Genetic dissection of the molecular pathogenesis of severe infection

A fundamental question for the intensivist is why some individuals but not others succumb to life-threatening infection. A growing body of evidence indicates that both the risk of acquiring infection and the risk of developing severe complications are determined by host genetic factors. These include a number of single gene defects with devastating consequences, e. g. interferon-gamma receptor mutations that lead to fatal infections with ubiquitous mycobacteria, but such examples are relatively rare. Of greater importance for routine clinical practice is the potentially vast number of genetic variants with subtle effects on the regulation or function of specific immunological, physiological and metabolic mediators. Such polygenic traits do not obey simple patterns of familial segregation seen for monogenic disorders, and their clinical investigation is further complicated by the environmental variability of infectious exposure. Recent advances in this field have therefore largely stemmed from hospital-based case-controlled studies that have uncovered disease associations with specific DNA polymorphisms in candidate gene regions. For example, tumour necrosis factor polymorphisms have been associated with susceptibility to malaria and other infections; chemokine receptor polymorphisms with susceptibility to HIV; natural resistance-associated macrophage protein 1 with tuberculosis; and mannose binding lectin polymorphisms with meningococcal disease. A much greater number of genetic associations will emerge as the full extent of human genomic diversity becomes known. The challenge for clinical investigators is to generate an epidemiological framework for population- and family-based association studies, which is sufficiently robust to exclude population artifacts and sufficiently powerful to be able to dissect true disease-causing polymorphisms from linked genetic markers. In the long term this approach promises to identify host mediators that are critical for pathogenesis and immunity and to yield molecular insights into the complex processes of human gene regulation. This information is likely to be of considerable value in designing more effective approaches to the treatment and prevention of life-threatening infectious disease.