Virulence Mechanisms of Mycobacterium abscessus: Current Knowledge and Implications for Vaccine Design

Abstract

Mycobacterium abscessus is a member of the non-tuberculous mycobacteria (NTM) group, responsible for chronic infections in individuals with cystic fibrosis (CF) or those otherwise immunocompromised. While viewed traditionally as an opportunistic pathogen, increasing research into M. abscessus in recent years has highlighted its continued evolution into a true pathogen. This is demonstrated through an extensive collection of virulence factors (VFs) possessed by this organism which facilitate survival within the host, particularly in the harsh environment of the CF lung. These include VFs resembling those of other Mycobacteria, and non-mycobacterial VFs, both of which make a notable contribution in shaping M. abscessus interaction with the host. Mycobacterium abscessus continued acquisition of VFs is cause for concern and highlights the need for novel vaccination strategies to combat this pathogen. An effective M. abscessus vaccine must be suitably designed for target populations (i.e., individuals with CF) and incorporate current knowledge on immune correlates of protection against M. abscessus infection. Vaccination strategies must also build upon lessons learned from ongoing efforts to develop novel vaccines for other pathogens, particularly Mycobacterium tuberculosis (M. tb); decades of research into M. tb has provided insight into unconventional and innovative vaccine approaches that may be applied to M. abscessus. Continued research into M. abscessus pathogenesis will be critical for the future development of safe and effective vaccines and therapeutics to reduce global incidence of this emerging pathogen.

Keywords: Mycobacterium abscessus; cystic fibrosis; reverse vaccinology; vaccines; virulence factors.

Figure 1

Virulence factors of M. abscessus. M. abscessus uses an extensive range of virulence factors to facilitate survival within host cells. These include membrane bound proteins, pores and secretion systems (i); secreted proteins with a role in virulence (ii); transcriptional regulators and nucleic acid associated proteins (iii); proteins involved in the modification (iv) and transport (v) of cell surface components; and molecules that comprise the outer mycobacterial membrane (vi).

Figure 2

Immune responses to M. abscessus infection. M. abscessus infection is followed by an influx of neutrophils and macrophages surrounded by lymphocytes which work to contain bacteria in the granuloma (A). Cytokines TNF and IFN-γ produced by macrophages and CD4⁺ T cells are required for granuloma formation and induce macrophage effector function, such as phagosome acidification and reactive oxygen species (ROS) production, while type I IFN production promotes nitric oxide (NO) production. IL-8 attracts neutrophils which are responsible for phagocytosis, NET production and secretion of antimicrobial peptide LL-37. However, release of M. abscessus into the extracellular space as a result of cell death leads to the formation of serpentine cords, which are resistant to innate immune defenses and leads to unchecked bacterial replication. M. abscessus also possesses numerous mechanisms of immune evasion to resist macrophage effector functions (B); these include bacterial escape from the phagosome to the cytosol through interference with the phagosomal membrane (i); prolonged survival within the phagosome by blocking phagosomal acidification and thereby preventing M. abscessus degradation (ii) and inhibition of macrophage TLR signaling which limits downstream immune cell activation and recruitment (iii). M. abscessus also persists in the extracellular environment by avoiding phagocytosis, which is enabled through adherence to macrophage phagocytic cups on the cell surface (iv) and by forming serpentine cords which are too large to be engulfed by macrophages (v).