The pathogenesis of influenza virus infections: the contributions of virus and host factors

Influenza viruses cause acute respiratory inflammation in humans and symptoms such as high fever, body aches, and fatigue. Usually these symptoms improve after several days; however, the 2009 pandemic H1N1 influenza virus [influenza A(H1N1) 2009] is more pathogenic than seasonal influenza viruses and the pathogenicity of highly pathogenic H5N1 viruses is still higher. The 1918 influenza pandemic virus caused severe pneumonia, resulting in an estimated 50 million deaths worldwide. Several virulence factors have been identified in these virus strains, but host factors are also responsible for the pathogenesis of infections caused by virulent viruses. Here, we review the contributions of both virus and host factors to the pathogenesis of these viral infections.

Introduction

Influenza viruses possess RNA as their genome and belong to the family Orthomyxoviridae [1]. Influenza A viruses (IAV), together with influenza B viruses, cause respiratory illness in humans. Wild aquatic birds are the natural reservoir of IAV [2]. Influenza pandemics occur when humans are introduced to IAVs with hemagglutinin (HA) to which they are immunologically naïve [3]. We have experienced four pandemics since the beginning of 20th century: Spanish influenza (H1N1) in 1918/1919, Asian influenza (H2N2) in 1957, Hong Kong influenza (H3N2) in 1968, and H1N1 influenza in 2009. Of these pandemic viruses, the 1918 virus was the most devastating, causing massive acute pulmonary hemorrhage and edema [4]. As antibiotics were not available then, secondary bacterial pneumonia was a major cause of death among those infected with the virus [5]. Until recently, it has been difficult to precisely evaluate the pathogenicity of the 1918 virus relative to other influenza virus strains. However, in 1999, the reverse genetics of influenza virus was established, enabling us and others to generate the 1918 virus from cloned cDNAs [6]. Infection of cynomolgus macaques with 1918 virus generated by reverse genetics resulted in severe lung damage and high virus titers, as well as disruption of the macaques’ antiviral immune responses [7]. These studies directly demonstrated that the 1918 virus possessed sufficiently high pathogenicity to cause fatal pulmonary disease.

The genome of IAV consists of eight RNA segments, encoding HA, neuraminidase (NA), nucleoprotein (NP), M1, M2, nonstructural protein (NS) 1, NS2, polymerase acidic protein (PA), polymerase basic (PB) 1, PB1-F2, and PB2. Recently, research has focused on using reverse genetics to elucidate the role of each viral protein in the pathogenicity of influenza viruses. The range of severity of diseases caused by genetically similar IAV in humans is extremely wide, indicating that host conditions play an important role in determining the pathogenesis of IAV. Experiments with mammals such as mice, guinea pigs, ferrets, and non-human primates, are employed to analyze the involvement of host factors in IAV infections, while gene-targeted mouse models are useful for testing the function of individual host genes in vivo. The secretion of type 1 interferon is induced by viral infection and produces antiviral factors; IFNβ knockout mice are susceptible to influenza virus [8]. Therefore, type I IFN is a key molecule in the innate immune responses to infection with influenza virus and the magnitude of the type I IFN response influences the pathogenicity of the virus. Thus, the pathogenesis of influenza virus infection in humans depends on a combination of virus and host factors.