Dependence of the cocarcinogenic action of the influenza virus on the nature of the influenza infection

It was shown in experiments of CC57W mice that cocarcinogenic activity of influenza A/PR8/34 virus correlates with acute or chronic pattern of infection. Prolonged persistence of the virus resulted in significant stimulation of the lung tumor incidence in infected mice. The prevention with thymosin of chronic influenza infection development in CC57W mice lead to a decrease in the incidence of lung tumors to the control level.     

Resistance to influenza virus and vesicular stomatitis virus conferred by expression of human MxA protein.

MxA and MxB are interferon-induced proteins of human cells and are related to the murine protein Mx1, which confers selective resistance to influenza virus. In contrast to the nuclear murine protein Mx1, MxA and MxB are located in the cytoplasm, and their role in the interferon-induced antiviral state was unknown. In this report we show that transfected cell lines expressing MxA acquired a high degree of resistance to influenza A virus. Surprisingly, MxA also conferred resistance to vesicular stomatitis virus. Expression of MxA in transfected 3T3 cells had no effect on the multiplication of two picornaviruses, a togavirus, or herpes simplex virus type 1. Treatment of MxA-expressing cells with antibodies to mouse alpha-beta interferon did not abolish the resistance phenotype. The conclusion that resistance to influenza virus and vesicular stomatitis virus was due to the specific action of MxA is further supported by the observation that transfected 3T3 cell lines expressing the related MxB failed to acquire virus resistance.     

The pH-sensitive action of cholesterol-conjugated peptide inhibitors of influenza virus

Influenza viruses are major human pathogens, responsible for respiratory diseases affecting millions of people worldwide, with high morbidity and significant mortality. Infections by influenza can be controlled by vaccines and antiviral drugs. However, this virus is constantly under mutations, limiting the effectiveness of these clinical antiviral strategies. It is therefore urgent to develop new ones. Influenza hemagglutinin (HA) is involved in receptor binding and promotes the pH-dependent fusion of viral and cell endocytic membranes. HA-targeted peptides may emerge as a novel antiviral option to block this viral entry step. In this study, we evaluated three HA-derived (lipo)peptides using fluorescence spectroscopy. Peptide membrane interaction assays were performed at neutral and acidic pH to better resemble the natural conditions in which influenza fusion occurs. We found that peptide affinity towards membranes decreases upon the acidification of the environment. Therefore, the released peptides would be able to bind their complementary domain and interfere with the six-helix bundle formation necessary for viral fusion, and thus for the infection of the target cell. Our results provide new insight into molecular interactions between HA-derived peptides and cell membranes, which may contribute to the development of new influenza virus inhibitors.     

Galectin-1 binds to influenza virus and ameliorates influenza virus pathogenesis

Innate immune response is important for viral clearance during influenza virus infection. Galectin-1, which belongs to S-type lectins, contains a conserved carbohydrate recognition domain that recognizes galactose-containing oligosaccharides. Since the envelope proteins of influenza virus are highly glycosylated, we studied the role of galectin-1 in influenza virus infection in vitro and in mice. We found that galectin-1 was upregulated in the lungs of mice during influenza virus infection. There was a positive correlation between galectin-1 levels and viral loads during the acute phase of viral infection. Cells treated with recombinant human galectin-1 generated lower viral yields after influenza virus infection. Galectin-1 could directly bind to the envelope glycoproteins of influenza A/WSN/33 virus and inhibit its hemagglutination activity and infectivity. It also bound to different subtypes of influenza A virus with micromolar dissociation constant (K(d)) values and protected cells against influenza virus-induced cell death. We used nanoparticle, surface plasmon resonance analysis and transmission electron microscopy to further demonstrate the direct binding of galectin-1 to influenza virus. More importantly, we show for the first time that intranasal treatment of galectin-1 could enhance survival of mice against lethal challenge with influenza virus by reducing viral load, inflammation, and apoptosis in the lung. Furthermore, galectin-1 knockout mice were more susceptible to influenza virus infection than wild-type mice. Collectively, our results indicate that galectin-1 has anti-influenza virus activity by binding to viral surface and inhibiting its infectivity. Thus, galectin-1 may be further explored as a novel therapeutic agent for influenza.     

Characteristics of the action of the influenza virus on the microcirculatory vessels in an experiment

The dynamic light-optic and electron microscopic examination of the organs of experimental animals with the influenza infection have revealed the most pronounced pathology in vessels of the lung and brain microcirculation. The early developing perivascular edema around capillaries which is induced by an increase in the transcellular transport without a disturbance of the dense contact integrity is observed in the brain tissue. Variations in the lung microvessels manifested in a rise of the pinocytosis activity of endothelial cells, in a change of the luminal surface profile and damage of the supermembrane layer. A reversible aggregation of plate and erythrocytes was observed in the lung and brain microvessel lumen at early periods. The revealed changes, including the main of them--microvessel permeability disturbance, are associated with the dynamics of the concentration of the influenza virus and its complexes with antibodies in the organs under study.     

Resistance to influenza A virus infection by antigen-conjugated CpG oligonucleotides, a novel antigen-specific immunomodulator

Oligodeoxynucleotides (ODN) containing CpG motifs (CpG) act as modulators that bias the immune response towards a Th1-dominant phenotype. To investigate this effect further, we examined the protective effects of a covalently linked conjugate between CpG-ODN and HA-2kd antigen in mice infected with influenza A virus. The conjugated form of CpG-ODN and HA-2kd was more efficient in regulating influenza A virus than the unconjugated mixture of CpG-ODN and HA-2kd. The antigen-conjugated CpG-ODN induced an immune response with a Th1-dominant cytokine pattern characterized by the secretion of high levels of HA-2kd-specific interferon-gamma and IgG2a (Th1), which were only slightly induced by HA-2kd alone. These findings support the use of CpG-ODN-Ag conjugates as novel Ag-specific immunomodulators and suggest that CpG-ODN-HA-2kd might be a promising immune therapy for patients with influenza virus.     

Toxic action of influenza virus on lymphoid-macrophagal reactions in guinea pigs]

Influenza viruses with different degrees of virulence for the human being produced various reactions of the lymphoid-macrophagal elements in the peritoneal exudate of guinea pigs inoculated intraperitoneally. The higher the virulence of the strain for the human being -- the deeper the inhibition of the lymphoid and macrophagal cells of guinea pigs. Low virulent strains of influenza virus induced a considerable functional activity of macrophages, but were devoid of the lympholytic activity. Because of close corrleation between the virulence of the virus and the cellular content of the exudate the lymphocytic-macrophagal reaction in the animals resistant to influenza virus could serve for determination of the toxic activity of the viruses under study.     

Protective action of cytotoxic lymphocytes depending on the antigenic determinant composition of influenza virus hemagglutinin

The protective role of cytotoxic lymphocytes (CTL) in dependence on composition of antigenic determinants of hemagglutinin of influenza viruses H3N2 was studied. It was established that CTL do not exert protective effect under conditions of adoptive transfer, when there is one common antigenic determinant in hemagglutinins of the virus forming immunity. When all antigenic determinants in hemagglutinins of influenza viruses are identical, CTL-like antibodies represent one of the main factors of antivirus immunity.