2009 pandemic H1N1 influenza virus elicits similar clinical course but differential host transcriptional response in mouse, macaque, and swine infection models

Abstract

BackgroundThe 2009 pandemic H1N1 influenza virus emerged in swine and quickly became a major global health threat. In mouse, non human primate, and swine infection models, the pH1N1 virus efficiently replicates in the lung and induces pro-inflammatory host responses; however, whether similar or different cellular pathways were impacted by pH1N1 virus across independent infection models remains to be further defined. To address this we have performed a comparative transcriptomic analysis of acute phase responses to a single pH1N1 influenza virus, A/California/04/2009 (CA04), in the lung of mice, macaques and swine.ResultsDespite similarities in the clinical course, we observed differences in inflammatory molecules elicited, and the kinetics of their gene expression changes across all three species. We found genes associated with the retinoid X receptor (RXR) signaling pathway known to control pro-inflammatory and metabolic processes that were differentially regulated during infection in each species, though the heterodimeric RXR partner, pathway associated signaling molecules, and gene expression patterns varied among the three species.ConclusionsBy comparing transcriptional changes in the context of clinical and virological measures, we identified differences in the host transcriptional response to pH1N1 virus across independent models of acute infection. Antiviral resistance and the emergence of new influenza viruses have placed more focus on developing drugs that target the immune system. Underlying overt clinical disease are molecular events that suggest therapeutic targets identified in one host may not be appropriate in another.

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

“…Previous pH1N1 infections of rhesus macaques have relied on high-dose administration of virus to tracheal, nasal, ocular, and oral mucosal surfaces. This resulted in limited clinical signs despite the recovery of virus at multiple days postinfection (6,11). In this study, we challenged naive animals with a mixed-particle aerosol composed of large and small virus particles.…”

“…These studies revealed species-specific differences in the host responses between rhesus and cynomolgus macaques. Cynomolgus macaques infected with strain influenza A/California/04/2009 (H1N1) (pH1N1 Cal04) virus exhibited moderately severe clinical signs by day 6 postinfection, with a concurrent activation of the inflammatory response genes in the lung (11). In comparison, rhesus macaques infected with the same pH1N1 strain remained asymptomatic despite sustained viral shedding for 21 days postinfection (10).…”

The use of nonhuman primates in research on seasonal, pandemic and avian influenza, 1893–2014

“…Tissues collected at necropsy on day 4 showed that the pandemic virus replicated to a greater extent in the lower respiratory tract, causing diffuse alveolar damage. A later study found that, although the pandemic virus infects mice, pigs and macaques, it elicits different sets of transcriptional responses in the three species (Go et al, 2012). …”

Similarity of currently circulating H1N1 virus with the 2009 pandemic clone: Viability of an imminent pandemic

“…Clinical symptoms associated with the 2009 pandemic H1N1 strain (H1N1 pdm09) include mild respiratory irritations that extend up to severe pneumonia, associated with acute respiratory distress syndrome (ARDS) with the gradual progress of infection (Chowell et al, 2009;Perez-Padilla et al, 2009;Go et al, 2012). The H1N1 pandemic that initiated in 2009 resulted in nearly 300,000 deaths globally within the first year of its outbreak (Dawood et al, 2012).…”

“…The H1N1 pandemic that initiated in 2009 resulted in nearly 300,000 deaths globally within the first year of its outbreak (Dawood et al, 2012). A distinctive feature of influenza virus infection is a successful viral entry into the host system followed by subsequent destruction of the host immune responses and inception of disease (Go et al, 2012;de Jong et al, 2006;Kobasa et al, 2007). Continuous antigenic variations occur in influenza A virus that ensure its competent replication inside the human host (Schmolke and Garcia-Sastre, 2010).…”