The Enigmatic PE/PPE Multigene Family of Mycobacteria and Tuberculosis Vaccination

Abstract

The genome of Mycobacterium tuberculosis, the bacterium responsible for the disease tuberculosis, contains an unusual family of abundant antigens (PE/PPEs). To date, certain members of this multigene family occur only in mycobacteria that cause disease. It is possible that the numerous proteins encoded by these mycobacterial genes dictate the immune pathogenesis of this bacterial pathogen. There is also evidence that some of these antigens are present at the cell surface and that they affect the pathology and immunology of the organism in many ways. Also, they elicit both antibodies and T cells, they may be involved in antigenic variation, and they may be good candidates for vaccines and drugs. However, since they are plentiful and extremely homologous, these PE/PPEs are very challenging to study, and it is difficult to be certain what role(s) they have in the pathogenesis of tuberculosis. Consequently, how to develop treatments like vaccines using these antigens as candidates is complex.

Keywords: PE/PPE family of genes; tuberculosis; vaccines.

FIG 1

Schematic showing known PE/PPE bacterial ligands and how they may interact with mycobacterial or host receptors. (A) PE-PGRS and PPEs are found in the outer membrane matrix of mycobacteria, and they can elicit cross-reactive antibodies. The PPEs and PEs can elicit T cells. PEs can act like chaperones directing PGRS and other heterologous proteins like MPT64 to the outer membrane of mycobacteria. Some PE-PGRSs also have a domain at the C terminus, such as a lipase, which has enzymatic activity. PPEs and PEs often interact as “couplets” and are found associated with ESX domains in mycobacterial genes. The type VII secretion system is known to secrete PE/PPEs as well as other antigens. (B) PE-PGRS and PPEs interact with TLR2 receptor on macrophages and dendritic cells. This binding has been shown to cause apoptosis, necrosis, autophagy, release of cytokines like tumor necrosis factor alpha (TNF-α) and cell activation. (C) Necrosis of the cells resulting from the interaction of PE-PGRS 33 with mitochondria. Other PE-PGRSs like PE-PGRS 1, 18, and 24 do not interact with mitochondria.

FIG 2

Schematic showing the position of PPE 18 (Mtb39a) in the M72 GSK vaccine (A) or PPE 42 (Rv2608) as part of the IDRI ID93 vaccine (B) which are presently in clinical trials.