Human genetics of intracellular infectious diseases: molecular and cellular immunity against mycobacteria and salmonellae

The ability to develop adequate immunity to intracellular bacterial pathogens is unequally distributed among human beings. In the case of tuberculosis, for example, infection with Mycobacterium tuberculosis results in disease in 5-10% of exposed individuals, whereas the remainder control infection effectively. Similar interindividual differences in disease susceptibility are characteristic features of leprosy, typhoid fever, leishmaniasis, and other chronic infectious diseases, including viral infections. The outcome of infection is influenced by many factors, such as nutritional status, co-infections, exposure to environmental microbes, and previous vaccinations. It is clear, however, that genetic host factors also play an important part in controlling disease susceptibility to intracellular pathogens. Recently, patients with severe infections due to otherwise poorly pathogenic mycobacteria (non-tuberculous mycobacteria or Mycobacterium bovis BCG) or Salmonella spp have been identified. Many of these patients were unable to produce or respond to interferon gamma, due to deleterious mutations in genes that encode major proteins in the type 1 cytokine (interleukin 12/interleukin 23/interferon gamma) axis (interleukin 12p40/interleukin 23p40, IL12 receptor beta1/IL23 receptor beta1, interferon gamma receptors 1 and 2, or signal transducer and activator of transcription 1). This axis is a major immunoregulatory system that bridges innate and adaptive immunity. Unusual mycobacterial infections were also reported in several patients with genetic defects in inhibitor of NFkappaB kinase gamma, a key regulatory molecule in the nuclear factor kappaB pathway. New findings discussed in this review provide further and sometimes surprising insights into the role of type 1 cytokines, and into the unexpected heterogeneity seen in these syndromes.

Susceptibility to leprosy is associated with PARK2 and PACRG.

Leprosy is caused by Mycobacterium leprae and affects about 700,000 individuals each year. It has long been thought that leprosy has a strong genetic component, and recently we mapped a leprosy susceptibility locus to chromosome 6 region q25-q26 (ref. 3). Here we investigate this region further by using a systematic association scan of the chromosomal interval most likely to harbour this leprosy susceptibility locus. In 197 Vietnamese families we found a significant association between leprosy and 17 markers located in a block of approx. 80 kilobases overlapping the 5' regulatory region shared by the Parkinson's disease gene PARK2 and the co-regulated gene PACRG. Possession of as few as two of the 17 risk alleles was highly predictive of leprosy. This was confirmed in a sample of 975 unrelated leprosy cases and controls from Brazil in whom the same alleles were strongly associated with leprosy. Variants in the regulatory region shared by PARK2 and PACRG therefore act as common risk factors for leprosy.