Abstract
Rapidly growing mycobacteria (RGM) are environmental organisms classified under the broader category of nontuberculous mycobacteria. The most common RGM to cause human diseases are Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, and Mycobacterium massiliense. Infections due to the RGM are an emerging health problem in the United States. Chronic pulmonary disease and skin/soft-tissue infections are the two most common disorders due to these organisms. Clinical outcomes in the treatment of M. abscessus infections are generally disappointing. Because less is known about the nature of the immune response to M. abscessus than for tuberculosis, we herein highlight the major clinical features associated with infections due to M. abscessus and other RGM, and review the known host immune response to RGM, drawing from experimental animal and clinical studies. Based on in vitro and in vivo murine models, Toll-like receptor 2, dectin-1, tumor necrosis factor (TNF)–α, IFN-γ, leptin, T cells, and possibly neutrophils are important components in the host defense against RGM infections. However, excessive induction of TNF-α by the R morphotype of M. abscessus may allow it to be more pathogenic than the S morphotype. Clinical observations and/or genetic studies in humans corroborate many of the findings in animals in that those with cell-mediated immunodeficiency, genetic defects in IFN-γ–IL-12 axis, and those individuals on TNF-α blockers are at increased risk for nontuberculous mycobacteria infections, including the RGM. However, much remains to be discovered on why seemingly healthy individuals, particularly slender postmenopausal women with thoracic cage anomalies, appear to be at increased risk.
Nontuberculous mycobacteria (NTM), which includes rapidly growing mycobacteria (RGM), are environmental microorganisms found in soil, bioaerosols, and natural and chlorinated water (1, 2). The prevalence of chronic lung disease due to NTM is increasing, and, in many areas of the United States, exceeds that of Mycobacterium tuberculosis (3).
NTM can form biofilms on water-exposed surfaces, such as in pools, hot tubs, and water pipes, which makes them even more resistant to common disinfectants, including chlorine (2). The most common NTM to cause human infections in the United States are Mycobacterium avium complex, Mycobacterium kansasii, and certain strains of RGM. RGM were originally identified as mycobacteria that, on subculture, formed colonies within 7 days. More recently, species-specific identification of RGM are made by sequencing of the 16S RIBOSOMAL RNA (16S rRNA) gene and/or pattern of restriction fragments of the HEAT SHOCK PROTEIN 65 (hsp65) gene (4).
The three most common RGM that cause diseases in man are Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum. M. abscessus was previously classified as a subspecies of M. chelonae, but is now recognized as a separate species. Precise classification of these organisms is in flux, as evinced by the finding in Korea that nearly 50% of organisms in the M. chelonae–M. abscessus group were identified to be Mycobacterium massiliense, based on PCR restriction analysis and comparative sequence analysis of 16S rRNA, rpoB, and hsp65 genes (5). The two most common disorders due to these organisms are skin/soft tissue infections and chronic lung disease, the latter manifested by bronchiectasis, nodules, and cavitations.
Little is known about the nature of the effective immune response to RGM. Because treatment success against RGM is generally poor, with an estimated sputum conversion rate of 50–60% even in the best circumstances (6), a greater understanding of host immune responses to these organisms is needed. We discuss below the microbial and host factors that help determine whether a pathogenic infection occurs.
Ehlers and Richter studied the susceptibility of wild-type and IFN-γ knockout (KO) mice to various NTM species that are uncommon to rare causes of human diseases, such as Mycobacterium branderi, Mycobacterium celatum, and Mycobacterium bohemicum, among others (7). Although some NTM species were eliminated by both the wild-type and IFN-γ KO mice, others replicated well in both mice strains, whereas others replicated only in the IFN-γ KO mice (7). These findings indicate that intrinsic factor(s) of the organism help determine whether an established infection develops after exposure to NTM. Even within the same mycobacterial species, different morphotypes can display differences in pathogenecity. For example, based on colony morphology on solid growth medium, two major variants of M. abscessus exist—the smooth (S) and rough (R) morphotypes. The S morphotype contains abundant glycopeptidolipids (GPLs) in its cell wall and is the predominant morphotype in the environment, consistent with the role of GPLs in biofilm formation. With serial passage of the S strain in the laboratory or replication in vivo, spontaneous reversion from the S to the R morphotype can occur, and this latter revertant is more likely to cause invasive disease (8). Thus, S variants of M. abscessus are typically found at early stages of infections, and R variants generally appear several years later, replacing the initial S variant. An example of this phenomenon was illustrated by a recent report of a patient with cystic fibrosis (CF) with chronic lung disease due to an S morphotype of M. abscessus, who, many months later, developed sepsis and acute lung injury. This development was coincident with the emergence of an R morphotype with the same clonality, leading the authors to speculate that conversion from the S to the R morphotype resulted in a more fulminant illness (9). This S-to-R conversion of M. abscessus is also seen experimentally in that intravenous infection of the S variant in Ig μ chain KO mice resulted in the recovery of the R morphotype in their organs 90 days later (10). Importantly, the R strain was found to be hyperlethal compared with the S strain. Although tumor necrosis factor (TNF)–α is considered to be protective against mycobacterial infections, one proposed mechanism for the increased lethality of the GPL-deficient R strain is that it induced excess amounts of TNF-α, resulting in increased pathologic tissue damage (10, 11). Rhoades and colleagues (12) recently reported that expression of GPL by the S morphotype masked the recognition of the mycobacterial cell wall component, phosphatidyl-myo-inositol mannosides, by macrophage Toll-like receptor (TLR) 2, interfering with pathogen recognition by the host innate immune system, and blocking TNF-α induction and subsequent inflammation. They further hypothesized that the R morphotype, with loss of the “cloaking” molecule, GPL, is more likely to cause inflammation and invade lung tissues. In contrast to these findings, Sampaio and colleagues (13) found that, although M. abscessus induced more cytokines and chemokines than M. avium avium or M. avium intracellulare in human peripheral blood mononuclear cells, there was no difference in the induction of TNF-α by the R and S morphotypes of M. abscessus.
Although murine models of NTM/RGM infections, usually associated with disseminated disease in susceptible animals, do not necessarily mirror the isolated lung disease seen in most patients with such infections, they do provide a glimmer of the important host immune factors. For example, increased susceptibility to disseminated tuberculosis in mice with genetic disruption of TNF-α receptor, IFN-γ, or CD4+ have accurately predicted the importance of these host immune components in pulmonary tuberculosis. A limited number of studies have investigated the role of innate immunity in RGM infections (14–16). In a murine model of M. fortuitum infection, it was found that the early neutrophilic response was an important contributor in controlling the infection (14). Although increased neutrophilic infiltration in the lungs was observed in the more susceptible leptin-deficient OB/OB mice to an aerosol M. abscessus infection (16), it was not specifically addressed whether neutrophils were important in the host defense or pathogenesis of M. abscessus lung infection. Shin and colleagues (15) reported that, in murine macrophages infected with M. abscessus, there is a transient interaction between the pattern recognition receptors, TLR2 and dectin-1, present on cell surfaces, resulting in the induction of host protective cytokines, such as TNF-α, IL-6, and p40 subunit of IL-12, and enhanced phagocytosis. Sampaio and colleagues (13) also found that, in murine macrophages, M. abscessus induced TNF-α production through TLR2 and myeloid differentiation 88 signaling pathways.
The adaptive immune response has been better characterized with RGM infections. Because murine studies have demonstrated the importance of CD4+ and CD8+ T cells in the acquired immune response to other mycobacterial infections, particularly M. tuberculosis (17), T cells are likely an essential component of the protective immune response against M. abscessus. In a seminal study, Byrd and Lyons (18) infected BALB/c and SCID mice with a high inoculum of M. abscessus (105 organisms per mouse) intratracheally (18). In both mouse strains, M. abscessus persisted in the lungs up to the observed period of 28 days after infection. The BALB/c mice controlled the infection in the spleen better than the SCID mice, suggesting that, similar to tuberculosis and leprosy, cell-mediated adaptive immunity is crucial in the host defense against M. abscessus. Rottman and coworkers (19) infected mice with genetic disruption to Rag2, CD3ε, or μMT, and showed that both the Rag2−/− and CD3ε−/− mice had significantly greater burden of viable M. abscessus in the liver and spleen, by a few orders of magnitude, than wild-type mice; in the μMT−/− mice, there was significantly greater M. abscessus isolated from the liver, but not from the spleen. These findings indicate that murine control of M. abscessus infection was primarily T cell dependent in the spleen, and both T and B cell dependent in the liver. In addition, they used the same M. abscessus infection model in the IFN-γ receptor 1 KO mice and TNF-α KO mice, and found that mice with either genetic disruption had significantly more M. abscessus isolated from their livers and spleens than the wild-type mice. This indicates that TNF-α and IFN-γ were essential in the host defense against M. abscessus in the murine model (19).
We characterized the lung immune responses in mice and guinea pigs exposed to aerosolized infection with M. abscessus (16). For the murine studies, we compared the ability of wild-type C57BL/6 mice with that of leptin-deficient OB/OB mice and the IFN-γ KO mice to defend against M. abscessus infection. The reason for examining the OB/OB mice was that leptin is known to enhance immune function against microbial pathogens, including the ability to skew undifferentiated T helper (Th) type 0 cells to the IFN-γ–producing Th1 phenotype (20). Wieland and colleagues (21) had previously shown that leptin-deficient mice had reduced lung IFN-γ levels and greater susceptibility to M. tuberculosis than did C57BL/6 mice. Neither C57BL/6 nor OB/OB mice developed a productive infection when they were challenged with a low-dose aerosol (∼100 organisms per mouse) of M. abscessus (16). In contrast, when challenged with a high-dose aerosol (∼1,000 organisms per mouse), there was a productive infection in both mice strains. Whereas C57BL/6 mice were able to clear M. abscessus from the lungs and spleen by 30 and 60 days, respectively, it took 30 days longer to clear M. abscessus from the lungs of the OB/OB mice. By 60 days of the study period, there was still abundant and viable M. abscessus recoverable from the spleens of the OB/OB mice (16). Efficient eradication of M. abscessus by the C57BL/6 mice was associated with an early influx of IFN-γ–producing CD3+CD4+ T cells into the lungs. In contrast, the more susceptible OB/OB mice had a delay in the influx of these T cells into the lungs (16).
In contrast to the C57BL/6 and OB/OB mice, IFN-γ KO mice challenged with either a low- or a high-dose aerosol of M. abscessus showed a progressive lung infection even at 60 days after infection, despite a robust influx of T cells, macrophages, and dendritic cells into the lungs (16). By Day 60 after infection, the extensive migration of immune cells into the lungs ultimately resulted in widespread pulmonary consolidation in the IFN-γ KO mice, likely contributing to worsening lung function. Furthermore, with high-dose aerosol challenge of the IFN-γ KO mice, we observed the emergence of IL-4– and IL-10–producing CD4+CD25+ and CD8+CD25+ T regulatory cells in the lungs, whereas this was not seen with a low-dose aerosol infection. These studies indicate that IFN-γ–producing T cells and leptin are important in the host defense against M. abscessus lung infection. In addition, based on our experimental findings, we posit that a larger inoculum of M. abscessus is also more likely to result in a productive infection, and that this inoculum dependency may be due, in part, to the induction of the Th2 or Th2-like cytokine responses with larger infectious doses (16). In addition, the sustained and progressive infection seen in the IFN-γ KO mouse provides a useful in vivo model in which to test novel drugs against M. abscessus.
Parti and colleagues (22) infected BALB/c mice with 5 × 107 M. fortuitum per mouse intravenously, and showed recovery of organisms from the liver, lungs, spleen, and kidneys. Curiously, the kidneys had the greatest sustainable number of organisms recovered among the organs, although the reason for this is not known.
The host immune events that are initiated in the lungs after M. abscessus or another RGM infection in experimental animals are relatively well characterized (8, 14, 16, 18, 19, 22). However, few studies have been conducted in the immune response to RGM in human cells. In one such study, M. abscessus induction of TNF-α in primary human monocytes was found to be dependent on TLR2 and the mitogen-activated protein kinase p38 and extracellular signal–regulated kinase (13). Nevertheless, given similarities in the effective host immune response against M. tuberculosis and M. abscessus in the murine model of infection (16, 18, 19), we predict that, in humans, phagocytosis of RGM by antigen-presenting cells, such as alveolar macrophages and dendritic cells, is likely an early occurrence. Autocrine and paracrine activation of dendritic cells by IL-12 p40, and migration of the infected dendritic cells to the regional mediastinal lymph nodes, then occurs where they present mycobacterial antigens to uncommitted T cells, resulting in the differentiation and activation of effector T cells. Additional influx of monocytes, macrophages, B cells, and neutrophils form the granulomatous lesion at the site of mycobacterial replication to contain and prevent further dissemination of the mycobacteria. Cytotoxic CD4+ T cell subsets and CD8+ T cells are also able to produce antimicrobial peptides, such as perforin and granulysin, which can kill intracellular mycobacteria (23, 24).
Using the aforementioned paradigm as a guide, the one obvious clinical example of the importance of cell-mediated immunity in controlling mycobacterial infections is seen in patients with acquired immune deficiency syndrome, where reduction of CD4+ T cells puts such individuals at extreme risk for M. tuberculosis, M. avium complex, and M. kansasii infections. However, it is less clear whether human immunodeficiency virus (HIV) itself predisposes individuals to RGM infections, whether isolated lung disease or disseminated disease, based upon clinical anecdotal observations that RGM disease appears to be less common than disease due to M. avium complex (25). Whether this suggests that RGM may not be controlled by the usual host defenses for M. tuberculosis or M. avium complex, or whether there are reporting biases, is not known (26). In support of the latter possibility of underreporting are published papers that indicate that those infected with HIV, or who have other forms of T cell defects—such as renal transplant recipients—are more susceptible to M. fortuitum (25, 27, 28). It is also possible that, in patients with nonadvanced HIV infection (i.e., CD4 cell count >500/μl), isolated lung disease due to NTM/RGM still occurs, but is likely not reported due to their relative commonality and insidious presentation. A plausible explanation for the paucity of disseminated RGM disease in acquired immune deficiency syndrome is that the emergence of M. abscessus and other RGM infections over the past 10–15 years has overlapped with the widespread use of highly active antiretroviral therapy in patients who are HIV positive. This has likely reduced the frequency of disseminated disease due to these organisms, similar to the marked decline in the number of disseminated M. avium complex infections since the introduction of highly active antiretroviral therapy (29). Further support that cell-mediated immunity is important in host defense against the RGM is seen in a study from Malawi, where individuals with marked dermal reactivity to RGM, but not to the slowly growing mycobacteria, were at a reduced risk of contracting tuberculosis, suggesting that effective immune responses to tuberculosis and RGM may be similar (30).
Despite the fact that NTM are ubiquitous in the environment, only a fraction of individuals exposed to RGM or other NTM develop lung disease. Thus, identification of individuals with medical conditions and/or genetic disorders that predispose them to RGM infections provide a unique opportunity to shed light on what host immune factors are essential in protection against these organisms.
Perhaps the most common predisposing medical conditions to RGM lung diseases are underlying structural lung abnormalities, including bronchiectasis (e.g., as a sequela of tuberculosis, prior NTM infection, or CF), emphysema, and various pneumoconioses, such as silicosis (31, 32). Other conditions that may predispose to RGM lung diseases include α1-antitrypsin (AAT) anomalies (33), achalasia, chronic aspiration (34), neutropenia (35), immunodeficiency, particularly cancer, and the use of TNF-α inhibitors (36, 37).
CF is a common genetic disorder, characterized predominantly by recurrent bacterial lung infections resulting in severe bronchiectasis. Chronic respiratory infections due to NTM—particularly M. abscessus—is also common in patients with CF (32). Whether patients with CF have an intrinsic susceptibility to NTM and/or whether the bronchiectasis provides a suitable milieu for colonization of the environmental mycobacteria is not known. Because individuals with CF have a functional defect of β-defensins, and this antimicrobial peptide has been shown to be important in killing M. tuberculosis and possibly NTM (38), patients with CF may indeed have innate susceptibility to mycobacterial infections.
Individuals with phenotypic anomalies of AAT may be predisposed to NTM, including the RGM (33). In a study of 100 patients with RGM lung disease, 27 (27%) possessed anomalous AAT phenotypes, a frequency that is significantly greater than the estimated prevalence in the U.S. population of approximately 17%. Furthermore, a physiologic concentration of AAT inhibited M. abscessus infection of monocyte-derived human macrophages (33). The implication of this is that AAT may help block entry of M. abscessus into a protective intracellular sanctuary. Because a pharmacologic serine protease inhibitor also inhibited M. abscessus infection of human macrophages, it suggests that inhibition of host cell surface serine proteases is a possible mechanism by which AAT reduced macrophage infection (33).
Five patients with RGM infections in the setting of neutropenia secondary to leukemia treatment have been reported (35). However, it is not known if the neutropenia per se predisposed to the infections and/or if the susceptibility was due to other forms of immunosuppression from the leukemia itself and/or the chemotherapy. There is increasing evidence that neutrophils play a host defense role in tuberculosis, including the ability of macrophages to acquire neutrophilic granules that contain antimicrobial peptides, such as α-defensins (human neutrophil peptide [HNP]–1, HNP-2, and HNP-3) (39). In that the more susceptible leptin-deficient OB/OB mice have greater influx of neutrophils into their lungs after an aerosol infection with M. abscessus than the wild-type C57BL/6 mice, and patients with RGM lung disease have a predominance of neutrophils in their bronchoalveolar lavage (E.D.C., unpublished data), it would be important to elucidate whether activated neutrophils play a role in the clearance of RGM.
In young children with disseminated NTM infections, including those due to RGM, genetic defects in the components of the IFN-γ–IL-12 costimulatory axes have been described (40–42), and are summarized in Figure 1. Although not systematically studied, it is quite unlikely that adults with isolated NTM/RGM lung disease have intrinsic defect in IFN-γ–IL-12 signaling, because they typically are diagnosed with the infections much later in life, usually in the fifth to seventh decades. Rare cases of adults with anti–IFN-γ autoantibodies and NTM infection have been reported, but are associated with disseminated NTM disease rather than isolated lung disease (43).
Figure 1. Genetic defects in the IFN-γ–IL-12 signaling pathways predisposing to mycobacterial infections. See text for discussion. APC, antigen presenting cell; STAT, signal transducer and activator of transcription.
[More] [Minimize]Use of TNF-α blockers for rheumatoid arthritis and inflammatory bowel disease not only predispose individuals to reactivation tuberculosis, but also to RGM infections (36, 44, 45). A report of six children from the Mediterreanean region with disseminated NTM infections, including some due to M. chelonae and M. fortuitum, showed defective TNF-α production in response to endotoxin and IFN-γ in affected children and their parents (46). In contrast to these well described potential risk factors, two separate studies from Thailand reported a total of 36 patients with predominantly lymphadenitis or skin-soft tissue infections due to RGM, with no obvious risk factors (47). Among these patients, only two were HIV positive, and eight had prior infection or coinfection with other opportunistic infections.
Epidemiological studies involving very large numbers of subjects have shown that the body mass index (BMI) inversely correlates with the risk of reactivation of latent tuberculous infection (i.e., thin subjects are more likely to develop active tuberculosis) (48). Conversely, obesity was recently reported to protect against reactivation tuberculosis (49). Clinical experience has led to the view among physicians that a greater than expected proportion of individuals with NTM lung infection have slender body habitus (50). In a recently reported study from the National Institutes of Health (NIH), Kim and colleagues (51) prospectively enrolled 63 patients with NTM lung disease, and confirmed that the slender body morphotype was frequently present. These investigators found that female patients with NTM lung disease were significantly thinner than National Health and Nutrition Examination Survey (NHANES) control subjects, and even thinner than patients with disseminated NTM disease. Measurement of cytokines levels from their blood cells and enumeration of lymphocyte subpopulations showed no evidence of innate or adaptive immunity defects in the patients with NTM lung disease. Okumura and colleagues (52) noted that, in 273 Japanese patients with newly diagnosed M. avium complex lung disease (over two-thirds of whom were women), overall BMI indicated low body weight (i.e., BMIs were 17.9 kg/m2 and 18.4 kg/m2 in those with cavitary or nodular bronchiectasis type, respectively, where BMI < 18.5 kg/m2 is defined as “low body weight” by the Japanese Society of Obesity). Although patients with emphysema may be at increased risk for NTM/RGM lung infections due to structural lung abnormalities, perhaps low BMI with reduced body fat, commonly seen in patients with advanced emphysema, may also increase their risk as well. Although these case series and anecdotal clinical observations on low body weight and NTM lung disease are compelling, none definitively prove that low BMI is an independent risk factor for the development and/or progression of NTM lung disease, because one cannot be certain whether low body weight is the result of the infection. Addressing whether thin body habitus is a risk factor for NTM lung infection will require a large, prospective, long-term study in which body morphometric measurements of subjects are known before their NTM infection, similar to the large-scale studies performed for BMI and risk of reactivation tuberculosis (48, 53, 54).
Nevertheless, there is increasing biological evidence that fat tissues, invariably surrounding lymphoid tissues, modulate immune function (20, 55), and that a lack of fat, as seen in thin individuals, predisposes them to infections (56). Two adipokines that may play a role in modulating susceptibility to infections are leptin and adiponectin. Because the amount of leptin produced is proportional to the amount of fat, the increased susceptibility to mycobacterial infections in thin individuals may be due to a relative deficiency of leptin, supported by the increased susceptibility of leptin-deficient OB/OB mice to various infections, including Klebsiella pneumoniae, Streptococcus pneumoniae, M. tuberculosis, and M. abscessus (16, 21, 57). Unlike leptin, adiponectin levels are increased in individuals with decreased body fat. Adiponectin is known to induce the expression of two immunosuppressive modulators, IL-1 receptor antagonist and IL-10, and to suppress the expression of TNF-α. Because IL-1 receptor antagonist and IL-10 may predispose individuals to various mycobacterial infections (16, 58, 59), the increased adiponectin in thin individuals may indeed be another mechanism by which thin individuals are predisposed to mycobacterial infections, including NTM and RGM. In addition, fewer fat cells can lead to a decrease in TNF-α, IL-6, and Th17 cells, potentially increasing the risk of mycobacterial infections (45, 60). The hypothesized role of depressed leptin and elevated adiponectin levels in increasing susceptibility to RGM and other NTM infections are schematically shown in Figure 2.
Figure 2. Diagram illustrating the hypothesized mechanisms by which low leptin levels and elevated adiponectin levels seen in thin individuals may predispose to rapidly growing mycobacteria (RGM) infections. See text for discussion. IL-1Ra, IL-1 receptor antagonist; Th, T helper; TNF, tumor necrosis factor.
[More] [Minimize]In addition to slender body habitus, it has been previously reported that patients with isolated NTM lung disease have a greater incidence of thoracic anomalies, including scoliosis, pectus excavatum, and mitral valve prolapse (50). This association was recently corroborated by the prospective NIH study, in which it was noted that the incidence of pectus excavatum (11%) and scoliosis (51%) in patients with NTM lung disease was significantly greater than their control populations (51). Interestingly, the NIH study also noted that patients with NTM were also significantly taller than NHANES control subjects (51). Indeed, the combination of slender body habitus, increased height, scoliosis, pectus excavatum, and mitral valve prolapse is suggestive of individuals having Marfanoid features. Therefore, it is interesting to speculate that anomalies in the FIBRILLIN-1 gene, of which there are a few hundred mutations identified, with some associated with Marfan's syndrome, may be responsible for the increased susceptibility to NTM/RGM infections in individuals with such body morphotype. In the fibrillin-1–deficient mice and in humans with Marfan's syndrome, there is evidence that increased levels of transforming growth factor (TGF)–β in tissues is responsible for the connective tissue abnormalities seen (61, 62). Because increased TGF-β may increase host susceptibility to M. tuberculosis (63) and M. avium complex (64, 65), it would be important to test the hypothesis that patients with NTM lung disease possessing this distinct body phenotype have increased TGF-β expression in the lungs to account for their increased susceptibility to RGM and other NTM.
Lung disease due to RGM is reported to be most common in postmenopausal women. (66). In two separate reports of 154 and 100 patients with RGM pulmonary disease, the prevalence of female sex was 65 and 85%, respectively (31, 33). The reason for the increased prevalence of NTM/RGM lung disease in women is not known, although it has been posited that it may be due to what is an accepted belief, that women expectorate less than men, and thus are more predisposed to chronic colonization with and subsequent lung diseases from NTM, the so-called “Lady Windermere syndrome” (67, 68).
Another proposed hypothesis for why older women are more likely than men to contract NTM lung disease is that low estrogen levels found in postmenopausal women predispose them to such infection. Experimentally, binding of estrogen to estrogen receptors on macrophages has been shown to augment phagocytic function and Fcgamma receptor expression on macrophages (69). This "estrogen-deficiency hypothesis" is corroborated by a murine study that showed that ovarectarized mice were more susceptible to M. avium complex infections than sham-treated mice; replacement of estrogen in the ovarectarized mice reduced their vulnerability through enhancement of production of reactive nitrogen intermediates (70). Furthermore, a link can be made between leptin, estrogen, and increased susceptibility in slender individuals in that a deficiency of leptin may also lead to decreased secretion of gonadotropin-releasing hormone, the gonadotropins, and estrogen (71). In contrast, other in vitro studies do not support the “estrogen-deficient hypothesis” and susceptibility to NTM. For example, estrogen receptor α–deficient mice infected with M. avium showed greater production of IFN-γ and IL-18 in the spleen than did wild-type mice (72). Furthermore, peritoneal macrophages of the estrogen receptor α–deficient mice infected with M. avium produced more TNF-α and had reduced intracellular burden of bacteria (73). To our knowledge, there are no studies in humans that have specifically addressed the relationship between hormone replacement therapy (HRT) and NTM lung disease. In the one observational NTM study that reported the use of HRT, only 22 of 55 (40%) patients with NTM reported ever using HRT, and this was not statistically different when compared with the NHANES control population (51).
In summary, M. abscessus is an emerging infection in man, causing disfiguring skin and soft-tissue infections, and refractory chronic lung disease. Based primarily on studies in mice, documented cases of infections after the use of TNF-α inhibitors, predisposing medical conditions, and genetic studies involving the IFN-γ–IL-12 costimulatory axis, there is a variety of immune components that are important in the host defense against M. abscessus. These include innate and adaptive cell-mediated immunity, pattern recognition receptors, TLR2 and dectin-1, AAT, antimicrobial peptides, such as β-defensins, the cytokines, TNF-α, IFN-γ, IL-12, and leptin, and possibly B cells and neutrophils. To counter this highly drug-resistant form of NTM, a greater understanding of the host immune response and host susceptibility factors is needed in both animal models and in human subjects.
The authors thank Mischa T. McGibney for help in preparing this article.
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