H5N1 Influenza Virus Pathogenesis in Genetically Diverse Mice Is Mediated at the Level of Viral Load

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
mBio (Impact Factor: 6.79). 08/2011; 2(5). DOI: 10.1128/mBio.00171-11
Source: PubMed


The genotype of the host is one of several factors involved in the pathogenesis of an infectious disease and may be a key parameter in the epidemiology of highly pathogenic H5N1 influenza virus infection in humans. Gene polymorphisms may affect the viral replication rate or alter the host’s immune response to the virus. In humans, it is unclear which aspect dictates the severity of H5N1 virus disease. To identify the mechanism underlying differential responses to H5N1 virus infection in a genetically diverse population, we assessed the host responses and lung viral loads in 21 inbred mouse strains upon intranasal inoculation with A/Hong Kong/213/03 (H5N1). Resistant mouse strains survived large inocula while susceptible strains succumbed to infection with 1,000- to 10,000-fold-lower doses. Quantitative analysis of the viral load after inoculation with an intermediate dose found significant associations with lethality as early as 2 days postinoculation, earlier than any other disease indicator. The increased viral titers in the highly susceptible strains mediated a hyperinflamed environment, indicated by the distinct expression profiles and increased production of inflammatory mediators on day 3. Supporting the hypothesis that viral load rather than an inappropriate response to the virus was the key severity-determining factor, we performed quantitative real-time PCR measuring the cytokine/viral RNA ratio. No significant differences between susceptible and resistant mouse strains were detected, confirming that it is the host genetic component controlling viral load, and therefore replication dynamics, that is primarily responsible for a host’s susceptibility to a given H5N1 virus.

Download full-text


Available from: David B Finkelstein,

Click to see the full-text of:

Article: H5N1 Influenza Virus Pathogenesis in Genetically Diverse Mice Is Mediated at the Level of Viral Load

1.16 MB

See full-text
  • Source
    • "Moreover, the NOD-like receptors play a primary role in host defence against invading pathogens and regulating NFκB signalling, IL1β production, and cell death, indicating that they are crucial to the pathogenesis of a variety of inflammatory human diseases [49]. The cytokine-cytokine receptor interaction and Jak-STAT signalling pathway are also well known antiviral response pathways [50,51]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Influenza A virus (IAV) infection-induced inflammatory regulatory networks (IRNs) are extremely complex and dynamic. Specific biological experiments for investigating the interactions between individual inflammatory factors cannot provide a detailed and insightful multidimensional view of IRNs. Recently, data from high-throughput technologies have permitted system-level analyses. The construction of large and cell-specific IRNs from high-throughput data is essential to understanding the pathogenesis of IAV infection. In this study, we proposed a computational method, which combines nonlinear ordinary differential equation (ODE)-based optimization with mutual information, to construct a cell-specific optimized IRN during IAV infection by integrating gene expression data with a prior knowledge of network topology. Moreover, we used the average relative error and sensitivity analysis to evaluate the effectiveness of our proposed approach. Furthermore, from the optimized IRN, we confirmed 45 interactions between proteins in biological experiments and identified 37 new regulatory interactions and 8 false positive interactions, including the following interactions: IL1beta regulates TLR3, TLR3 regulates IFN-beta and TNF regulates IL6. Most of these regulatory interactions are statistically significant by Z-statistic. The functional annotations of the optimized IRN demonstrated clearly that the defense response, immune response, response to wounding and regulation of cytokine production are the pivotal processes of IAV-induced inflammatory response. The pathway analysis results from the Kyoto Encyclopaedia of Genes and Genomes (KEGG) showed that 8 pathways are enriched significantly. The 5 pathways were validated by experiments, and 3 other pathways, including the intestinal immune network for IgA production, the cytosolic DNA-sensing pathway and the allograft rejection pathway, are the predicted novel pathways involved in the inflammatory response. Integration of knowledge-driven and data-driven methods allows us to construct an effective IRN during IAV infection. Based on the constructed network, we have identified new interactions among inflammatory factors and biological pathways. These findings provide new insight into our understanding of the molecular mechanisms in the inflammatory network in response to IAV infection. Further characterization and experimental validation of the interaction mechanisms identified from this study may lead to a novel therapeutic strategy for the control of infections and inflammatory responses.
    BMC Systems Biology 10/2013; 7(1):105. DOI:10.1186/1752-0509-7-105 · 2.44 Impact Factor
  • Source
    • "In contrast, the resistant mouse strains had reduced virus titers in the lung that resulted in lower production of pro-inflammatory mediators and less lung immunopathology. Boon et al. (2011) concluded that the genetic component of susceptible hosts controlling disease severity is primarily influencing viral replication, though it can also be argued that the genetic component of susceptible hosts causes mice to mount an uncontrolled or overly aggressive immune response with pathologic consequences. As complex genetic traits are involved in the host response to influenza infection, new resources such as the Collaborative Cross (CC) mouse resource are providing unique opportunities to probe the contribution of host genetics to infectious disease susceptibility in greater detail (Churchill et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The dynamics of H5N1 influenza virus pathogenesis are multifaceted and can be seen as an emergent property that cannot be comprehended without looking at the system as a whole. In past years, most of the high-throughput studies on H5N1-host interactions have focused on the host transcriptomic response, at the cellular or the lung tissue level. These studies pointed out that the dynamics and magnitude of the innate immune response and immune cell infiltration is critical to H5N1 pathogenesis. However, viral-host interactions are multidimensional and advances in technologies are creating new possibilities to systematically measure additional levels of 'omic data (e.g. proteomic, metabolomic, and RNA profiling) at each temporal and spatial scale (from the single cell to the organism) of the host response. Natural host genetic variation represents another dimension of the host response that determines pathogenesis. Systems biology models of H5N1 disease aim at understanding and predicting pathogenesis through integration of these different dimensions by using intensive computational modeling. In this review, we describe the importance of 'omic studies for providing a more comprehensive view of infection and mathematical models that are being developed to integrate these data. This review provides a roadmap for what needs to be done in the future and what computational strategies should be used to build a global model of H5N1 pathogenesis. It is time for systems biology of H5N1 pathogenesis to take center stage as the field moves towards a more comprehensive view of virus-host interactions.
    Virus Research 03/2013; 178(1). DOI:10.1016/j.virusres.2013.02.011 · 2.32 Impact Factor
  • Source
    • "Importantly, comparison of murine and human genomes has shown that there is a homologue for ~99 % of murine genes in the human genome (Chinwalla et al., 2002). An international programme where KOs for all genes of the mouse are being produced is under way (Austin et al., 2004), as well as infection challenge studies in different mouse strains (Boon et al., 2011), and this is now supported by the complete genome sequences of 17 mouse strains (Keane et al., 2011; Yalcin et al., 2011). In addition, the four members of the KO mouse consortium, namely the European Conditional Mouse Mutagenesis Programme (EUCOMM; http://www. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent RNA interference (RNAi) studies have identified many host proteins that modulate virus infection, but small interfering RNA 'off-target' effects and the use of transformed cell lines limit their conclusiveness. As murine embryonic stem (mES) cells can be genetically modified and resources exist where many and eventually all known mouse genes are insertionally inactivated, it was reasoned that mES cells would provide a useful alternative to RNAi screens. Beyond allowing investigation of host-pathogen interactions in vitro, mES cells have the potential to differentiate into other primary cell types, as well as being used to generate knockout mice for in vivo studies. However, mES cells are poorly characterized for virus infection. To investigate whether ES cells can be used to explore host-virus interactions, this study characterized the responses of mES cells following infection by herpes simplex virus type 1 (HSV-1) and influenza A virus. HSV-1 replicated lytically in mES cells, although mES cells were less permissive than most other cell types tested. Influenza virus was able to enter mES cells and express some viral proteins, but the replication cycle was incomplete and no infectious virus was produced. Knockdown of the host protein AHCYL1 in mES cells reduced HSV-1 replication, showing the potential for using mES cells to study host-virus interactions. Transcriptional profiling, however, indicated the lack of an efficient innate immune response in these cells. mES cells may thus be useful to identify host proteins that play a role in virus replication, but they are not suitable to determine factors that are involved in innate host defence.
    Journal of General Virology 07/2012; 93(Pt 10):2118-30. DOI:10.1099/vir.0.043406-0 · 3.18 Impact Factor
Show more