[Global Gene Regulation in M. tb]

Several years ago our lab discovered a central regulator of M. tb called Lsr2.  Lsr2 is a small protein that is ubiquitous in mycobacteria and related actinomycetes.  Unexpectedly, we found that Lsr2 is a functional analog of H-NS, an extensively studied nucleoid-associated protein in Gram-negative bacteria.  Like H-NS, Lsr2 selectively binds and silences AT-rich DNA sequences that often encode genes involved in antibiotic resistance and virulence and are acquired by horizontal gene transfer from a foreign source.  Despite the fact that Lsr2 and H-NS share no sequence homology and structural similarity, these two proteins are functionally equivalent and can complement one another, thus representing a striking example of convergent evolution.  Our recent work indicates that Lsr2 and H-NS employ a common mechanism to selectively target DNA sequences that are more AT-rich than its core genome, which provides a molecular mechanism by which xenogeneic silencing proteins (like Lsr2 and H-NS) distinguish genetic materials that is self from non-self.  Our finding has profound implications on the evolution of bacterial genome and virulence.


Current projects in this area include:

What is the role of Lsr2 in M. tb infection?
How does Lsr2 regulate specific virulence genes?
What is the role of Lsr2 in the maintenance of genome stability of M. tb?
What is the structure of the oligomerization domain of Lsr2?
What is the function of Lsr2 homologs in other actinomycetes such as Streptomyces? 

lsr2


[Novel Strategies to Improve the Efficacy of BCG]

BCG is currently the only available vaccine against TB.  BCG was developed about 100 years ago and has been one of the most widely used (> 3 billion doses) vaccines in human history.  However, BCG is not an ideal vaccine and only affords some levels of protection for children against severe forms of TB.  The protection of BCG against the main form of TB, pulmonary TB in adults, is highly variable and generally poor.  Nonetheless, currently the main strategies to develop the next generation of TB vaccines are to construct recombinant BCG strains with improved antigenicity and combine these with subunit vaccines (DNA or protein).

Over the past 3 years, our lab has undertaken a systematic approach to compare the different BCG strains that are currently used worldwide.  By comparative genomic analysis, coupled with biochemical analysis and reviewing of historical records, we have now identified several molecular factors that influence the clinical properties of BCG, namely, the safety, immunogenicity and protective efficacy. Currently we are working on several novel strategies to construct recombinant BCG, with the ultimate goal of developing a safe, more effective TB vaccine than current BCG.  We are also working on several novel subunit vaccine candidates identified by our analysis.

Current projects in this area include:

Do these recombinant BCG exhibit enhanced immunogenicity in vaccinated hosts?
Are these recombinant BCG safe, particularly in immunocompromised hosts?
Is there a relationship between the level of virulence and immunogenicity?

BCG


[Virulence and Host-Pathogen Interactions]

A long-standing interest in the Liu Lab is the mycobacterial cell wall, particularly its structure and function.  Our current interests are to understand the biological function of various cell wall components in the context of virulence and pathogenesis. We have isolated mutants that are defective in different forms of these lipids and are currently working on the biosynthesis of glycolipids such as PDIM/PGL, and LOS.  In addition, we have been working on the specialized protein secretion systems (Type VII) that are important for mycobacterial virulence.

Current questions in this area include:

Are these cell wall defective mutants attenuated in infected animals?
What is the biosynthetic pathway of individual cell wall components?
How is the biosynthesis of the cell wall component regulated especially during infection?
How are different component of the ESX secretion system organized in cells to produce the active pathway?

cell wall

 

[Novel Drug Targets]

We are interested in identifying and validating metabolic pathways that are potential targets for drug development. In collaboration with others, we have also initiated searching of novel compounds that target these pathways, and we have now identified several promising compounds.

Current questions in this area include:

What is the in vivo target of the identified compounds?
Are these compounds effective in infected animals?

drugs