'"Why me, why now?" Using clinical immunology and epidemiology to explain who gets nontuberculous mycobacterial infection

Abstract

Background: The prevalence of nontuberculous mycobacterial (NTM) disease is rising. An understanding of known risk factors for disease sheds light on the immunological and physical barriers to infection, and how and why they may be overcome. This review focuses on human NTM infection, supported by experimental and in vitro data of relevance to the practising clinician who seeks to understand why their patient has NTM infection and how to further investigate.

Discussion: First, the underlying immune response to NTM disease is examined. Important insights regarding NTM disease susceptibility come from nature's own knockouts, the primary immune deficiency disorders. We summarise the current knowledge surrounding interferon-gamma (IFNγ)-interleukin-12 (IL-12) axis abnormalities, followed by a review of phagocytic defects, T cell lymphopenia and rarer genetic conditions known to predispose to NTM disease. We discuss how these define key immune pathways involved in the host response to NTM. Iatrogenic immunosuppression is also important, and we evaluate the impact of novel biological therapies, as well as bone marrow transplant and chemotherapy for solid organ malignancy, on the epidemiology and presentation of NTM disease, and discuss the host defence dynamics thus revealed. NTM infection and disease in the context of other chronic illnesses including HIV and malnutrition is reviewed. The role of physical barriers to infection is explored. We describe how their compromise through different mechanisms including cystic fibrosis, bronchiectasis and smoking-related lung disease can result in pulmonary NTM colonisation or infection. We also summarise further associations with host factors including body habitus and age. We use the presented data to develop an over-arching model that describes human host defences against NTM infection, where they may fail, and how this framework can be applied to investigation in routine clinical practice.

Keywords: Bronchiectasis; Cystic fibrosis; Host defence; Immune response; Interferon gamma; Interleukin 12; Nontuberculous mycobacteria; Primary immune deficiency.

Fig. 1

The immune response to mycobacterial infection and known sites of dysfunction. Human genetic syndromes which affect the immune response to mycobacterial infection are known to result from disorders in the following genes: ISG15, IL-12B, IL12RB1, IFNGR1, IFNGR2, STAT1, IRF8, ISG-15, GATA2 and NADPH oxidase complex subunit genes such as CYBB. Nontuberculous mycobacteria (A) are phagocytosed (B), triggering release of IL-12 (C), a heterodimeric cytokine formed from the gene products of IL12A and IL12B, which binds a receptor heterodimer (D) of IL-12RB1 and IL-12RB2 on T cells and NK cells. Signalling to the nucleus mediated by TYK2 (E) then results in IFNγ production. IFN gamma binds its receptor (F), a heterodimer of IFNGR1 and IFNGR2, triggering phosphorylation of JAK2, JAK1, and STAT1 (G). The resultant phosphorylated STAT1 molecule homodimerises to form the pSTAT1 complex which translocates to the nucleus and binds the IFN gamma activating sequence. This triggers transcription of interferon stimulated genes (ISG) via IRF8 (H), and increases IL12, TNFα, ISG15 (I), and potentiation of macrophage activation. Activated macrophages demonstrate enhanced phagosome maturation and increased killing of intracellular pathogens, and upregulated antigen presentation, thereby activating Th1-phenotype T cells to proliferate and release further IFNγ. TNFα drives development of granulomas. IRF8 aids differentiation of myeloid progenitors into monocytes, and controls transcriptional responses of mature myeloid cells to interferons (IFNs) and Toll-like receptor (TLR) agonists. NFκB is a rapid-acting transcription factor modulated by NEMO (J) and activated by stimuli including signalling through CD40 (K), TLR (L), reactive oxygen species and TNFα. Activation allows a host of inflammatory and immune responses, including IL12 release. Effective intraphagosomal killing through reactive oxygen species requires an intact NADPH oxidase complex (M). Intact haematopoiesis of monocyte lineages is also required via GATA2 (N)

Fig. 2

Systemic factors predisposing to NTM disease. Apparently ‘immunocompetent’ individuals may have an elevated risk of NTM disease due to structural lung disease or specific host features such as advanced age, female gender or polymorphisms of immune, cilia, connective tissue or CFTR genes. Immunocompromise causing susceptibility to NTM disease can be caused by primary immune deficiency, drugs targeting the immune system such as anti-TNFα reagents, or systemic disease

Fig. 3

Flowchart for investigation of adult patients presenting with NTM disease