Technologies for Proteome-Wide Discovery of Extracellular Host-Pathogen Interactions

Martinez-Martin, Nadia

Discovery. Pathogens are among the most intriguing and prominent drivers of human evolution. Humans have adapted to the pressure imposed by microorganisms through genomic diversification, particularly through variation of genes involved in immune system function, constantly challenged by the rapidly coevolving pathogen genomes. The advent of new technologies such as next-generation sequencing and the computational tools associated have opened new avenues for the study of human genetics, making it possible to evaluate the contribution of genetic diversity to susceptibility to infection at the genomic level. The emergence of datasets of genomic variation in multiple human populations, as well as pathogen genomes, allows detection of signatures of selection, which can be exploited to identify genes with major roles in immunity (for an excellent review see [138] ). Remarkably, the cell surface-expressed receptors are among the most polymorphic gene families in mammals, subjected to strong positive selection and rapid evolution, in many instances possibly driven by pathogen molecules that remain unknown [87, [139] [140] [141] . Polymorphisms in receptors and immunomodulatory genes contribute to the natural susceptibility of different individuals to infection [142] [143] [144] , as illustrated by protection against HIV infection in individuals carrying homozygous polymorphisms in the viral coreceptor CCR5 [145] . The identification and further study of genes under positive selection may represent a mainstream approach to dissect novel genes involved in disease and hostpathogen interaction. A notable example is the identification of glycophorin B as the erythrocyte receptor for P. falciparum protein EBL-1 through examination of highly polymorphic genes in populations from malaria-endemic regions [50] . Further population genetics studies promise key insights into novel immunological mechanisms and have the potential to provide molecular details that will ultimately help design effective therapies.