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    Genetic predisposition plays role in severity of illness following H5N1 infection


    Richard J. Webby, PhD

    Patients with the genetic foundation to marshal an efficient, rapid response to the H5N1 influenza virus are more likely than others to survive the bird flu, according to a team led by St. Jude investigators.

    The study, published in the August 12 online edition of the Journal of Virology, provides the first evidence of a genetic predisposition to serious illness following H5N1 infection. Researchers focused on H5N1, rather than the current H1N1 pandemic flu strain. Although H1N1 has sickened more individuals worldwide, H5N1 has proven more virulent.

    In this study, researchers working in mice tracked differences in the H5N1 immune response to regions of five chromosomes. Within one of these regions was a candidate gene, hemolytic complement (HC), which investigators went on to show plays a critical role in modulating the mouse’s response to H5N1 infection.

    Efforts are underway to link other specific genes with the risk of illness or death following an H5N1 infection, said the paper’s senior author, Richard Webby, PhD, Infectious Diseases. Webby is also director of the World Health Organization (WHO) Collaborating Center for Studies on the Ecology of Influenza in Animals and Birds, which is based at St. Jude.

    The results may ultimately yield new anti-viral therapies or new genetic screening tests to identify previously unrecognized high-risk patients, Webby said. “Even a negative answer would have been important for control measures, as a lack of a genetic marker might indicate those getting infected were engaged in particularly high-risk activities,” he explained.

    In humans, H5N1 outbreaks typically occur in clusters. Historically, more than 90 percent of those clusters involved genetically related family members. This study provides researchers with a roadmap to begin searching for the genes involved.

    Webby said the role genetics plays in fighting other flu viruses, including the H1N1 pandemic virus, is also being studied. Early evidence suggests that some genes might be important in combating all flu infections, while others likely play a specific role against H5N1. He added that genetics might be particularly important in protecting against serious illness following infection with the bird flu virus.

    Scientists have long recognized that individual genetic variations influence susceptibly and response to a variety of infectious agents, including the human immunodeficiency virus (HIV), tuberculosis and the H3N2 flu strain. But Webby and his co-authors noted that the genetic basis for increased susceptibility to flu infection or illness was largely unknown.

    “We became very interested in the question of why so few individuals have contracted H5N1 influenza disease despite the many millions of people in contact with infected poultry. Epidemiologic data from the field hinted at a possible role for host genetics,” Webby said.

    H5N1 remains primarily a disease of birds. The WHO estimates the virus has sickened tens of millions of birds, but just 440 individuals. For humans, the primary risk factor remains exposure to sick or dead birds.

    For this study, researchers started by infecting two different mouse strains with the H5N1 virus. The resulting immune responses were dramatically different.

    Despite receiving up to a 10,000-fold greater dose of the virus, H5N1-resistant mice produced lower levels of proteins called cytokines than did the more susceptible mice. Cytokines can trigger inflammation and help regulate the immune response, but if overproduced can cause damage. Three days after infection, levels of certain cytokines were up to eight times higher in the susceptible mice than in the resistant mice. Among the cytokines measured in this study were tumor necrosis factor alpha, interferon alpha and beta plus chemokine ligand 2.

    The resistant mice also did a better job than susceptible mice of clearing the virus from their lungs. In the two days immediately after the infection and again a week later, researchers reported the susceptible mice had 10 times more flu virus in their lungs than their resistant counterparts.

    “The link between disease severity and high viral load plus increased production of pro-inflammatory cytokines was previously found in humans infected with the H5N1 viruses,” said Adrianus CM Boon, PhD, a postdoctoral fellow in Webby’s laboratory and the paper’s lead author. In 2006, researchers linked high levels of TNF-alpha and another cytokine in throat swabs to poor patient prognosis.

    Investigators used a variety of tools, including genome-wide linkage analysis and RNA expression, to search for the genes involved in viral replication or the early innate immune response. The researchers identified regions of increased activity on chromosomes 2, 7, 11, 15 and 17 that were associated with milder illness, longer survival and lower mortality. RNA expression is a sign of gene activity.

    Along with the HC gene, the tests identified more than 10 additional genes where the level of expression varied dramatically between the resistant and susceptible mice.

    The genes included Eif2ak2 and Xdh, both previously linked to flu infections, as well as a number of genes whose proteins have known antiviral properties or are believed to help regulate cytokine activity. The list includes Trim12, Trim34, the Trim-30 like gene called A145617, as well as Ifi35.

    Other authors include Jennifer deBeauchamp of Infectious Diseases; and David Finkelstein, PhD, and Geoffrey Neale, PhD, both of the Hartwell Center for Bioinformatics and Biotechnology.

    This research was supported in part by the National Institute of Allergy and Infectious Diseases and ALSAC.

    September 2009