SUMMARY
Tuberculosis remains a major global public health threat. Although relatively effective drug regimens are
available, treatment failure remains a major roadblock to tuberculosis control. This is in part due to a high
incidence of drug-resistant Mycobacterium tuberculosis (Mtb) strains, as well as the phenomenon of bacterial
persistence. Persisters represent a reservoir of latent infection, which may progress to active disease when host
immunity is compromised (e.g., with HIV co-infection), and also potentially contribute to the emergence of further
drug resistance. Mtb is able to subvert key innate immune defence mechanisms exerted by the host macrophage;
it can dampen the immune response, subvert macrophage killing and create a protected niche within this host
cell. In the proposed work, the capacity of engineered nanoparticles to favourably modulate the response of
macrophage, through delivered immunomodulatory signals, and achieve death of intracellular Mtb, will be
investigated. These unique nanoparticles mimic Mtb (i.e. bacteriomimetic) in selected aspects of size, shape and
composition. The nanoparticles proposed here are lipid polymer hybrid nanoparticles and metal organic
frameworks (spherical and rod shaped) incorporating mycolic acids and/or the fungal wall polysaccharide ß-
glucan. Strong published and preliminary data demonstrates the capacity of the polymer nanoparticles to induce
killing of virulent Mtb in macrophages. This killing is only evident in intracellular Mtb and is similar to that achieved
using an antibiotic. Metal organic framework nanoparticles can be synthesized and coated with macrophage
targeting materials. The hypothesis of the project is that bacteriomimetic, immunotherapeutic nanoparticles will
be effective against all forms of Mtb (including drug-resistant and persister populations) through immune
modulation. Specifically, the project has 3 aims: 1) Characterize a panel of bacteriomimetic immunotherapeutic
NPs; 2) Investigate response of infected macrophages and intracellular bacteria to the panel of NPs; 3) Assess
in vivo response to, and efficacy of, NPs in murine infection model. This project is at the cutting edge of
nanotechnology and tuberculosis research, and will provide several exciting research capacity development
opportunities for scientists from South Africa and Zimbabwe (through a partnership with an on-going NIH funded
HIV Research Training Program). The multi-national research team will be led by 3 new investigators, with
research teams from Stellenbosch University, South Africa, the University of the Western Cape (a historically
disadvantaged institution in South Africa) and South Dakota State University in the USA, partnered to propose a
novel immunotherapy approach for tuberculosis based on nanoparticle-based delivery systems. The team has
expertise in nanoparticle formulation and characterisation, in vitro and in vivo infection models, and tuberculosis
immunology. Our results will advance the development of nanoparticle-based, host-directed therapies for
tuberculosis.