The Drivers of Pathology in Zoonotic Avian Influenza: The Interplay Between Host and Pathogen

Abstract

The emergence of zoonotic strains of avian influenza (AI) that cause high rates of mortality in people has caused significant global concern, with a looming threat that one of these strains may develop sustained human-to-human transmission and cause a pandemic outbreak. Most notable of these viral strains are the H5N1 highly pathogenic AI and the H7N9 low pathogenicity AI viruses, both of which have mortality rates above 30%. Understanding of their mechanisms of infection and pathobiology is key to our preparation for these and future viral strains of high consequence. AI viruses typically circulate in wild bird populations, commonly infecting waterfowl and also regularly entering commercial poultry flocks. Live poultry markets provide an ideal environment for the spread AI and potentially the selection of mutants with a greater propensity for infecting humans because of the potential for spill over from birds to humans. Pathology from these AI virus infections is associated with a dysregulated immune response, which is characterized by systemic spread of the virus, lymphopenia, and hypercytokinemia. It has been well documented that host/pathogen interactions, particularly molecules of the immune system, play a significant role in both disease susceptibility as well as disease outcome. Here, we review the immune/virus interactions in both avian and mammalian species, and provide an overview or our understanding of how immune dysregulation is driven. Understanding these susceptibility factors is critical for the development of new vaccines and therapeutics to combat the next pandemic influenza.

Keywords: H5N1; H7N9; avian influenza virus; highly pathogenic avian influenza virus; zoonosis.

Figure 1

Zoonotic influenza pathology is linked to host biology. H5N1, H7N9, and H9N2 avian influenza (AI) viruses causing varying degrees of clinical manifestations across different species is shown against different host and their sialic acid properties. AI viral hemagglutinin proteins selectively and preferentially bind to sialic residues with either an α-2,3-Gal or α-2,6-Gal terminating sequence on the host cell surface to allow for viral fusion and entry. This represents viral fitness and is a potential mechanism underlying the degree of disease severity and susceptibility in the different hosts.

Figure 2

Age-related mortality trends highlight impact of host–pathogen relationships. Frequency of age groups of patients who succumb to different strains of influenza is graphed as a proportion of total fatalities for a given strain. When we assessed the age of patients who succumb to different strains of influenza, as a proportion of the total mortalities for a given strain, trends emerge as to the host susceptibilities. For seasonal influenza, older patients (>60 years old) were the most susceptible, however, for a variation on seasonal influenza, pdmH1N1 2009, the age of patients who succumbed was reduced and included significant mortalities between 20 and 59 years old. Interestingly, the highly pathogenic AI H5N1 was predominantly fatal in those under 40 years old, whereas H7N9, a low pathogenicity AI strain, followed a similar trend to seasonal influenza.

Figure 3

Mechanisms leading to severe clinical outcomes involve both host and pathogen elements. A number of factors have been elucidated to contribute to the severity of influenza disease outcomes. This include viral fitness elements, such as the presence of a multi-basic cleavage site (MBCS), mutations to the polymerase basic 2 (PB2) genes, as well as the presentation of hemagglutinin (HA) protein capable of binding to human sialic acids. These viral fitness elements work in concert with host factors such as modified interferon-induced transmembrane (IFITM) proteins, with reduced ability to combat the virus and MHCI diversity which can or cannot present the antigen appropriately and efficiently to host T cells. Ultimately, these and other elements lead to changes in production of key cytokines as well as cellular activation that drives inflammation, cell death, and clinical manifestation of disease.