Genetic susceptibility to childhood infections

There has been increasing recognition in recent years that genetic factors play a role in determining both susceptibility and outcome of many infectious diseases. In the case of tuberculosis, one-third of the world's population is infected by Mycobacterium tuberculosis but clinical disease develops in only a small proportion of cases. Familial occurrence of cases, twin studies and differences in racial susceptibility have all suggested that genetic factors play a role in determining susceptibility to tuberculosis. Studies in mice have identified a number of key genes controlling murine susceptibility to tuberculosis including the macrophage expressed NRAMP gene, the interferon gamma and IL-12 receptor genes, the interferon gamma gene, and the TNF receptor gene. Over the past 5 years a number of human genes controlling susceptibility to mycobacteria have also been identified. Our group at Imperial College identified mutations in the interferon gamma receptor gene as the cause of the unique susceptibility to atypical mycobacterial infection in early childhood. Other mutations in the same gene have now been shown to control susceptibility to both BCG and tuberculosis in other familial cases and recently mutations in the IL-12 receptor gene have also been shown to control susceptibility to both mycobacteria and salmonella infections. In population studies polymorphisms in the NRAMP gene have recently been associated with tuberculosis in West Africa. The role of polymorphisms in many of the genes controlling cytokines or their receptors in tuberculosis is currently under intensive investigation. Meningococcal disease is an important bacterial infection in many tropical countries particularly in sub-Saharan Africa. Although complement deficiencies have long been established as being important in determining susceptibility to the meningococcus, there is now evidence that mannosebinding lectin which controls the recently recognized third pathway of complement activation is also important in controlling susceptibility to meningococcal disease. Polymorphisms in the TNF promotor region have been associated with the increased risk of cerebral malaria. More recently the same polymorphisms have also been associated with a poor outcome from meningococcal disease. The polymorphisms in the plasminogen activator inhibitor gene which control the plasma levels of this important inhibitor of the thrombolytic pathway have now been shown to be important determinants of outcome from meningococcal disease. This growing body of data suggests that host factors are important determinants of both severity and outcome of many childhood infections.