Improving TB vaccine design by natural selection of intracellularly processed epitopes presented in primary tissues of murine model for protective imm

SUMMARY
One of the main hallmarks of Mycobacterium tuberculosis (MTB) pathogenesis is its ability to manipulate the timing of the immune response to its own advantage by changing expression of its antigens to avoid early recognition and destruction. MTB has capacity for infection of a wide range of tissues [Fanning A, 1999] with extrapulmonary TB representing approximately 15% of newly reported cases and 20-30% of relapsed cases [Global Tuberculosis Report 2017, WHO] and while macrophages constitute its main primary host, other cell types, such as professional phagocytes (i.e. dendritic cells) and non-professional antigen presenting cells (APCs) i.e. epithelial cells are submissive to the pathogen [Mvubu NE 2016, Harrif MJ, 2014, Lerner TR 2016] and can process and present MTB antigens [Flyer DC 2002, Penn BH 2018]. Cross-presentation of foreign antigens by host is a critical part of the process and in MTB infection this predominantly involves MHC-I receptors associated with short peptides derived via the intracellular proteasome-focused processing pathway [Adiko AC, 2015; Chen H, 2016; Ivanyi J, 2014]. Understanding and being able to influence this system is a fundamental part of next generation vaccine design.
HYPOTHESIS
The leading project hypothesis is that stimulation of Mtb antigens cross-presentation pathways may translate in identification of new protective antigens for next generation of vaccines.
AIMS
Objective 1. To examine BCG and MTB presentation upon in vitro infection in various mouse organs grouped as follows:
Primary and secondary lymphoid organs Urinary system Respiratory system Cardiac system
Differentiated bone marrow cells
Objective 2. To ascertain antigenic changes in BCG and MTB presentation upon cross-presentation pathways stimulation
METHODS AND TECHNIQUES
- organ collection for in vitro infection assays and tissue culture
- extraction and purification of immunogenic complexes
- antigen(s) identification via mass spectrometry (collaborative work)
FUTURE PROSPECTS
Any new identified antigens / methods enhancing their presentation may be included into the current TB vaccination strategies to improve their efficacy
REFERENCES
1. https://www.who.int/tb/publications/global_report/gtbr2017_main_text.pdf
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