Pathogenesis of 1918 Pandemic and H5N1 Influenza Virus Infections in a Guinea Pig Model: Antiviral Potential of Exogenous Alpha Interferon To Reduce Virus Shedding

Abstract

Although highly pathogenic avian influenza H5N1 viruses have yet to acquire the ability to transmit efficiently among humans, the increasing genetic diversity among these viruses and continued outbreaks in avian species underscore the need for more effective measures for the control and prevention of human H5N1 virus infection. Additional small animal models with which therapeutic approaches against virulent influenza viruses can be evaluated are needed. In this study, we used the guinea pig model to evaluate the relative virulence of selected avian and human influenza A viruses. We demonstrate that guinea pigs can be infected with avian and human influenza viruses, resulting in high titers of virus shedding in nasal washes for up to 5 days postinoculation (p.i.) and in lung tissue of inoculated animals. However, other physiologic indicators typically associated with virulent influenza virus strains were absent in this species. We evaluated the ability of intranasal treatment with human alpha interferon (␣-IFN) to reduce lung and nasal wash titers in guinea pigs challenged with the reconstructed 1918 pandemic H1N1 virus or a contemporary H5N1 virus. IFN treatment initiated 1 day prior to challenge significantly reduced or prevented infection of guinea pigs by both viruses, as measured by virus titer determination and seroconversion. The expression of the antiviral Mx protein in lung tissue correlated with the reduction of virus titers. We propose that the guinea pig may serve as a useful small animal model for testing the efficacy of antiviral compounds and that ␣-IFN treatment may be a useful antiviral strategy against highly virulent strains with pandemic potential.

Comparative Pathology of Select Agent Influenza A Virus Infections

“…Direct contact transmission required the 1918 H1N1 HA, but efficient respiratory droplet transmission required the 1918 H1N1 PB2 gene segment. 152 The NP and 3 polymerase complex genes were necessary for high-replication efficiency in the respiratory tract of ferrets. 158 Experimental pH1N1 virus infection causes morbidity and mortality in ferrets.…”

“…83 Neither H5N1 HPAI nor 1918 H1N1 viruses cause severe clinical signs or mortality. 74,152 Historically, the first select agent influenza infections in guinea pigs may have occurred naturally, based on a report of guinea pigs dying with severe pneumonia in a vivarium that was spatially and chronologically associated with influenza in soldiers during the Spanish influenza pandemic. 75 Lesions with 1918 H1N1 and H5N1 HPAI viruses have been limited to the respiratory tract and are milder than those seen in mice or ferrets.…”

“…75 Lesions with 1918 H1N1 and H5N1 HPAI viruses have been limited to the respiratory tract and are milder than those seen in mice or ferrets. 74,152 The domestic pig has been proposed and used as a model of human influenza because of cross transmission of human and swine influenza viruses between pigs and people under natural settings. 96 The pig respiratory epithelium has a-2,6-and a-2,3-linked sialic acid moiety receptors that can bind avian, swine, and human influenza viruses.…”

Autopsy series of 68 cases dying before and during the 1918 influenza pandemic peak

“…Archaevirological sequence determination (2)(3)(4)(5)(6)(7)(8) and viral reconstruction make it possible to study structure and in vivo pathogenicity of the 1918 pandemic virus (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). The origin of the 1918 virus, how and where it evolved before global pandemic spread, and the mechanisms by which this virus caused extraordinarily high mortality have not been fully elucidated.…”

Seasonal influenza vaccination and the risk of infection with pandemic influenza: a possible illustration of non-specific temporary immunity following infection

“…In a guinea pig model of influenza infection, daily intranasal administration of recombinant human interferon alpha completely blocked transmission of pandemic influenza A(H1N1) both from and to treated animals [15]. Further, prophylaxis with interferon alpha reduced virus shedding of ferrets and guinea pigs infected with highly pathogenic influenza strains and morbidity following seasonal influenza challenge [16,17].…”