Pathogenesis of nontuberculous mycobacterial infections

INTRODUCTION — Mycobacteria other than Mycobacterium tuberculosis and Mycobacterium leprae are generally free-living organisms that are ubiquitous in the environment (table 1). They have been recovered from surface water, tap water, soil, domestic and wild animals, milk, and food products. Although nontuberculous mycobacteria (NTM) can inhabit body surfaces and secretions without causing disease, they can, in broad terms, induce four distinct clinical syndromes. (See "Overview of nontuberculous mycobacterial infections".)

●Progressive pulmonary disease is usually associated with bronchiectasis or chronic obstructive lung disease and is primarily caused by Mycobacterium avium complex (MAC) Mycobacterium kansasii and Mycobacterium abscessus, especially in older persons.

●Superficial lymphadenitis, especially cervical lymphadenitis, in children is mostly caused by MAC, Mycobacterium scrofulaceum, and, in northern Europe, Mycobacterium malmoense (M. tuberculosis is a more common cause of lymphadenitis in tuberculosis-endemic countries).

●Disseminated disease can occur in severely immunocompromised patients.

●Skin and soft tissue infections usually are a consequence of direct inoculation.

The pathogenesis of NTM infections will be discussed here. An overview of NTM infections in patients with and without human immunodeficiency virus (HIV), as well as the microbiology, epidemiology, diagnosis, and treatment of NTM infections are reviewed separately. (See "Overview of nontuberculous mycobacterial infections" and "Overview of nontuberculous mycobacteria (excluding MAC) in patients with HIV" and "Microbiology of nontuberculous mycobacteria" and "Epidemiology of nontuberculous mycobacterial infections" and "Diagnosis of nontuberculous mycobacterial infections of the lungs" and "Treatment of Mycobacterium avium complex pulmonary infection in adults" and "Mycobacterium avium complex (MAC) infections in persons with HIV".)

PULMONARY INFECTION — The pathogenesis of lung disease due to nontuberculous mycobacteria (NTM) is poorly understood. Pulmonary infection with NTM is probably acquired by inhalation, most likely aerosols from natural surface water or from domestic and institutional hot water systems. Gastroesophageal reflux has been associated with MAC lung disease, raising the possibility that initial acquisition may be through ingestion with subsequent aspiration from the stomach [1,2]. (See "Epidemiology of nontuberculous mycobacterial infections".)

Comparative studies with tuberculosis (TB) in the pre-HIV era established that the granulomatous lesions caused by different species of mycobacteria were indistinguishable to trained pathologists [3,4]. Therefore, it is presumed that there are substantial similarities to the pathogenesis of TB.

Mycobacterium avium complex — The observation that pulmonary M. avium complex (MAC) disease is relatively rare, despite the high prevalence of skin test reactivity to MAC in young adulthood [5], suggests that the host immune response is highly effective at containing or eliminating the infecting microbes. Both age and preexisting lung disease or lung injury are major risk factors for active NTM lung disease.

Cellular response — If inhaled, MAC encounters alveolar macrophages. Macrophages bind to MAC through fibronectin receptors, receptors for mannosyl and fucosyl moieties of the mycobacterial cell wall, and complement components such as C3b and C4b [6,7]. Thus, serum enhances phagocytosis of mycobacteria through complement bound to the mycobacterial surface [8]. The multiple pathways by which NTM are able to enter macrophages suggest that the intracellular niche is a favorable adaption for the bacilli if the phagocytes are not primed to kill the bacteria. Bound mycobacteria are taken up in primary phagosomes that fuse with vacuoles in the phagocyte’s cytoplasm and attempt to destroy its contents through acidification, toxic oxygen metabolites, defensins (in neutrophils, small protein molecules that disrupt the bacterial cell wall), and possibly other mechanisms [9,10]. In general terms, MAC is taken up by macrophages and survives and proliferates within vacuoles in their cytoplasm as an intracellular pathogen. Immune-evasion mechanisms by which NTM are able to survive within macrophages include inhibition of phagosome-lysosome fusion, shift in metabolism to a more anaerobic intracellular environment, induction of NTM-related genes that enhance replication, direct inhibition of host macrophage function and lymphocyte proliferation, and possibly through induction of macrophage apoptosis by downregulation of the Bcl-2 gene product that normally inhibits apoptosis [11-15].

Macrophages also process mycobacterial antigens and present them on their surface in conjunction with MHC class I and class II molecules to T lymphocytes. This results in tremendous expansion of T lymphocyte clones that specifically recognize those antigens and forms the basis of both acquired immune responses and immunologic memory that are central to host defense against mycobacteria. This process is exemplified by the delayed hypersensitivity response elicited by the tuberculin skin test. T helper (CD4) lymphocytes recruited to the site of mycobacterial infection secrete IL-2 and interferon gamma that activate macrophages and enhance cytotoxic lymphocyte activity [7]. (See 'Role of cytokines' below.)

If inhaled, MAC survive their initial encounter with alveolar macrophages blood-borne host defenses, lymphocytes and monocytes that differentiate into macrophages are recruited. Lymphocytes ultimately interact with the infected macrophages to induce intracellular destruction of the mycobacteria or to destroy the infected macrophage itself. T helper lymphocytes are the basis of acquired (antigen-specific) immunity, while natural killer (NK) cells are key components of the innate immune response for these pathogens. NK cells are lymphocytes that destroy certain neoplastic or infected cells, targeting cells with a paucity of major histocompatibility complex (MHC) class I surface molecules [16].

These dynamic cellular events are mirrored histopathologically in the formation of granulomas in which infected foci become surrounded by mononuclear inflammatory cells and epithelioid histiocytes. However, the release of cytolytic enzymes and other cytotoxic proteins ultimately may result in the necrosis and encapsulating fibrosis of both infected and adjacent tissues [17]. These events lead to two major forms of pulmonary MAC disease in adults, the fibrocavitary and fibronodular forms described below. (See 'Fibrocavitary disease' below and 'Nodular/bronchiectatic disease' below.)

Furthermore, in one study evaluating the response of mouse monocytes exposed to MAC, heme oxygenase-1 (HO-1) was found to be important for monocyte chemoattractant protein-1 (MCP-1) trafficking, which is necessary for granuloma formation and containment of mycobacterial infection [18]. Well-formed lung granulomas are characteristic of pulmonary NTM disease, whereas patients with disseminated NTM disease associated with immune dysfunction have poorly formed granulomatous inflammation [19]. (See 'Disseminated disease in HIV-infected patients' below.)

Neutrophils have traditionally been viewed as relatively unimportant in defense against mycobacteria. For example, in one study, it was found that human neutrophils released less superoxide anion in response to M. abscessus than to Staphylococcus aureus [20]. Mycobacteria may exploit a neutrophil-rich setting to promote its survival.

This chain of events is presumably similar to that described for tuberculosis; although, in contrast to tuberculosis, a reliable animal model for evaluating nontuberculous mycobacterial disease pathogenesis has not yet been developed. It is not yet known if NTM infection leads to latent infection that later causes reactivation disease or if most NTM lung disease is the result of primary infection.

Role of cytokines — Macrophages elaborate cytokines and other chemical messengers that recruit lymphocytes and other macrophages to the site of the infection, leading to complex interactions between these cell types that enhance killing of these microorganisms. Interleukin-12 (IL-12), tumor necrosis factor-alpha (TNFa), and interferon (IFN) gamma are especially important in the antimycobacterial immune response.

Macrophages that phagocytose mycobacteria respond with production of IL-12 [21], which activates T lymphocytes, and NK cells [22,23]. The NK cells respond to intracellular and extracellular MAC and are stimulated by IL-2, IL-12, and TNFa to release granules containing cytotoxic enzymes that lyse infected cells and also to secrete TNFa and IFN-gamma, which augment macrophage mycobactericidal capacity [16,24,25].

Binding of IL-12 results in the transcription of IL-12 responsive genes, in particular IFN-gamma. IFN-gamma activates neutrophils and macrophages to produce superoxide and nitric oxide, increases surface display of MHC molecules and Fc receptors, decreases lysosomal pH, and increases the intracellular concentration of certain antibiotics [26-28]. IFN-gamma signals ultimately influence IFN-gamma responsive genes such as IL-12, MHC genes, and TNFa [27,29]. The positive feedback loop between IFN-gamma and IL-12 is pivotal in the immune response to mycobacteria. Defects in any of these receptors or cytokine genes may negatively affect the production of IFN-gamma and/or IL-12 and, consequently, enhance mycobacterial susceptibility [30].

The importance of this pathway in susceptibility to infection due to otherwise poorly pathogenic mycobacteria (non-tuberculous mycobacteria or Mycobacterium bovis BCG) is borne out in genetic studies of patients with severe infections due to these organisms [31]. Many of these patients are unable to produce or respond to IFN-gamma due to mutations in genes that encode major proteins in the type 1 cytokine pathway. Similarly, in studies of adults of Asian origin, disseminated nontuberculous mycobacterial infection has been associated with the presence of neutralizing auto-antibodies to IFN-gamma [32] (see "Mendelian susceptibility to mycobacterial diseases: Specific defects"). Additionally, suppressed levels of IFN-gamma and IL-10 have been found in the stimulated whole blood of patients with NTM lung disease [33].

TNF-alpha is produced by activated macrophages and NK cells and is also an important immune modulator for controlling mycobacterial infection. TNFa has a significant additive effect on macrophage killing of MAC [34]. The release of TNF-alpha is stimulated by and is probably responsible for the antimycobacterial effects of IFN-gamma [34]. It appears that TNF-alpha inhibitors used in the treatment of rheumatoid arthritis and other chronic inflammatory conditions may significantly exacerbate nontuberculous mycobacterial infections [35]. (See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)

IL-2 greatly augments the capacity of NK cells to lyse MAC-infected monocytes. NK cells stimulated by IL-2 also enhance intracellular monocyte killing of MAC, again, likely via TNF-alpha [36]. As mentioned above, IL-12 is a major stimulant for T lymphocytes and NK cells to produce IFN-gamma and TNF-alpha. IL-12 release, in turn, is stimulated by IFN-gamma and TNF-alpha [37,38]. Granulocyte-macrophage colony stimulation factor (GM-CSF) is produced by MAC-infected monocytes and NK cells and appears to augment mycobacterial killing [39]. In contrast, IL-6 and IL-10 down-modulate the inflammatory response, especially the effect of TNF-alpha, and are therefore permissive factors for proliferation of intracellular mycobacteria [40,41]. Additionally, transforming growth factor beta (TGF-beta), which can suppress IFN-gamma, is elevated following ex vivo stimulation of blood with live Mycobacterium intracellulare [42].

Immune modulators act in a complicated fashion, and it is difficult to isolate and measure any single aspect of the complicated inflammatory cascade in vivo. However, understanding these processes can produce practical results as illustrated by a family with a monocyte defect in IL-12 production that was associated with disseminated MAC infection in the absence of HIV infection. This defect was overcome by exogenous administration of IFN-gamma in addition to other antimycobacterial therapy, resulting in successful treatment of the disseminated MAC infection [43,44]. Identification of specific genetic defects in the IFN-gamma and IL-12 response pathways, especially receptor deficiencies, has elucidated key pathways in immune surveillance and NTM control and identified other patients at risk for disseminated NTM infection [45]. To date, however, no specific immune deficiency has been identified for patients with NTM lung disease.

Evasion of the host response — Mycobacteria have evolved mechanisms to protect themselves from the host immune response. Biofilm formation and NTM-mediated inhibition of inflammatory cytokine production are mechanisms that can subvert host immunity and promote colonization and subsequent invasion of the bronchial epithelium [15]. Components of the mycobacterial cell wall scavenge reactive oxygen intermediates, block acidification of the phagocytic vacuoles, suppress the synthesis of cytokines, and downregulate lymphocyte proliferation [46-48].

The glycopeptidolipids (GPL) are produced by NTM but not M. tuberculosis. The composition and concentration of GPL vary between NTM species and can impact colony morphology. M. abscessus-containing nsGPL show a smooth morphotype, while those lacking nsGPL manifest as rough morphotypes. M. abscessus smooth variants survive in the environment and are relatively noninvasive. To deter recognition by toll-like receptor 2 (TLR2) present on innate immune cells, GPL of smooth M. abscessus form an outer layer that covers the mycobacterial TLR2 ligand phosphatidyl-myo-inositol mannosides, effectively preventing the glycolipid from being recognized by TLR2 [49]. The more virulent, rough morphotype emerges later, sometimes several years after the initial infection [50]. In the murine model, it was shown that human monocytes eradicated infection by smooth M. abscessus, whereas rough variants persisted and propagated in the intracellular phagosome [51]. Clinical and epidemiologic data also associate rough variants with more severe and persistent pulmonary disease [52]. The triggers for M. abscessus morphotype switching in vivo remain unknown, however, based on whole-genome analysis, switching between forms is likely an infrequent occurrence [53].

M. avium also produces smooth and rough variants, but unlike M. abscessus, the transition between forms is irreversible and caused by the loss of genes involved in GPL biosynthesis [54]. Isolates with smooth-domed colony morphology are less pathogenic than those with smooth-transparent colony morphology. MAC of the smooth-domed colony types elicits greater production of inflammatory cytokines, while smooth-transparent colonial types tend to be relatively silent immunologically, causing little production of cytokines and less vigorous host responses [55,56]. While the absence of nsGPL from M. abscessus facilitates intracellular survival, M. avium ssGPL is required for intracellular survival and impacts cytokine responses, suggesting serovar oligosaccharides contribute to species-specific pathogenesis.

Biofilm formation is a successful survival strategy for environmental NTM. NTM organized in biofilms are difficult to eradicate with common decontamination practices and are resistant to standard disinfectants. Microbial pathogens found in biofilms in vivo are also very resistant to high concentrations of antimicrobial drugs. This resistance may be due to virulence enhancement in biofilms via multiple mechanisms. In one study, three rapidly growing mycobacteria (Mycobacterium smegmatis, Mycobacterium fortuitum, and Mycobacterium chelonae) were able to assemble biofilms on surfaces, and this was associated with the ability to spread on solid media [57]. Investigation into the role of biofilms in the pathogenesis and treatment of NTM disease is in an early stage, but it will likely be important, especially for improving treatment outcomes with these very treatment-refractory organisms.

Host susceptibility — Lung disease due to MAC can be differentiated into two distinct forms: fibrocavitary and nodular/bronchiectatic.

Fibrocavitary disease — In the fibrocavitary form, upper lobe disease occurs most commonly in older male smokers with chronic pulmonary symptoms due to underlying lung disease. Symptoms and radiographic changes may be difficult to differentiate from the underlying disease, but MAC is often easily recovered from the sputum of these patients. These patients are almost universally diagnosed as a consequence of suspected tuberculosis. (See "Overview of nontuberculous mycobacterial infections", section on 'Clinical manifestations'.)

Nodular/bronchiectatic disease — The nodular/bronchiectatic form of MAC lung disease appears most frequently in nonsmoking women over the age of 50 who do not have a known history of underlying lung disease [58,59] but invariably have bronchiectasis at the time of NTM lung disease diagnosis. (See "Overview of nontuberculous mycobacterial infections", section on 'Clinical manifestations'.)

Body morphotype is a possible predisposition to nodular/bronchiectatic MAC lung disease. Some patients appear to have similar clinical characteristics and body types, including scoliosis, pectus excavatum, mitral valve prolapse, and joint hypermobility [33,60-62]. The constellation of phenotypic abnormalities may represent a forme fruste of a connective tissue disease hitherto unidentified and associated with NTM pulmonary disease. However, the mechanism by which this body morphotype predisposes to pulmonary mycobacterial infection is not certain. In one study, whole exome sequencing of patients with NTM lung disease found a significantly higher number of low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue categories compared with controls [63]. This study supports the hypothesis that the predisposition for NTM lung disease in these patients is likely due to bronchiectasis formation resulting from multi-gene abnormalities, although the exact pathways of that formation remain to be determined. Additionally, there are a number of heritable connective tissue disorders that are associated with bronchiectasis and NTM lung disease, including Marfan syndrome [64], hyper-IgE syndrome [65], and congenital contractural arachnodactyly (CCA) [66]. The identification of familial clusters of pulmonary NTM lung disease strongly supports the concept that at least some patients have NTM lung disease as a result of hereditary predispositions [67]. (See 'Genetic predisposition' below.)

There is additional evidence that some of these patients may be predisposed to NTM lung disease because of preexisting bronchiectasis. Some potential etiologies for bronchiectasis in this population include gastroesophageal reflux with chronic aspiration, alpha-1 antitrypsin deficiency, cystic fibrosis [62,68], primary ciliary dyskinesia [69], and connective tissue disorders as outlined above. Of particular interest are patients with bronchiectasis and MAC lung disease who are heterozygous for cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations [62]. Single CFTR mutations appear to occur more frequently in selected populations of MAC patients with bronchiectasis. Although these patients do not meet criteria for frank cystic fibrosis, there is evidence that they have bronchial epithelial ion and water transport abnormalities that might be a mechanism for the development of bronchiectasis [70].

Immune defects — Among patients without HIV infection, no severe or consistent predisposition or immune deficiency has been identified to explain susceptibility to MAC infection. Although familial clusters with NTM (mostly MAC) infections have been identified, no specific immune defect was documented [67].

One study that included patients with both cavitary and noncavitary MAC lung disease found that Mycobacterium-stimulated peripheral blood monocytes (PBMC) produced higher concentrations of interleukin 10 (IL-10) but lower concentrations of interferon (IFN)-gamma, IL-12, and tumor necrosis factor alpha (TNF-alpha) compared with PBMC from control subjects with a delayed hypersensitivity skin test response to M. avium sensitin. This suggested that IFN-gamma, TNF-alpha, and IL-12 may contribute to protection against MAC lung disease, whereas IL-10 may be immunosuppressive [71].

Another small case series noted a decreased IFN-gamma response to mitogen stimulation in five patients with MAC lung disease, and it did not improve in two patients despite successful antimycobacterial therapy [72]. A prospective study of patients with NTM nodular/bronchiectatic disease found no cytokine pathway abnormalities to explain the apparent susceptibility to MAC infection [62].

Genetic predisposition — Research on susceptibility to NTM infection has shifted focus to potential genetic predispositions. Emerging evidence suggests that NTM pulmonary disease is a multigenic disease, in which combinations of variants across gene categories, plus environmental exposures, increase susceptibility to infection.

In a study of 69 patients with NTM lung disease and 18 unaffected family members, whole-exome sequencing identified more low-frequency, protein-affecting variants in immune, cystic fibrosis transmembrane regulator (CFTR), cilia, and connective tissue categories among the patients than among controls [63]. In a subsequent study, variant-level and gene-level parametric linkage analyses were performed on nine NTM pulmonary disease families (16 affected and 20 unaffected individuals), and a gene-level association analysis were performed on those families and 55 sporadic cases [73]. All genes on chromosome 6 were tested in the gene-level linkage analysis. The TTK protein kinase gene on chromosome 6q14.1 was the most significant association with NTM infection. The TTK gene encodes a protein kinase that is essential for mitotic check points and the DNA damage response.

Mycobacterium kansasii infection — M. kansasii lung disease most closely resembles typical TB in its clinical and radiographic features. Older age, male sex, smoking, and underlying lung disease are common features. Unlike most NTM, M. kansasii is not an environmental contaminant or colonizer (M. kansasii, so far, has been isolated only from municipal water supplies); thus, even a single positive culture may be considered diagnostic of disease (although diagnosis of M. kansasii lung disease should still be based on ATS diagnostic criteria).

Rapidly growing mycobacteria — Rapidly growing mycobacteria, especially M. abscessus, also cause lung disease. In contrast to the fibrocavitary form of MAC and M. kansasii, affected patients tend to be females, nonsmokers, and do not have preexisting lung disease similar to patients with fibronodular MAC lung disease. In fact, M. abscessus is sometimes recovered from sputum of patients with MAC lung disease [74]. Noteworthy exceptions include cystic fibrosis, prior granulomatous disease, lipoid pneumonia, and esophageal dysmotility (eg, achalasia) with chronic vomiting [74,75]. As in other forms of NTM lung disease, symptoms are indolent and include cough, fever, and weight loss.

Other — Mycobacterium simiae, Mycobacterium xenopi, and M. malmoense have also been reported to cause chronic progressive granulomatous lung disease [76-78]. The pathogenesis of these infections, as distinct from tuberculosis and MAC lung disease, has not been elucidated, although M. xenopi and M. malmoense are associated with cigarette smoking and chronic obstructive lung disease in Europe.

DISSEMINATED DISEASE IN HIV-INFECTED PATIENTS — Nontuberculous mycobacteria (NTM) infection in patients with HIV infection primarily presents as disseminated disease in association with very low CD4 cell counts (usually below 100 cells/microL) in resource-rich countries. Exposure has been documented from potable hot water [79]. Disseminated NTM disease occurred in 5.5 percent of acquired immunodeficiency syndrome (AIDS) cases reported to the Centers for Disease Control and Prevention (CDC) from 1981 to 1987, 96 percent of which were due to M. avium complex (MAC) [80]. However, effective MAC prophylaxis with clarithromycin and azithromycin, as well as the advent of potent antiretroviral therapy, has led to a decline in the incidence of disseminated disease. (See "Epidemiology of nontuberculous mycobacterial infections", section on 'Disseminated disease'.)

Initial observations on disseminated MAC disease in patients with AIDS found that heavy bacteremia, widespread disease, and a high tissue burden of organisms were typical [81]. However, these reports focused on the more severe and conspicuous manifestations of this disease. More recent data have demonstrated that this illness develops progressively from bacteremia arising from initially localized infection, especially from a respiratory or gastrointestinal source [82-85]. In one large series, among AIDS patients with CD4 lymphocytes <50/mL, nearly 60 percent of those with respiratory or fecal MAC developed MAC bacteremia within one year [82]. The risk of MAC bacteremia was increased 2.3-fold for patients with respiratory MAC and 6.0-fold for patients with fecal MAC compared to those without respiratory or fecal MAC, respectively. Patients may be infected simultaneously with two different strains of MAC and these strains may have different susceptibility patterns [86].

At first, bacteremia from these localized infections may be infrequent and intermittent. In patients followed with serial blood cultures through death and postmortem examination, the tissue burden of organisms and the number of tissues involved increased in direct proportion to the time after the initial positive blood cultures and to the fraction of blood cultures that were positive [83]. Disseminated MAC in AIDS is very rare in countries in which tuberculosis is endemic, despite the presence of MAC in the environment and skin test evidence of MAC exposure in these regions. These observations suggest a role for cross-protective immunity from childhood BCG and/or latent TB [87,88].

Thus, the pathogenetic model proposes that mycobacteria from the environment infect a mucosal surface (gut or lung), multiply locally, and eventually enter the bloodstream and disseminate, seeding other organs and tissues [84,85]. As metastatic foci of infection progress, bacteremia becomes more constant and heavier, and tissue involvement increases.

LYMPHADENITIS — Nontuberculous mycobacteria (NTM) can cause lymphadenitis, primarily in children younger than five years of age. The frequent involvement of cervical lymph nodes suggests that ingestion and direct tissue penetration by the organism is the usual pathogenesis of this disease. This is discussed in greater detail separately. (See "Nontuberculous mycobacterial lymphadenitis in children".)

SUMMARY

●Mycobacteria, other than Mycobacterium tuberculosis and Mycobacterium leprae, are generally free-living organisms that are ubiquitous in the environment (table 1). They have been recovered from surface water, tap water, soil, domestic and wild animals, milk, and food products. Although nontuberculous mycobacteria (NTM) can inhabit body surfaces and secretions without causing disease, they can, in broad terms, induce four distinct clinical syndromes:

•Pulmonary disease is usually associated with bronchiectasis or chronic obstructive lung disease and caused primarily by Mycobacterium avium complex (MAC) Mycobacterium kansasii and Mycobacterium abscessus, especially in older persons.

•Superficial lymphadenitis, especially cervical lymphadenitis, in children is caused mostly by MAC, Mycobacterium scrofulaceum, and, in northern Europe, Mycobacterium malmoense (M. tuberculosis is a more common cause of lymphadenitis in tuberculosis-endemic countries).

•Disseminated disease can occur in severely immunocompromised patients.

•Skin and soft tissue infection usually is a consequence of direct inoculation. (See 'Introduction' above.)

●Pulmonary infection with NTM is probably acquired by inhalation; most likely aerosols from natural surface water or from domestic and institutional hot water systems. (See 'Pulmonary infection' above.)

●The observation that pulmonary MAC disease is relatively rare, despite the high prevalence of skin test reactivity to MAC in young adulthood, suggests that the host immune response is highly effective at containing or eliminating the infecting microbes. If inhaled MAC survive their initial encounter with alveolar macrophages, blood-borne host defenses are called into play, most importantly lymphocytes and monocytes that differentiate into macrophages. MAC is taken up by macrophages and survives and proliferates within vacuoles in their cytoplasm as an intracellular pathogen. (See 'Mycobacterium avium complex' above.)

●Lymphocytes ultimately interact with the infected macrophages to induce intracellular destruction of the mycobacteria or to destroy the infected macrophage itself. T helper lymphocytes are the basis of acquired (antigen-specific) immunity, while natural killer (NK) cells are key components of the innate immune response to these pathogens. This interaction between macrophage, lymphocyte, and microbe is the focal point in the pathogenesis and immunology of MAC infection that leads to granuloma formation, successful control of the infection, or clinical disease. This chain of events is similar to those described for tuberculosis. (See 'Mycobacterium avium complex' above.)

●NTM infection in patients with AIDS primarily presents as disseminated disease in association with very low CD4 lymphocyte counts (usually below 100/microL). In such patients, mycobacteria from the environment infect a mucosal surface (gut or lung), multiply locally, and eventually enter the bloodstream and disseminate, seeding other organs and tissues. As metastatic foci of infection progress, bacteremia becomes more constant and heavier, and tissue involvement increases. (See 'Disseminated disease in HIV-infected patients' above.)

Disseminated NTM disease is also seen in patients with rare genetic defects that alter IL-12 and IFN-gamma production and in association with TNF-alpha inhibitors.

●NTM can cause lymphadenitis, primarily in children younger than five years of age. The frequent involvement of cervical lymph nodes suggests that ingestion and direct tissue penetration by the organism is the usual pathogenesis of this disease. (See 'Lymphadenitis' above.)