Macrophage-induced drug tolerant persisters in tuberculosis

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More than 1.8 million people die worldwide each year from Tuberculosis (TB), making it the biggest cause of mortality due to a single bacterial infection. This equates to the passengers of more than 10 full Boeing 747's succumbing to the disease every single day. This is despite the availability of antibiotics against the causative agent of the disease Mycobacterium tuberculosis (Mtb). Antibiotic treatment for any disease is a lengthy process; however, in TB, eradication of the infecting bacilli takes 6-9 months and requires at least 3 highly toxic drugs. This is primarily due to the presence of a small group or sub-population of bacteria that can resist and survive antibiotic treatment. Termed drug-tolerant persisters, these bacilli were first discovered in 1942 and yet we are still a long way from understanding these elusive bacteria. One of the reasons for this is that they are present at such low numbers (approximately 1 persistent bacilli in 10, 000) that they are difficult to study. Preliminary results from our laboratory have shown that interacting with the very cell that we, the host, deploy to kill invading pathogens can induce much higher numbers of these persister bacilli. Upon infection with Mtb or many other invading pathogens, our immune system deploys white blood cells to kill the invader, one of which is called the macrophage. From our results it appears that Mtb uses our own macrophages as a Trojan Horse and when inside this host cell changes into a virtually untreatable drug-tolerant persister cell. We have called these macrophage-induced persisters or MIPs. The trigger(s) for the formation of drug-tolerant persisters is currently unknown but could represent an ideal target for future drug developmentOur aims1) To identify the bacterial trigger genes required for the formation of MIPs. Discovering the bacterial genes vital to the formation of drug-tolerant persisters would add to our understanding of how Mtb is able to evade killing and could represent future drug targets.2) To determine the macrophage conditions responsible for MIP formation. Persister cells are notoriously difficult to treat due to their rarity in a population. By identifying what factors or conditions the bacterium is sensing to induce the formation of MIPs, we will be able to generate enough persisters to enable further study. We also intend to develop a novel drug testing platform so we can identify drugs capable of killing these MIPs, i.e. persisters formed whilst within our own bodies.Potential applications and benefits Targeting drug-tolerant persisters is key to combatting TB. Understanding the nature of this sub-population of bacteria will enable us to develop new treatment strategies that either attack the bacteria themselves or push the host immune response in the right direction. This could improve treatment tolerance among patients, and improve treatment success rates. The current threat of drug resistance combined with the HIV epidemic makes the development of new TB treatment strategies of the upmost importance.