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Phenotypic screening the host antimicrobial responses towards the eradication of Mycobacterium tubercuosis

Periodic Reporting for period 1 - PHANTOM (Phenotypic screening the host antimicrobial responses towards the eradication of Mycobacterium tubercuosis)

Reporting period: 2018-10-01 to 2020-09-30

The co-evolution between hosts and their parasites is one of the most fascinating – yet still almost unexplored - examples of evolutionary adaptation. There is a paucity of information, however, on how the human immune system co-adapts to the parasites phenotypic plasticity, and how it dynamically rearranges its molecular phenotypes aiming to counteract the pathogenic threats. Hence, many therapies for the treatment of intracellular bacteria-related infections are currently obsolete, especially because of the rise in drug resistance. In this framework, the goal of my proposal was to decipher the unexplored phenotypic ‘bar-codes’ of host-pathogen interaction, to reversely engineer a drug delivery platform targeting infected cells only, and to eradicate intracellular parasites. The final aim will be the eradication of the severe intracellular pathogens Mycobacterium tuberculosis (Mtb), as is the major cause of mortality related to bacterial infection worldwide.
I focused first on the artificial recreation of the hallmark of every human tuberculosis infection, which is a necrotic granuloma. I was able to reconstruct not only its phenotypical features but also the macrophages sub-population characterizing it. I then infected these organoids and screened what kind of receptors macrophages express upon infection. This can be considered as a sort of ‘flag’ of infection, which makes it easier to produce drug directed towards infected cells only. I used this information to create nanoparticles able to recognize and target only those macrophages having the ‘flag’ of infection.
To date, the only way we approach infectious diseases is the use of antibiotics which are administered through all the body. Inevitably, the big problem is that these drugs diffuse passively and several times they can interact with random and not-desired target (off-target), which are the reasons behind the rise in side effect and drug resistance. This project demonstrates we can do a big step ahead in the development of highly precise drugs that target only infected cells and that are much more effective in the delivery process. This means we can treat patients with much less drug for a shorter period of time, and boost thus the eradication of drug resistance phenomenon.