London School of Hygiene & Tropical Medicine

Have you ever wondered why there is not an effective vaccine against tuberculosis (TB), a disease that kills one and half million people each and every year? Or why having an episode of TB does not give protection against a new infection like other diseases such a measles? The answer lies in the fact that TB is an ancient disease and the bacterium (Mycobacterium tuberculosis) has, over the millennia, evolved clever ways of evading the human immune system. To make an effective vaccine we first need to understand the tricks employed by the bacteria to allow them to survive and thrive within the human body.

It was hoped that the revolution in molecular biology and whole genome sequencing would quickly answer these questions as it did for meningitis B, but TB has proved a stubborn opponent. Some of the most interesting parts of the genome have been difficult to decipher and two gene families in particular have been problematic. The PE and PPE genes comprise approximately 10% of the genome (168 genes).  They have been largely excluded in most previous genome studies because the standard methods of analysis did not work for them. These two families contain a disperse collection of genes that have been grouped together because of structural similarities. They include genes for some important bacterial proteins that are believed to interact with the external environment, including the immune cells produced in response to the infection.

In recent years it is has become apparent that TB bacteria evolved independently in different parts of the world to create strain types, or lineages, each with slightly different characteristics. Not all the strains behave in the same way. Some lineages appear better at infecting people than others (more virulent), they can affect the patient’s immune system in different ways. By examining each of the 168 PE and PPE genes in over 500 different clinical isolates (bacteria that were isolated from individual TB patients) we were able to untangle the data and identify some unexpected differences between strains.  We found that on average the PE and PPE genes had more mutations and were considerably more variable than other TB genes. We also found by analysing small changes in the genome (single nucleotide polymorphisms, SNPS) that most of the PE and PPE genes within a specific lineage appeared to have evolved in similar ways. For a few genes however, the pattern of evolution did not fit within the classic lineages and a different mechanism of evolution appears to be at play.

The current BCG vaccine for TB is only partially effective among children , and against certain forms of the disease such a meningitis, so the race is on to develop a vaccine that is effective for all age groups and all forms of the disease, including highly infectious pulmonary TB.

Now that we know how TB bacteria vary in their response to the human immune system, vaccine developers can design strategies to protect against all the different TB lineages. We may finally turn the tables on this intriguing but treacherous bacteria.

Publication:      

• Phelan J et al. Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages. BMC Genomics 2016; 17:151 DOI: 10.1186/s12864-016-2467-y

Image: Phylogenetic tree of pe/ppe genes, constructed with SNPs.  Source: Phelan J et al. “Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages” BMC Genomics 2016.