Extracellular vesicles in mycobacteria: new findings in biogenesis, host-pathogen interactions, and diagnostics

Abstract

Since the discovery of extracellular vesicles (EVs) in mycobacterial species 15 years back, we have learned that this phenomenon is conserved in the Mycobacterium genus and has critical roles in bacterial physiology and host-pathogen interactions. Mycobacterium tuberculosis (Mtb), the tuberculosis (TB) causative agent, produces EVs both in vitro and in vivo including a diverse set of biomolecules with demonstrated immunomodulatory effects. Moreover, Mtb EVs (MEVs) have been shown to possess vaccine properties and carry biomarkers with diagnostic capacity. Although information on MEV biogenesis relative to other bacterial species is scarce, recent studies have shed light on how MEVs originate and are released to the extracellular space. In this minireview, we discuss past and new information about the vesiculogenesis phenomenon in Mtb, including biogenesis, MEV cargo, aspects in the context of host-pathogen interactions, and applications that could help to develop effective tools to tackle the disease.

Keywords: Mycobacterium tuberculosis; biogenesis; extracellular vesicles.

Fig 1

General and specific vesiculogenesis mechanisms in Mtb. In Gram-positive bacteria, EVs originate at the cell membrane giving CMVs through mechanisms involving cell wall modifications. In addition, chemical modifications via sublethal exposure to β-lactams or genetic deletion of PBPs, as well as the action of prophage endolysins, increase CMV release in a similar mechanism to that of Gram-negative explosive cell lysis. In Gram-negative bacteria, EVs are produced through outer membrane blebbing, forming OMVs (B-type MVs) or explosive cell lysis via prophage endolysins, forming OIMVs and EOMVs (E-type MVs). The composition of the EVs depends on the mechanism of biogenesis. In mycobacteria, MEVs are produced in the cell membrane and different factors influence their production, such as iron availability, virR, dynamin-like proteins IniAC, and the Pst/SenX3-RegX3 system. CMV, cytoplasmic membrane vesicle. OIMV, outer-inner membrane vesicle. EOMV, explosive outer membrane vesicle. OMV, outer membrane vesicle. MV, membrane vesicle. PBPs, penicillin-binding proteins. LM, lipomannan. LAM, lipoarabinomannan. PIM2, phosphatidylinositol dimannoside. PIM6, phosphatidylinositol hexamannoside. AM, arabinomannan. mAG complex, mycolyl arabinogalactan complex.