Edward D. Chan
Veronica Schmitz
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- 1Department of Academic Affairs, National Jewish Health, Denver, CO, United States
- 2Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- 3Department of Medicine, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, United States
- 4Laboratório de Hanseníase, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
Editorial on the Research Topic
Nontuberculous mycobacterial pulmonary disease: immunopathogenesis and immunological risk factors
Mycobacteria are comprised of Mycobacterium tuberculosis complex, Mycobacterium leprae, and non-tuberculous mycobacteria (NTM). While NTM contain approximately 200 distinct species and subspecies, diseases in humans are predominantly caused by three main groups: (i) Mycobacterium avium complex (which is comprised of several members, with the most clinically relevant being M. avium subsp hominissuis, M. intracellulare subsp intracellulare, and M. intracellulare subsp chimaera); (ii) Mycobacterium abscessus group (which consists of three subspecies: abscessus, massiliense, and bolletii); and (iii) Mycobacterium kansasii complex. NTM are ubiquitous in natural and built environs, especially in fresh water, soil, and biofilms, making NTM infections environmentally- acquired.
Upon encountering a patient with an NTM infection, four elements should be determined: the specific NTM responsible, how the infection was contracted, the location and extent of the infection, and the presence of any host risk factors. The last two elements are interrelated because the degree of underlying host risk factors often dictates the scope of the infection. Thus, it is useful to categorize the NTM infection into one of four main types: (i) skin, soft tissue, and osteoarticular infections, which are typically due to accidental trauma or medical procedures; (ii) isolated infection of the head and neck lymph nodes (also known as cervical lymphadenitis or “scrofula”); (iii) isolated NTM lung disease; (iv) disseminated or extrapulmonary visceral disease. Identifying or distinguishing the latter two types helps dictate what investigative actions to embark upon to determine the presence of any underlying host risk factors.
This Research Topic of Frontiers in Immunology, titled “Nontuberculous mycobacterial pulmonary disease: immunopathogenesis and immunological risk factors,” is comprised of five papers. Hicks et al. investigated the pathogenesis of NTM disease from the host’s perspective. Yang et al. and Wang et al. examined specific interactions of the host with NTM and M. tuberculosis, respectively. Keefe et al. focused on how a specific NTM species is able to thrive in the environment and infect host cells. Mediaas et al. investigated a novel host-directed therapy against NTM.
Hicks et al. reported three infants with complete DiGeorge anomaly (cDGA) – a genetic condition resulting in the complete absence of the thymus resulting in severe T cell deficiency – all with disseminated NTM infections. These cases are rare, likely due to the highly infrequent intersection of two uncommon conditions (DGA and NTM infection). The authors recommend that DGA should be considered in the differential diagnoses of children with disseminated NTM infections. Currently, mutations of genes that encode for elements of the interferon-gamma (IFNγ)–interleukin-12 (IL-12) axis should be suspected in very young children with disseminated NTM disease. In adults with disseminated NTM infections, acquired immune disorders like AIDS, anti-IFNγ antibody syndrome, or use of immunosuppressive drugs are more likely risk factors.
Various mouse strains have been used to explore host susceptibility to NTM infections. However, most murine infection models result in systemic NTM infection rather than exhibit isolated NTM lung disease, the latter characterized by bronchiolitis and bronchiectasis in humans. Yang et al. developed a mouse model using intratracheal infection with M. abscessus embedded in agar beads, which better simulates airway infection. The infected mice developed granulomas, a common feature M. abscessus infection in humans. Others have also employed a fibrin plug model where M. abscessus is suspended in thrombin and fibrinogen, trapping the bacteria in the airways as the plugs coagulate (1). Models such as these intuitively more closely replicate isolated NTM lung disease. Future studies could investigate whether such inoculation methods also enhance NTM biofilm formation in the airways, a barrier known to resist penetration by immune cells and antibiotics.
The co-evolution of humans and mycobacteria has enabled reciprocal adaptation in a mutual struggle for dominance. A recurring example is that the same host factors or mycobacterial components can be used by either side to gain an advantage, analogous to a “tug o’ war” event. Wang et al. reviewed the role of CD36, a cell surface scavenger receptor which mycobacteria have hijacked for their own advantage. Although their focus was on M. tuberculosis, similar mechanisms may also be involved in the pathogenesis of NTM disease. They discussed that M. tuberculosis engages CD36 leading to: (i) increased fatty acid uptake by host cells, aiding bacillary persistence; (ii) monocyte differentiation into macrophages with an immunosuppressive phenotype; and (iii) enhanced uptake of surfactant lipids by macrophages, supporting mycobacterial growth. Additionally, they highlighted studies showing CD36 expression in various cell types that are involved in granuloma formation, including macrophages, granulocytes, lymphocytes, and fibroblasts. It was previously demonstrated that the M. avium complex manipulates macrophage lipid metabolism, leading to the formation of lipid-laden foamy macrophages that create a favorable environment for mycobacterial growth (2). Recent studies using a mouse model demonstrated that CD36 expression is elevated on macrophages during M. avium infection (3). In line with this, inhibiting CD36 has been shown to reduce the growth of M. avium. Choi et al. (4) confirmed that blocking CD36 leads to decreased growth of M. avium, which aligns with earlier research. These findings highlight the crucial role of CD36 in the pathology of mycobacterial diseases as well as a potential therapeutic target.
Bronchiectasis, a common feature of chronic NTM lung disease, is characterized by repeated cycles of infection and inflammation. Airway injury may be exacerbated by NTM-generated biofilms, a complex matrix of extracellular polymeric substances – comprised of DNA, proteins, polysaccharides, and lipids – released from live and dead microbes (5–9). NTM lung cavity walls have also been demonstrated to contain biofilms (10). This biofilm matrix provides protection and nutrients for the microbes (11). Keefe et al. identified gene products from M. abscessus in biofilms using a transposon library of M. abscessus along with surface proteomic analysis. They uncovered specific proteins related to the mycobacteria’s ability to detach and establish new biofilms as well as attach to and infect both epithelial cells and macrophages.
The primary treatment for NTM lung disease involves antibiotics, airway clearance, and targeted therapies for underlying conditions, e.g., anti-retroviral drugs for HIV infection, modulators for defective cystic fibrosis transmembrane conductance regulator, and alpha-1-antitrypsin (AAT) replacement therapy for those with AAT deficiency. For those with disseminated NTM disease, host-directed therapies may include IFNγ replacement therapy for subjects with defects in the IFNγ-IL-12 axis, anti-B cell therapy for those with anti-IFNγ autoantibodies, and immune checkpoint inhibitors for individuals with severe T cell immunosuppression (12, 13), though the lattermost is controversial (13, 14). Adjunct therapies directed more specifically against the mycobacteria include inhibitors of M. abscessus β-lactamase for those on β-lactam antibiotics (15), efflux pump inhibitors (16), and biofilm disrupters (8). Mediaas et al. found that metformin, commonly used to treat diabetes mellitus, significantly reduced M. avium burden in mice. One mechanism for this salubrious effect was by enhancing the ability of macrophages to kill or control the infection by activating the AMPK (5’ adenosine monophosphate-activated protein kinase) pathway, increasing mitochondrial reactive oxygen species and enhancing phagosome maturation and acidification.
In summary, the five articles featured in this Research Topic enhance our understanding of the pathogenesis of NTM infections. This increase in knowledge is crucial since we are all likely exposed to NTM and yet NTM infections occur in relatively few individuals. The interplay between specific host susceptibility and NTM virulence factors is likely critical in the development of NTM disease. Each of these papers contributes to our collective understanding of this relationship. Ongoing research into innovative strategies and therapies, as highlighted by these five papers, is essential for improving outcomes for patients with NTM disease.
Author contributions
EC: Writing – original draft, Writing – review & editing. VS: Writing – review & editing.
Acknowledgments
We thank Drew Narum, B.S. for excellent editorial assistance.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The author(s) declare that no Generative AI was used in the creation of this manuscript.
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References
1. Caverly LJ, Caceres SM, Fratelli C, Happoldt C, Kidwell KM, Malcolm KC, et al. Mycobacterium abscessus morphotype comparison in a murine model. PloS One. (2015) 10:e0117657. doi: 10.1371/journal.pone.0117657
2. Kajiwara C, Shiozawa A, Urabe N, Yamaguchi T, Kimura S, Akasaka Y, et al. Apoptosis inhibitor of macrophages contributes to the chronicity of mycobacterium avium infection by promoting foamy macrophage formation. J Immunol. (2023) 210:431–41. doi: 10.4049/jimmunol.2200306
3. Hawkes M, Li X, Crockett M, Diassiti A, Finney C, Min-Oo G, et al. CD36 deficiency attenuates experimental mycobacterial infection. BMC Infect Dis. (2010) 10:299. doi: 10.1186/1471-2334-10-299
4. Choi S, Lee JM, Kim KES, Park J-H, Kim L-H, Park J, et al. Protein-energy restriction-induced lipid metabolism disruption causes stable-to-progressive disease shift in mycobacterium avium-infected female mice. eBioMedicine. (2024) 105:105198. doi: 10.1016/j.ebiom.2024.105198
5. Esteban J, García-Coca M. Mycobacterium biofilms. Front Microbiol. (2018) 8:2651. doi: 10.3389/fmicb.2017.02651
6. Ilinov A, Nishiyama A, Namba H, Fukushima Y, Takihara H, Nakajima C, et al. Extracellular DNA of slow growers of mycobacteria and its contribution to biofilm formation and drug tolerance. Sci Rep. (2021) 11:10953. doi: 10.1038/s41598-021-90156-z
7. Liu X, Hu J, Wang W, Yang H, Tao E, Ma Y, et al. Mycobacterial biofilm: mechanisms, clinical problems, and treatments. Int J Mol Sci. (2024) 25:7771. doi: 10.3390/ijms25147771
8. Nasrollahian S, Pourmoshtagh H, Sabour S, Hadi N, Azimi T, Soleiman-Meigooni S. Biofilm formation in mycobacterial genus; mechanism of biofilm formation and anti-mycobacterial biofilm agents. Curr Pharm Biotechnol. (2024). doi: 10.2174/0113892010277107240227054933
9. Patel RR, Arun PP, Singh SK, Singh M. Mycobacterial biofilms: Understanding the genetic factors playing significant role in pathogenesis, resistance and diagnosis. Life Sci. (2024) 351:122778. doi: 10.1016/j.lfs.2024.122778
10. Fennelly KP, Ojano-Dirain C, Yang Q, Liu L, Lu L, Progulske-Fox A, et al. Biofilm formation by mycobacterium abscessus in a lung cavity. Am J Respir Crit Care Med. (2016) 193:692–3. doi: 10.1164/rccm.201508-1586IM
11. Bamford NC, MacPhee CE, Stanley-Wall NR. Microbial Primer: An introduction to biofilms - what they are, why they form and their impact on built and natural environments. Microbiol (Reading). (2023) 169:001338. doi: 10.1099/mic.0.001338
12. Liu L, Song Z, Xun J, Liu D, Wei J, Wang Z, et al. PD-1 inhibitor for disseminated mycobacterium avium infection in a person with HIV. Open Forum Infect Dis. (2022) 10:ofac700. doi: 10.1093/ofid/ofac700
13. Vaddi A, Hulsebus HJ, O’Neill EL, Knight V, Chan ED. A narrative review of the controversy on the risk of mycobacterial infections with immune checkpoint inhibitor use: Does Goldilocks have the answer? J Thorac Dis. (2024) 16:1601–24. doi: 10.21037/jtd-23-1395
14. Chan ED. The controversy of immune checkpoint inhibition and risk of mycobacterial infections: the need for further studies and continued discussions on this puzzling issue. J Thorac Dis. (2024) 16:5487–9. doi: 10.21037/jtd-24-1005
15. Dubée V, Bernut A, Cortes M, Lesne T, Dorchene D, Lefebvre AL, et al. [amp]]beta;-Lactamase inhibition by avibactam in Mycobacterium abscessus. J Antimicrob Chemother. (2015) 70:1051–8. doi: 10.1093/jac/dku510
16. Cernicchi G, Rampacci E, Massari S, Manfroni G, Barreca ML, Tabarrini O, et al. Discovery of 2-phenylquinazolines as potent Mycobacterium avium efflux pump inhibitors able to synergize with clarithromycin against clinical isolate. Arch Pharm (Weinheim). (2024) 357:e2400296. doi: 10.1002/ardp.202400296
Keywords: NTM (nontuberculous mycobacteria), NTM infections, NTM disease, NTM host interaction, NTM therapy
Citation: Chan ED and Schmitz V (2025) Editorial: Nontuberculous mycobacterial pulmonary disease: immunopathogenesis and immunological risk factors. Front. Immunol. 16:1582489. doi: 10.3389/fimmu.2025.1582489
Received: 24 February 2025; Accepted: 10 March 2025;
Published: 21 March 2025.
Edited and Reviewed by:
Ian Marriott, University of North Carolina at Charlotte, United StatesCopyright © 2025 Chan and Schmitz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Edward D. Chan, Y2hhbmVAbmpoZWFsdGgub3Jn