Smegmatis meets tuberculosis

Abstract

have created an attenuated strain of Mycobacterium smegmatis containing M. tuberculosis genes. The vector conferred better protection against tuberculosis than the standard bacillus Calmette-Guérin (BCG) vaccine in mice. 1 The not-for-profit Aeras has licensed the technology and is now working with the researchers to determine an optimal combination of genes to use in M. smegmatis.The only prophylactic for TB is the BCG vaccine, which is prepared from a live, attenuated bacterial strain closely related to M. tuberculosis called M. bovis. In BCG, deletion of the region of difference 1 locus is responsible for its attenuation and loss of virulence. 2 Although the vaccine protects infants from pulmonary TB, it is not effective at protecting adults, nor can it prevent transmission or clear latent infections.Albert Einstein College of Medicine's new vaccine originated from research on Mycobacterium secretion systems and their role in helping the bacteria evade the host immune system.M. tuberculosis employs multiple strategies to do this, including a specialized secretion system encoded by genes in the bacterium's esx-1 locus. The M. tuberculosis genome contains four additional esx loci-esx-2 through esx-5-that may encode secretion systems, but their functions are poorly understood.The researchers were exploring the role of the esx-3 locus in immune evasion because it is the only esx locus conserved across all strains of Mycobacterium. 3,4 The locus is essential for the growth of M. tuberculosis and the attenuated M. bovis strain used in BCG. 5 The team found that unlike M. tuberculosis and BCG, the more distant relative M. smegmatis could grow normally when esx-3 was deleted, and thus they selected the strain to study the locus' role.In mouse models of M. smegmatis infection, an esx-3-deleted strain was unable to evade the host innate immune system, whereas wildtype and esx-1-deleted strains did not elicit a strong innate immune response. Moreover, the esx-3-deleted strain had attenuated virulence.Next, the researchers inserted a set of 26 M. tuberculosis genes including all 11 esx-3 genes into the attenuated M. smegmatis strain. Despite the addition of esx-3 genes, the strain still was not virulent and could not evade the immune system.At this point, the researchers began to think they had the makings of a vaccine vector in hand.In proof-of-concept studies in mouse models of lethal M. tuberculosis infection, i.v. or subcutaneous immunization with the recombinant attenuated M. smegmatis strain increased survival and resulted in greater decreases in tissue bacterial load compared with immunization using the BCG vaccine. Several of the mice receiving the recombinant M. smegmatis vaccine had tissue bacterial load reductions that were over 1,000-fold greater than those for mice given BCG.Results were published in Nature Medicine. "This is the first time we have seen a vaccine that can produce over three-log reductions in tissue bacterial burdens over BCG and a bactericidal immune response that causes a sustained decline...