Significance of extracellular vesicles in orchestration of immune responses in Mycobacterium tuberculosis infection

Abstract

Mycobacterium tuberculosis (M.tb), the causative agent of Tuberculosis, is an intracellular bacterium well known for its ability to subvert host energy and metabolic pathways to maintain its intracellular survival. For this purpose, the bacteria utilize various mechanisms of which extracellular vehicles (EVs) related mechanisms attracted more attention. EVs are nanosized particles that are released by almost all cell types containing active biomolecules from the cell of origin and can target bioactive pathways in the recipient cells upon uptake. It is hypothesized that M.tb dictates the processes of host EV biogenesis pathways, selectively incorporating its molecules into the host EV to direct immune responses in its favor. During infection with Mtb, both mycobacteria and host cells release EVs. The composition of these EVs varies over time, influenced by the physiological and nutritional state of the host environment. Additionally, different EV populations contribute differently to the pathogenesis of disease at various stages of illness participating in a complex interplay between host cells and pathogens. These interactions ultimately influence immune responses and disease outcomes. However, the precise mechanisms and roles of EVs in pathogenicity and disease outcomes remain to be fully elucidated. In this review, we explored the properties and function of EVs in the context of M.tb infection within the host microenvironment and discussed their capacity as a novel therapeutic strategy to combat tuberculosis.

Keywords: Mycobacterium tubercilosis; exosomes; extracellular vesicles; lung cancer; tuberclosis.

Figure 1

The mechanisms of EVs during infection with Mycobacterium tuberculosis. During M.tb infection, the pathogen resides in the phagolysosome, and the mycobacterial components, including antigen molecules, exit the phagosome either via host-derived EVs or bacterial ones. Bacterial-released EVs can be produced inside the phagosomes or by extracellular mycobacteria in granuloma. (A) Bacterial and host-derived EVs contain TLR ligands and activate TLR signaling pathways in uninfected cells, leading to the production of proinflammatory cytokines by the uninfected cells through NF-κB pathways. (B) These EVs block the response to interferon-gamma in the uninfected cell by inhibiting the corresponding genes at the transcriptional level by downregulation of transcription factor CIITA and its interaction with p300 (Ting et al., 1999; Singh et al., 2011) (C) Promoting macrophages differentiation through TLR and MPK signaling pathways, which lead to increasing FAX and paxillin expression and actin polymerization. (D) Increasing permeability and cell migration in the epithelial cells. (E) Activation of endothelial cells by increasing MMPs expression and permeability of the monolayer and finally increasing the cell migration. (F) mRNAs from these EVs are active and can be translated in recipient cells. (G) RNAs from these EVs may activate RNA-sensing machinery in recipient cells.

Figure 2

(A) The outcome of the EVs effects on the phenotype of diseases, (B) Potential mechanisms used by EVs to generate TAMs during chronic TB inflammation. Overstimulation of TLRs due to increased production of Evs induces expression of immune suppressive cytokines including IL-10, IL-6, IL-4, and TGF-β. This new cytokine profile promotes the polarization of macrophages in favor of a M2-like phenotype that in turn promotes the shaping of TME. The reciprocal interactions between TAM and the tumor microenvironment contribute to tumor progression.