## 5 Mycobacteria Infection
### Human Infection  
_Mycobacterium_ species can be classified as strict or opportunistic pathogens, according to the relationship established with the host [12]. The research interest and focus in the _Mycobacterium_ field has been centered on two of the most clinically relevant strict pathogens for humans, _M. tuberculosis_ and _M. leprae_. Whilst unprecedented changes occur worldwide, populations aging and the underlying development of chronic conditions thread the ground for the increasing prominence of NTM as opportunistic pathogens. Most contacts with NTM in humans are transient and self-curing colonization, with the immune system being able to clear the bacilli in most immunocompetent patients, however in individuals with risk factors an infection might be established. Several routes of infection have been proposed including (1) aerosolization and inhalation, (2) swallowing and aspiration, and (3) introduction into wounds. The main source of nosocomial infection is water sources due to their low total microbial burden, leading to a proliferation of resistant and oligotrophic bacteria, among them NTM, together with the direct contact with the oronasal cavity and the possibility of aerosolization [243]. For that reason, most cases of NTM infection in humans have been reported due to contact with hot-tub use [183], showering [31], faucet use [244], gardening [240], commercial farming [245], aerosolized metalworking fluids [172], and tending of aquariums [246]. However, the existence of huge lag time (of 1 to 10 years) between estimated colonization and diagnosis of the disease makes it very difficult to accurately pinpoint the specific source [138]. In addition, inhalation, ingestion, and inoculation from environmental sources are also shown routes of transmission. There is no established evidence of human-to-human transmission. The slow-growing strains of NTM possess a higher potential to become pathogenic due to their close taxonomic relatedness to obligate pathogens that colinks with biological traits endorsing resilience to the host environment [247]. According to the available data, the incidence of NTM disease varies considerably with NTM species, geographic distribution, sex, race/ethnicity, age, and risk factors (e.g., comorbidities). While initial reports described older male patients with predisposing conditions, nowadays nearly 80% of patients are middle-aged or elderly females [176]. Pulmonary disease caused by NTM usually occurs in individuals that are sensitized by other lung-associated diseases, such as chronic obstructive pulmonary disease (COPD), changes in lung and chest architecture, \(\alpha\)-1-antitrypsin deficiency, cystic fibrosis, heterozygosity for cystic fibrosis transmembrane conductance regulator (CFTR) mutations, gastric reflux disease, rheumatoid arthritis, and immunodeficiency or immunosuppression due to human immunodeficiency virus (HIV) infection, organ transplant, cancer, or chemotherapy [73]. Additionally, increased susceptibility of human hosts to NTM has been observed due to mutations in five genes (_IFNGR1_, _IFNGR2_, _IL12 RB1_, _IL12B_, and _STAT1_) [195]. The major manifestations of NTM infection are pulmonary, in the lymphatic system, ostearticular, and skin and soft tissue [240]. Disseminated disease via hematogenous spread has also been described. Pulmonary infections are the most common, originating from aerosolized particles from water or soil sources, with a clinical presentation similar to TB [248]. Regarding extra-pulmonary infections, localized lymphadenitis (enlargement of one or more lymph nodes resulting from inflammation), is common in children between 1 and 5 years old and mostly caused by MAC, _M. scrofulaceum_, _M. malmoense_, and _M. hemophilum_[249]. Osteoarticular infections are rare since their development is usually driven by inoculation of the NTM for contiguous infection due to surgical procedures, penetrating trauma, injuries, or needle injections [250]. The most frequent NTM isolated in these cases are _M. chelonae_, _M. hemophilum_, _M.