Meeting report
Genetics and Genomics of Infectious Diseases
Infectious diseases pose an old problem for humans. Although they have been with us throughout our history, we have only a meagre understanding of how infectious diseases arise and spread, their consequences for the host, and the most effective methods for treatment and prevention. Successful research programs demand input from diverse areas of expertise, and must integrate knowledge of diverse and complex aspects of both pathogen and host biology, the clinical phenotype, and epidemiology – all areas with their own established scientific communities. Recent studies demonstrate that genetics can now be a common language for these diverse groups.
This conference was conceived by two human genetics societies to reach out to different scientific fields and different areas of the world than traditionally represented at their annual meetings, supported by a group of interdisciplinary journals. The goal of the conference was to bring together scientists from multiple areas of infectious disease research, spanning viral, bacterial and protozoan-caused illnesses, and studying ancient infections such as malaria and tuberculosis alongside emerging infectious diseases and viral pandemics. A key strength of the meeting was the placement of equal emphasis on pathogen biology and the response of the host, and a theme that ran through many of the talks was the need to have a firm grasp on both aspects to gain a full understanding of the emergence, dynamics and outcomes of infectious disease. Genetics and genomics turned out to be a powerful unifying theme to these discussions.
New technologies are accelerating our understanding of the host genes involved in susceptibility and response to infection. As highlighted in several talks at the meeting, many recent insights in this respect have come from the ability to carry out whole-genome studies, including both association studies and other designs, to unravel the complex, polygenic nature of host susceptibility. An important lesson to re-emerge was the need for a careful definition of the phenotype. Dengue fever was used as an example to illustrate that in the case of infectious diseases, different stages during infection may well need to be considered as distinct phenotypes. Moreover, it turns out that the genetic architecture of the host response can be surprisingly complex; for example, response to mycobacterial infections seems to be under control of a genetic continuum that ranges from Mendelian factors to complex multigenic influences, the balance of which varies depending on the host age. An important challenge for future genome-wide association studies will involve conducting these studies in African and other populations, where both population and genome structure present important challenges.
Numerous presentations highlighted the ways in which next-generation, high-throughput sequencing technologies are accelerating diverse areas of pathogen research and opening up new avenues of exploration. First, genome sequencing was crucial in the discovery of SARS, and other, emerging viral infections. Second, resequencing is beginning to uncover previously unexpected biology: for example, Salmonella typhi isolates have informed evolutionary studies and fine-scale molecular epidemiology even in this monomorphic pathogen for which such studies have previously been hard or outright impossible. Comparative and evolutionary genomics occasioned by resequencing have also provided new insight into epidemic outbreaks, such as is the case for the influenza virus. In this case, evidence suggests that antigenic drift in influenza populations is important for epidemic outbreaks. But the full understanding of pathogen population dynamics and host responses only came from studying both at once. Some studies lend support to another view in which antigenic diversity among the viral population is pre-shaped by the range of immune responses within the human population, limiting the possible forms that a new epidemic strain can take. Such a finite spectrum of pathogen diversity would have important implications for predicting occurrence of future influenza hotspots. Third, comparative genomics of samples from multiple precisely-defined locations, creating the field genomic geography, is shedding light on not only the evolution and spread of pathogen resistance but also human behaviours and migration patterns. Again dengue fever provides an instructive lesson; genomic sequencing suggests a 2005 epidemic in Singapore was not due to any new mutations in the pathogen, but rather changes in human behaviour or local ecology. Finally, perhaps unexpectedly, insights from microbial population genetics such as recombination patterns can be used to gain insights into human population history.
Some lively debate at the conference focused on the need to rethink the way we view the host-microbe relationship. Humans have long been 'cohabiting' with microorganisms, to the point where we each carry many more of their cells than our own, and many are commensal. The new field of microbiomics opens new avenues for exploring the ways that bacteria contribute to various aspects of human biology, ranging from metabolism to the development of the immune system. It is interesting to consider the role that microbes play in human biology on the background of recent indications that as a result of changes in our lifestyle our relationship with our 'indigenous organisms' becomes altered. The example most discussed in Singapore was Helicobacter pylori, shown to live with humans through multiple migrations around the world. There is evidence that the disappearance of H. pylori in developed countries is decreasing the incidence of peptic ulcers and gastric cancer, but is increasing that of oesophageal adenocarcinoma. Influences of this bacterium on susceptibility to asthma and the regulation of hormones involved in energy homeostasis have also been recently identified, emphasizing the importance of gaining a better understanding of the human microbiome.
What can be done to ensure that the opportunities provided by genetic and genomic approaches to studying infectious disease can be made use of to maximize the benefits for human health? In addition to the scientific talks, the meeting included a discussion session that explored ways that policymakers and researchers could work most effectively towards this goal. Many thought-provoking points were raised and some key themes emerged. At a basic level, there were questions about whether research funding is being directed to areas where most benefit could be gained - in some cases changes in human behaviours might be an important step towards preventing outbreaks of infection; much epidemiological research is carried out in the developed world - perhaps the least likely place for pandemic infectious to emerge. The need for equitable benefit-sharing when research is carried out in developing countries was also highlighted as a matter for urgent consideration. Importantly, concerns were raised about to the extent to which technologies and scientific knowledge that we already have are being turned into practical applications - there is a perceived imbalance between the funding that supports basic research and that directed towards translation.
Aravinda Chakravarti, Chris Gunter, Louisa Flintoft, Magdalena Skipper
