2009 pandemic H1N1 influenza A virus strains display differential pathogenicity in C57BL/6J but not BALB/c mice

Influenza A viruses are the causative agents of annual epidemics and occasional pandemics. The pathogenicity of influenza viruses is determined by complex interplay of viral and host factors. While some knowledge exists on viral determinants of pathogenicity, little is known on the host factors involved. Here, we discuss our recent findings on host genetic variations involved in disease outcome. We found that 2009 pandemic H1N1 influenza A virus strains (pH1N1) are low pathogenic in BALB/c but display differential pathogenicities in C57BL/6J mice. In contrast, a highly pathogenic avian influenza A virus (HPAIV) strain of the H5N1 subtype isolated from a fatal human case was more virulent in BALB/c than C57BL/6J mice. As a control, we used a seasonal H1N1 influenza virus which showed marginal pathogenicity in both mouse strains. Thus, differences in pH1N1 virulence become visible in C57BL/6J mice, while intrinsic pH1N1 pathogenicity markers are masked in BALB/c mice. Further, increased pH1N1 virulence correlated with a depressed cytokine response in C57BL/6J mice, while increased H5N1 virulence correlated with an elevated proinflammatory cytokine response in BALB/c mice. These findings indicate that disease severity can be strongly regulated by the host genetic background. Moreover, our findings suggest that differential host determinants contribute to the pathogenesis of pH1N1 and human H5N1 influenza viruses. Further studies are needed to identify the responsible viral factors involved in enhanced pH1N1 virulence in C57BL/6J mice. Also, extensive studies are needed to identify and characterize cellular factors regulating pH1N1 or H5N1 susceptibility in a host dependent manner. These observations extend our knowledge on influenza virus pathogenicity and highlight the role of host dependent factors, especially in pH1N1 susceptibility. We propose the C57BL/6J mouse strain as a convenient small animal model to study pH1N1 virulence determinants. Furthermore, the C57BL/6J mouse strain might also represent a suitable model for the assessment of pH1N1 vaccine candidates or the evaluation of antiviral therapies.