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- Title
Mycobacterium ulcerans challenge strain selection for a Buruli ulcer controlled human infection model.
- Authors
Muhi, Stephen; Buultjens, Andrew H.; Porter, Jessica L.; Marshall, Julia L.; Doerflinger, Marcel; Pidot, Sacha J.; O'Brien, Daniel P.; Johnson, Paul D. R.; Lavender, Caroline J.; Globan, Maria; McCarthy, James; Osowicki, Joshua; Stinear, Timothy P.
- Abstract
Critical scientific questions remain regarding infection with Mycobacterium ulcerans, the organism responsible for the neglected tropical disease, Buruli ulcer (BU). A controlled human infection model has the potential to accelerate our knowledge of the immunological correlates of disease, to test prophylactic interventions and novel therapeutics. Here we present microbiological evidence supporting M. ulcerans JKD8049 as a suitable human challenge strain. This non-genetically modified Australian isolate is susceptible to clinically relevant antibiotics, can be cultured in animal-free and surfactant-free media, can be enumerated for precise dosing, and has stable viability following cryopreservation. Infectious challenge of humans with JKD8049 is anticipated to imitate natural infection, as M. ulcerans JKD8049 is genetically stable following in vitro passage and produces the key virulence factor, mycolactone. Also reported are considerations for the manufacture, storage, and administration of M. ulcerans JKD8049 for controlled human infection. Non-technical author summary: In this paper, we progress our research towards establishing a controlled human infection model (CHIM) of Buruli ulcer, caused by Mycobacterium ulcerans. It is crucial that the challenge agent used for such experiments is thoroughly characterised; not only is this important to ensure standardisation between participants, but also to reinforce their safety. Using established criteria, we systematically demonstrate why the isolate M. ulcerans JKD8049 may be a suitable challenge strain. This strain is non-genetically modified, susceptible to antibiotics, can be cultured in relatively simple media, and can be filtered and preserved as individual bacteria to ensure accurate dosing of participants. Even after repeatedly culturing the organism for months, it remains genetically stable, so significant mutations are not expected to develop during manufacture. After preserving the isolate at -80°C, it can be revived and diluted for human inoculation at very low doses. Importantly, it produces the toxin mycolactone, so it is expected to recreate typical Buruli ulcer disease in participants, which will be important to properly test vaccines and other therapeutics. We also demonstrate a set of principles to ensure the produced batch is free from contamination.
- Subjects
BURULI ulcer; MYCOBACTERIUM; INFECTION control; NEGLECTED diseases; MYCOBACTERIAL diseases; VACCINE trials; FUNGAL viruses; MYCOBACTERIA
- Publication
PLoS Neglected Tropical Diseases, 2024, Vol 18, Issue 5, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0011979