosts. The protease (elastase), secreted by Stenotrophomonas maltophilia plays a role in the potentiation of influenza virus infection. Proteolytic activity was detected by casein agar test. Positive samples from animals and humans had either a potentiated influenza infectivity or cytopathic effect (CPE) in MDCK and NCI H292 cells, Stenotrophomonas maltophilia were always present. Virus and bacteria were observed ultrastructurally. These in vitro findings show that microbial proteases could contribute to respiratory complications by host protease activity increasing inflammation or destroying endogenous cell protease inhibitors.

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Efficacy of recombinant NP-M1 and NP-M1-CRT DNA vaccines against Influenza A viruses in mice C57/BL6

10.1101/2021.06.24.449692 ◽

2021 ◽

Author(s):

Hamidreza Attaran ◽

Wen He ◽

wei wang

Keyword(s):

Influenza Virus ◽

Murine Model ◽

Mammalian Cells ◽

Influenza A ◽

Matrix Protein ◽

Protective Efficacy ◽

Influenza Virus Infection ◽

Influenza Viruses ◽

Universal Vaccine

Effective vaccination against the influenza virus remains a challenge because of antigenic shift and drift in influenza viruses. Conservation is an important feature of the Nucleoprotein (NP)and Matrix protein 1(M1) qualifying them as potential candidates for developing a universal vaccine against the influenza A virus. Carliticulin (CRT), a member of heat shock protein (HSP) family, are conserved and widely distributed in many microorganisms and mammalian cells. In this study, a plasmid vector encoding the NP-M1-CRT sequence was constructed and compared with the NP-M1 sequence with respect to immunogenicity and protective efficacy in a murine model. The potency of the created construct for provoking humoral, cellular immune responses, and its protective immunity against the lethal influenza virus infection were then compared with commercial split vaccine and then evaluated in a murine model system. NP-M1-CRT as a DNA vaccine combined with in vivo electroporation could significantly improve the immunogenicity of constructed vectors. Serological evaluations demonstrated the potency of our approach to provoke strong anti-NP specific antibody responses. Furthermore, our strategy of immunization in prime-boost groups were able to provide protection against lethal viral challenge using H1N1 subtype. The ease of production of these types of vectors and the fact that they would not require annual updating and manufacturing may provide an alternative cost-effective approach to limit the spread of potential pandemic influenza viruses.

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