Abstract
PE_PGRS proteins are surface antigens of Mycobacterium tuberculosis (Mtb) and a few other pathogenic mycobacteria. The PE_PGRS33 protein is among the most studied PE_PGRSs. It is known that the PE domain of PE_PGRS33 is required for the protein translocation through the mycobacterial cell wall, where the PGRS domain remains available for interaction with host receptors. Interaction with Toll like receptor 2 (TLR2) promotes secretion of inflammatory chemokines and cytokines, which are key in the immunopathogenesis of tuberculosis (TB). In this review, we briefly address some key challenges in the development of a TB vaccine and attempt to provide a rationale for the development of new vaccines aimed at fostering a humoral response against Mtb. Using PE_PGRS33 as a model for a surface-exposed antigen, we exploit the availability of current structural data using homology modeling to gather insights on the PGRS domain features. Our study suggests that the PGRS domain of PE_PGRS33 exposes four PGII sandwiches on the outer surface, which, we propose, are directly involved through their loops in the interactions with the host receptors and, as such, are promising targets for a vaccination strategy aimed at inducing a humoral response.
Highlights
Tuberculosis (TB) is still the world’s leading infectious cause of death, according to theWorld Health Organization (WHO) [1,2]
Vaccine development against TB has been dominated by strategies aimed at the elicitation of robust T cell responses, while antibody-based strategies have been neglected due to the limited number and poor knowledge of Mycobacterium tuberculosis (Mtb) surface antigens that are the natural targets of protective humoral responses
We provide a brief summary of the main challenges associated with the development of a new vaccine against TB and highlight the importance of a structure/function view to investigate the vaccine potential of a unique class of Mtb surface antigens, the PE_PGRS proteins
Summary
Tuberculosis (TB) is still the world’s leading infectious cause of death, according to the. Mtb establishes a dynamic equilibrium with the host immune system that lasts for lifetime, with no signs or symptoms of disease [3,4]. Resuscitation from dormancy, which is orchestrated by a set of cell wall hydrolases [5,6,7,8,9], is a regular event in the homeostasis of Mtb infection that continuously replenishes the bulk of replicating bacilli after their elimination by the host immune response [10,11]. TB reactivation occurs when the equilibrium between Mtb and the host immune response is broken in favor of bacterial replication and tissue damage. (Rv1818c) as a prototype, this review provides a basis for the unraveling of the functional properties of PE_PGRS proteins as immune modulators
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