Seminar

Harnessing the Mycobacterium tuberculosis cell surface’s physiology to generate better tuberculosis vaccines

Rafael Prados, PhD

One of the historic ironies of tuberculosis (TB) research is that it has always been assumed that the current interventions would eliminate this disease as a major public health problem. BCG, an attenuated bovine tuberculosis strain, was discovered in 1908, and was thought to be the vaccine for tuberculosis. Streptomycin in the 1940s was hailed as the wonder drug for tuberculosis. Yet even with better antibiotics, tuberculosis remains a major global health problem. Paradoxically, TB is the first cause of death by a bacterial infection and by a curable infection. Bacille Calmette-Guérin (BCG) is being used today to prevent TB in infants. But even though BCG is the most widely used vaccine in the world, it has not successfully eliminated the disease due to its limited efficacy. We agree that new vaccines are central to future TB elimination program. However, the incomplete understanding of the physiology of its causative agent, Mycobacterium tuberculosis (Mtb), precludes the efficacy of the current vaccine approaches. Mtb and host cells initiate their encounter at the outermost part of the cell surface. The way this interaction occurs will determine the fate of the pathogen. Our group is interested in understanding how Mtb shapes its cell surface during the infection process. We are focused in two different physiological processes: (i) alternative secretion systems based on extracellular vesicles (EVs) and (ii) bacterial outermost capsule. (i) Mycobacterium tuberculosis (Mtb), the causative agent of TB, is one of the most successful human pathogens and like many intracellular microbes, depends on specialized protein export systems, which enable active virulence factors to gain access to tissues or bloodstream of the host organism. In a variety of both prokaryotic and eukaryotic microorganisms, many of these cellular factors have been associated with extracellular vesicles (EVs), implying that vesicles may serve as an export system. Our studies showed that EV production could be extended to the more medically important strains of mycobacteria, Mtb and M. bovis BCG. EV production may provide an alternative mechanism for transport of immunomodulatory compounds such as lipoproteins and may allow mycobacteria confined within phagosomes to deliver virulence factors to other cellular compartments affecting the physiology of neighboring cells. Our recent report on the first Mtb gene controlling vesiculogenesis with an attenuated phenotype suggests that EV production might be a regulated process with relevant implication in pathogenesis. Our current efforts are directed to unravel the molecular machinery of vesiculogenesis in Mtb and the development of novel TB vaccines based on EVs. (ii) Most approved vaccines against bacterial pathogens are believed to mediate protection by eliciting antibody responses. However, it has been difficult to apply this formula to TB because of the difficulty in reliably eliciting protective antibodies. We recently develop capsular polysaccharide conjugates by linking on the mycobacterial capsular polysaccharide (PS) arabinomannan (AM) to several immunogenic proteins. Conjugate vaccine immunized mice infected with Mtb had lower bacterial numbers in lungs and spleen, and lived longer than control mice. These findings provided additional evidence that humoral immunity can contribute to protection against Mtb. We also showed that AM is antigenically variable and could potentially form the basis for a serological characterization of mycobacteria based on serotypes. We recently demonstrated that culture conditions affecting the BCG capsule have very important implications for vaccine efficacy. We are currently interested in decipher the global antigenic variability of Mtb capsular AM. To this end we have combined bioinformatics, genetics, structural biology and genetics to unravel how Mtb has shaped it cell surface during its evolutionary history of interaction with the human being.