Emerging Role of Exosomes in Tuberculosis: From Immunity Regulations to Vaccine and Immunotherapy

Abstract

Exosomes are cell-derived nanovesicles carrying protein, lipid, and nucleic acid for secreting cells, and act as significant signal transport vectors for cell-cell communication and immune modulation. Immune-cell-derived exosomes have been found to contain molecules involved in immunological pathways, such as MHCII, cytokines, and pathogenic antigens. Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains one of the most fatal infectious diseases. The pathogen for tuberculosis escapes the immune defense and continues to replicate despite rigorous and complicate host cell mechanisms. The infected-cell-derived exosomes under this circumstance are found to trigger different immune responses, such as inflammation, antigen presentation, and activate subsequent pathways, highlighting the critical role of exosomes in anti-MTB immune response. Additionally, as a novel kind of delivery system, exosomes show potential in developing new vaccination and treatment of tuberculosis. We here summarize recent research progress regarding exosomes in the immune environment during MTB infection, and further discuss the potential of exosomes as delivery system for novel anti-MTB vaccines and therapies.

Keywords: Mycobacterium tuberculosis; exosomes; extracellular vesicles; immune evasion; innate immunity; vaccine.

Figure 1

Exosomes from Mtb-infected immune cells could induce multiple cellular responses. Exosomes from Mtb-infected immune cells contain various regulatory materials, such as Mtb antigens, Mtb RNA, Mtb peptide, lipoprotein, and miRNA. In fusion with cell membrane or passing through endocytosis, exosomes can release some Mtb specific contents to induce different anti-Mtb responses in immune cells. Mtb antigens from exosomes can be transferred into uninfected-DC, where the antigens can combine with MHCII for antigen presentation and activating the adaptive immune systems. Mtb RNA, peptide, and lipoprotein from exosomes are found to be responsible for exosomes induced-inflammation, which are in strong association with TLRs, MAPK, and NF-κB pathways. Furthermore, Mtb RNA from exosomes can also stimulate macrophage autophagy through nucleic acid-sensing pathways (RIG-1/MAVS/TBK1/IRF3). However, exosomes from Mtb-infected immune cells can also inhibit anti-Mtb functions. For example, lipoprotein from exosomes can suppress the IFN-γ induced MHCII and CD64 expression. Besides, miRNA from exosomes can inhibit autophagy of immune cells, while Mtb infection as well as PD1/PDL1 from exosomes can also act as immune inhibitor.

Figure 2

Exosomes-associated anti-TB strategies. (A) Exosomes can be loaded with drugs to achieve enhanced anti-TB therapy by combining the improved killing efficiency induced by the drugs and anti-TB responses induced by the exosomes. (B) Exosomes can be loaded with specific antigens to achieve enhanced anti-TB immune responses by combing the T cell and B cell activation induced by the specific antigen as well as anti-TB responses induced by the exosomes.

Figure 3

Advantages and disadvantages of exosomes-based vaccine. Representation of the process of exosomes-based vaccine generation, transportation, storage, and uptake with the advantages and disadvantages (mark in red) of each step.