Genetic determinants of virulence and drug resistance of mycobacterium avium subsp. hominissuis : A causative agent of mycobacteriosis in humans

Abstract

Among the members of the large group of non-tuberculous mycobacteria (comprising more than 180 species), M. avium subsp. hominissuis (MAH) is the most significant causative agent of pulmonary infection in immunocompetent individuals as well as disseminated infection in immunocompromised hosts, e.g. human immunodeficiency virus (HIV)-positive patients. Due to increased incidence rate of mycobacteriosis, especially in HIV infection, much still need to be learnt about the MAH genetic control and virulence mechanisms. Deciphering the genome contents of the M. avium strain 104 (isolated from an AIDS patient with disseminated MAH disease) allowed to compare genome sequences of M. avium strains to gain insights into genomic diversity associated with variable hosts and environments. Comparative genome analysis of MAH strains isolated from patients with pulmonary and disseminated forms of mycobacteriosis revealed differences in the structure of the genome, affecting the key virulence genes. This review provides current data on the genetic determinants of MAH virulence associated with the initial phase of infection. Several mycobacterial virulence-associated gene families, such as mce (mammalian cell entry), mmp (mycobacterial membrane proteins), pe/ppe and esx expressed by MAH during human infection are thought to be crucial for adhesion, entry, survival, and reproduction inside host macrophages. The genetic mechanisms of MAH survival in human macrophage cell culture as well as mice exposed to toxic effects of reactive oxygen, nitric oxide, bactericidal proteins (cathelicidin) are discussed. The MAH survival in the latency-like state is important for pathogen dissemination. Some genetic and phenotypic features of MAH (absence of a cord factor, presence of plasmids, potential to “switch” morphological types of colonies) are compared with M. tuberculosis. In addition, we summarized current state of MAH drug discovery, a role of MAH intrinsic multidrug resistance, genetic control, as well as mechanisms underlying formation of resistance to various groups of antibiotics in MAH strains.