Human H7N9 and H5N1 Influenza Viruses Differ in Induction of Cytokines and Tissue Tropism

Abstract

Since emerging in 2013, the avian-origin H7N9 influenza viruses have resulted in over 400 human infections, leading to 115 deaths to date. Although the epidemiology differs from human highly pathogenic avian H5N1 influenza virus infections, there is a similar rapid progression to acute respiratory distress syndrome. The aim of these studies was to compare the pathological and immunological characteristics of a panel of human H7N9 and H5N1 viruses in vitro and in vivo. Although there were similarities between particular H5N1 and H7N9 viruses, including association between lethal disease and spread to the alveolar spaces and kidney, there were also strain-specific differences. Both H5N1 and H7N9 viruses are capable of causing lethal infections, with mortality correlating most strongly with wider distribution of viral antigen in the lungs, rather than with traditional measures of virus titer and host responses. Strain-specific differences included hypercytokinemia in H5N1 infections that was not seen with the H7N9 infections regardless of lethality. Conversely, H7N9 viruses showed a greater tropism for respiratory epithelium covering nasal passages and nasopharynx-associated lymphoid tissue than H5N1 viruses, which may explain the enhanced transmission in ferret models. Overall, these studies highlight some distinctive properties of H5N1 and H7N9 viruses in different in vitro and in vivo models. IMPORTANCEThe novel avian-origin H7N9 pandemic represents a serious threat to public health. The ability of H7N9 to cause serious lung pathology, leading in some cases to the development of acute respiratory distress syndrome, is of particular concern. Initial reports of H7N9 infection compared them to infections caused by highly pathogenic avian (HPAI) H5N1 viruses. Thus, it is of critical importance to understand the pathology and immunological response to infection with H7N9 compared to HPAI H5N1 viruses. We compared these responses in both in vitro and in vivo models, and found that H5N1 and H7N9 infections exhibit distinct pathological, immunological, and tissue tropism differences that could explain differences in clinical disease and viral transmission.

The Hemagglutinin Stem-Binding Monoclonal Antibody VIS410 Controls Influenza Virus-Induced Acute Respiratory Distress Syndrome

“…As expected, infection with A(H7N9) virus induced the infiltration of NK cells (NK1.1 ϩ ), AMs (CD11b ϩ Ly6C high ), IMs (CD11b ϩ Ly6C hi ), and neutrophils (CD11b ϩ Ly6C int ) in control animals, compared to mock mice, by 3 dpi (see Fig. S1A to D in the supplemental material), which was consistent with previous reports (28). In the BALF of animals inoculated with A(H7N9) virus and treated with VIS410, we observed a trend toward decreased recruitment of inflammatory cells compared to that in control animals; however, this difference was not statistically significant (see Fig.…”

“…VIS410 treatment reduces lung viral load in mice. Rapid and robust virus replication in bronchial and alveolar cells of lungs is thought to be the major factor contributing to the pathogenicity of A(H7N9) influenza viruses (28). To determine the kinetics of the A(H7N9) virus load at the site of infection with and without treatment, we determined the virus titers in the lungs of infected mice.…”

“…In our model, ARDS was induced by an A(H7N9) influenza virus. The pathogenicity of this virus subtype stems mainly from uncontrolled viral replication throughout the respiratory tract (resulting from the ability of the virus to bind to both human-like ␣2,6and avian-like ␣2,3-linked sialic acid [SA] [26,27]), which results in extensive damage to the epithelial lung barrier and leads to increased lung permeability and a higher prevalence of ARDS, in contrast to the cytokine storm associated with A(H5N1) infections (28). To maximize translational relevance, we used both NAI-susceptible and NAIresistant (R292K NA substitution) influenza A(H7N9) viruses in our experiments.…”

ICAM-1 regulates the survival of influenza virus in lung epithelial cells during the early stages of infection

“…Airway epithelial cells responded to the viral invaders by expressing a variety of inflammatory and immune defense proteins that defend the cells against the viral infection (Medzhitov and Janeway, 2000). Also, tissue tropism plays a key role in viral infection and induction of inflammatory responses (Meliopoulos et al, 2014). The bronchial cells showed a higher fold increase in ICAM-1 expression compared to nasal epithelial cells.…”

Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola

“…In both experimental and human influenza, a greater degree of virus replication is generally associated with greater inflammation and more severe disease (93,94). However, individual influenza viruses may differ in the extent to which they elicit inflammatory responses, and the degree of hypercytokinemia is not always directly associated with levels of virus replication or mortality (88,95).…”