Integrated Clinical, Pathologic, Virologic, and Transcriptomic Analysis of H5N1 Influenza Virus-Induced Viral Pneumonia in the Rhesus Macaque

Abstract

h Viral pneumonia has been frequently reported during early stages of influenza virus pandemics and in many human cases of highly pathogenic avian influenza (HPAI) H5N1 virus infection. To better understand the pathogenesis of this disease, we produced nonlethal viral pneumonia in rhesus macaques by using an HPAI H5N1 virus (A/Anhui/2/2005; referred to as Anhui/2). Infected macaques were monitored for 14 days, and tissue samples were collected at 6 time points for virologic, histopathologic, and transcriptomic analyses. Anhui/2 efficiently replicated in the lung from 12 h to 3 days postinfection (p.i.) and caused temporal but severe pneumonia that began to resolve by day 14. Lung transcriptional changes were first observed at 6 h, and increased expression of vascular permeability regulators and neutrophil chemoattractants correlated with increased serum leakage and neutrophil infiltration in situ. Additional inflammatory, antiviral, and apoptotic genes were upregulated from 12 h, concurrent with viral antigen detection and increasing immune cell populations. A shift toward upregulation of acquired immunity was apparent after day 6. Expression levels of established immune cell molecular markers revealed remarkable similarity with pathological findings, indicating early and robust neutrophil infiltration, a slight delay in macrophage accumulation, and abundant late populations of T lymphocytes. We also characterized the putative mechanisms regulating a unique, pneumonia-associated biphasic fever pattern. Thus, this study is the first to use a comprehensive and integrative approach to delineate specific molecular mechanisms regulating influenza virus-induced pneumonia in nonhuman primates, an important first step toward better management of human influenza virus disease.

Immunologic Characterization of a Rhesus Macaque H1N1 Challenge Model for Candidate Influenza Virus Vaccine Assessment

“…In our rhesus macaque model, we observed a similar association of interferon activity with a biphasic fever that peaked on days 1 and 5 to 6 postchallenge. This biphasic fever was similar to that previously observed in H5N1 infection in children (28) and in H5N1-infected rhesus macaques (29). The relationship between the interferon responses and fever has long been established (30), and fever is the major side effect of interferon-based therapies in humans (31).…”

Antibody-Dependent Cellular Cytotoxicity Is Associated with Control of Pandemic H1N1 Influenza Virus Infection of Macaques

“…Although murine models have been valuable for dissecting NAb and T cell immunity, the ability of influenza virus to induce ADCC in mice remains relatively undefined. The macaque model of influenza virus infection has recently gained popularity, as most human strains of influenza virus readily infect macaques, a large number of nonhuman primate reagents are being established, and macaques show similar pathology and immune responses to influenza virus to those seen in humans (17,(40)(41)(42). Therefore, the use of the macaque influenza model allowed us to dissect the induction and protective capacity of influenza virus-specific ADCC.…”

Adaptive amino acid substitutions enhance the virulence of a reassortant H7N1 avian influenza virus isolated from wild waterfowl in mice

“…Although AIVs usually replicate efficiently in their natural avian hosts, there are reports that some AIVs can also infect dogs, cats, plateau pikas, rhesus macaques, and occasionally humans (Cheng et al, 2014b;Shinya et al, 2012;Songserm et al, 2006;Yu et al, 2014;Zhang et al, 2013aZhang et al, , 2013b. For example, human infections with a novel H7N9 AIV were first reported in China in 2013, and have been a growing public health concern (Gao et al, 2013).…”