Mycobacterium abscessus (Mabs), a nontuberculous mycobacterium (NTM), is an important emerging pathogen which causes treatment-refractory, progressive lung disease in patients with abnormal airways due to COPD and bronchiectasis. It is unique among bacteria in that it exists in a saprophytic form which is characterized by a smooth colony morphotype associated with cell surface expression of glycopeptidolipid (GPL). This form exhibits sliding motility and the capacity to form biofilm. It colonizes abnormal lung airways and when GPL expression is lost it exhibits a rough colony morphotype. The emergent rough colony morphotype is characterized by serpentine cording and an invasive, pro-inflammatory phenotype which is associated with progressive pulmonary parenchymal lung infection in patients with abnormal lung airways. The rough phenotype is able to invade and destroy a variety of cell types, including macrophages in monolayer culture, and exhibits virulence properties in the zebrafish infection model. In spite of this, mice and humans with normal lung airways are resistant to lung infection unless they are severely immunocompromised. This research topic seeks to bridge the gap between published basic research studies which have identified many virulence determinants of Mabs, and pulmonary infection models which show limited pathogenicity of this organism. A central question is why humans with abnormal lung airways are uniquely susceptible to infection with this mycobacterium.
Mabs is considered an emerging pathogen and a significant infectious disease threat. In recent years clonal outbreaks have occurred in clinical settings foreshadowing an increasing incidence of nosocomial infection. Many Mabs strains are multidrug resistant and Mabs subspecies differ in terms of their inherent antimicrobial susceptibility creating an enormous clinical challenge, particularly since patients often require months of therapy to achieve cure. Furthermore, in patients with bronchiectasis due to cystic fibrosis, colonization/infection of the lungs with Mabs is often a harbinger of a rapid decline in pulmonary function and often leads to complications following lung transplantation.
The goal of this research topic is two-fold. The first goal is to more fully understand the host defense mechanisms that are barriers to establishment of infection in normal lungs. For example, what is the role of innate immune effector cells such as phagocytic cells, epithelial and endothelial cells, natural killer cells, innate lymphoid cells in preventing establishment of Mabslung infection? What roles do lung surfactant and other innate immune effector molecules such as antimicrobial peptides, reactive oxygen intermediates and nitric oxide play innate immune defense? What is the role of cellular receptors such as toll-like receptors (TLRs), nod-like receptors (NLRs) and C-type lectin receptor (CLRs) in innate immune recognition and what role do specific cytokines/chemokines such as TNFa, IFN? and IL-8 play in pathogen clearance? The second goal is to understand the pathogenesis of Mabs in patients with abnormal lung airways. What components of the innate immune response are deficient in patients with abnormal lung airways which allow Mabs to establish parenchymal lung infection? The corollary to this is why adaptive immune responses in conjunction with adaptive immunity fail to control Mabs lung infection in patients with abnormal lung airways? Use of genetically modified mice and CRISPR-Cas technology are research tools that should enable these research questions to be answered. In addition, the bronchiectatic airways are often infected/colonized with other microbial organisms including fungal organisms and gram-negative bacteria. Thus, it would be important to determine how the presence of other organisms or their components affect host immunity, including biofilms, against M. abscessus; e.g., LPS is known to induce immune tolerance.
The scope of this Research Topic is defined by the stated goals. To summarize, studies that focus on host innate and adaptive immune mechanisms involved in the pathogenesis of Mabs pulmonary infection will be included in this Research Topic. Studies which shed light on this interaction at the cellular level, as well as the level of the lung and whole organism, using appropriate animal models are encouraged, as well as clinical research studies which utilize clinical materials from human research subjects as part of institutionally approved human research protocols.
Mycobacterium abscessus (Mabs), a nontuberculous mycobacterium (NTM), is an important emerging pathogen which causes treatment-refractory, progressive lung disease in patients with abnormal airways due to COPD and bronchiectasis. It is unique among bacteria in that it exists in a saprophytic form which is characterized by a smooth colony morphotype associated with cell surface expression of glycopeptidolipid (GPL). This form exhibits sliding motility and the capacity to form biofilm. It colonizes abnormal lung airways and when GPL expression is lost it exhibits a rough colony morphotype. The emergent rough colony morphotype is characterized by serpentine cording and an invasive, pro-inflammatory phenotype which is associated with progressive pulmonary parenchymal lung infection in patients with abnormal lung airways. The rough phenotype is able to invade and destroy a variety of cell types, including macrophages in monolayer culture, and exhibits virulence properties in the zebrafish infection model. In spite of this, mice and humans with normal lung airways are resistant to lung infection unless they are severely immunocompromised. This research topic seeks to bridge the gap between published basic research studies which have identified many virulence determinants of Mabs, and pulmonary infection models which show limited pathogenicity of this organism. A central question is why humans with abnormal lung airways are uniquely susceptible to infection with this mycobacterium.
Mabs is considered an emerging pathogen and a significant infectious disease threat. In recent years clonal outbreaks have occurred in clinical settings foreshadowing an increasing incidence of nosocomial infection. Many Mabs strains are multidrug resistant and Mabs subspecies differ in terms of their inherent antimicrobial susceptibility creating an enormous clinical challenge, particularly since patients often require months of therapy to achieve cure. Furthermore, in patients with bronchiectasis due to cystic fibrosis, colonization/infection of the lungs with Mabs is often a harbinger of a rapid decline in pulmonary function and often leads to complications following lung transplantation.
The goal of this research topic is two-fold. The first goal is to more fully understand the host defense mechanisms that are barriers to establishment of infection in normal lungs. For example, what is the role of innate immune effector cells such as phagocytic cells, epithelial and endothelial cells, natural killer cells, innate lymphoid cells in preventing establishment of Mabslung infection? What roles do lung surfactant and other innate immune effector molecules such as antimicrobial peptides, reactive oxygen intermediates and nitric oxide play innate immune defense? What is the role of cellular receptors such as toll-like receptors (TLRs), nod-like receptors (NLRs) and C-type lectin receptor (CLRs) in innate immune recognition and what role do specific cytokines/chemokines such as TNFa, IFN? and IL-8 play in pathogen clearance? The second goal is to understand the pathogenesis of Mabs in patients with abnormal lung airways. What components of the innate immune response are deficient in patients with abnormal lung airways which allow Mabs to establish parenchymal lung infection? The corollary to this is why adaptive immune responses in conjunction with adaptive immunity fail to control Mabs lung infection in patients with abnormal lung airways? Use of genetically modified mice and CRISPR-Cas technology are research tools that should enable these research questions to be answered. In addition, the bronchiectatic airways are often infected/colonized with other microbial organisms including fungal organisms and gram-negative bacteria. Thus, it would be important to determine how the presence of other organisms or their components affect host immunity, including biofilms, against M. abscessus; e.g., LPS is known to induce immune tolerance.
The scope of this Research Topic is defined by the stated goals. To summarize, studies that focus on host innate and adaptive immune mechanisms involved in the pathogenesis of Mabs pulmonary infection will be included in this Research Topic. Studies which shed light on this interaction at the cellular level, as well as the level of the lung and whole organism, using appropriate animal models are encouraged, as well as clinical research studies which utilize clinical materials from human research subjects as part of institutionally approved human research protocols.
