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Principal Investigator: Admire Dube
Organization: STELLENBOSCH UNIVERSITY
Fiscal Year: 2024
Award: $303,416
Funding agency: National Institute of Allergy and Infectious Diseases
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 β-
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.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Adherence><Advanced Development><Alveolar Macrophages><Animal Model><Animal Models and Related Studies><Anti-Bacterial Response><Antibacterial Response><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antimicrobial Effect><Appearance><Architecture><Artificial nano particles><Artificial nanoparticles><Award><Bacteria><Bacterial Infections><Biocompatible Materials><Biological Mimetics><Biomaterials><Biomimetics><Bone Marrow><Bone Marrow Reticuloendothelial System><Case Study><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><Clinical><Communicable Diseases><Country><Data><Death><Defense Mechanisms><Development><Disadvantaged><Disease><Disorder><Drug Therapy><Drug Tolerance><Drug resistance><Drug resistance in Mtb><Drug resistance in Mycobacterium Tuberculosis><Drug resistant M Tuberculosis><Drug resistant Mtb><Drug resistant Mycobacteria Tuberculosis><Drugs><Engineering / Architecture><Exhibits><Fluorescence><Formulation><Funding><Glycans><Goals><HIV><Health><Human><Human Immunodeficiency Viruses><Hybrids><Immune><Immune mediated therapy><Immune response><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologically Directed Therapy><Immunologics><Immunology><Immunomodulation><Immunotherapeutic agent><Immunotherapy><In Vitro><Incidence><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Institution><Intracellular Communication and Signaling><Invaded><Investigators><Kinetics><Knowledge><LAV-HTLV-III><Lipids><Lymphadenopathy-Associated Virus><M tb><M tuberculosis><M tuberculosis H37Rv><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis H37Rv><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MDR Tuberculosis><MDR-TB><MTB infection><Macrophage><Macrophage Activation><Mediating><Medication><Metals><Methods><Mice><Mice Mammals><Miscellaneous Antibiotic><Modeling><Modern Man><Molecular><Mtb drug resistance><Multi-Drug Resistant Tuberculosis><MultiDrug Resistance Tuberculosis><Multidrug-Resistant Tuberculosis><Murine><Mus><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis H37Rv><Mycobacterium tuberculosis infection><Mycolic Acid><Mφ><NIH><Nanotechnology><National Institutes of Health><Outcome><Pathway interactions><Persons><Pharmaceutical Preparations><Pharmacotherapy><Phenotype><Polymers><Polysaccharides><Population><Position><Positioning Attribute><Property><Public Health><Publishing><Pulmonary Macrophages><R-Series Research Projects><R01 Mechanism><R01 Program><Regimen><Reporter><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Research Training><Researchers><Rod><Scientist><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><South Africa><South Dakota><Southern Rhodesia><Standardization><Structure><System><TB infection><TB therapy><TB treatment><Training Programs><Treatment Failure><Treatment Protocols><Treatment Regimen><Treatment Schedule><Tuberculosis><United States><United States National Institutes of Health><Universities><Virulent><Virus-HIV><Work><Zimbabwe><Zimbabwe Rhodesia><anti-microbial><anti-microbial effect><antimicrobial><bacteria infection><bacterial disease><bacterial persister><beta-Glucans><biological material><biological signal transduction><case report><co-infection><coinfection><developmental><disseminated TB><disseminated tuberculosis><drug resistance M Tuberculosis><drug resistance Mycobacteria Tuberculosis><drug resistant><drug resistant M.tb><drug treatment><drug-sensitive><drug/agent><engineered nano particle><engineered nanoparticle><host response><immune drugs><immune modulation><immune regulation><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunologic reactivity control><immunologic therapeutics><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunotherapeutics><immunotherapy agent><improved><in vivo><infection due to Mycobacterium tuberculosis><innovate><innovation><innovative><latent infection><mimicry><model of animal><mtb><multidisciplinary><multidrug-resistant TB><mycobacterial><nano medicinal><nano medicine><nano particle><nano polymer><nano tech><nano technology><nano-sized particle><nano-technological><nanomedicinal><nanomedicine><nanoparticle><nanopolymer><nanosized particle><nanotech><nanotechnological><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathogen><pathway><persistent bacteria><polycaprolactone><polymer><polymeric><psychological defense mechanism><resistance strain><resistance to Drug><resistant strain><resistant to Drug><response><therapy failure><tool><trafficking><treat M. tuberculosis><treat Mtb><treat Mycobacterium tuberculosis><treat tb><treat tuberculosis><tuberculosis infection><tuberculosis therapy><tuberculosis treatment><tuberculous spondyloarthropathy><uptake><β-Glucans>