Biological function and Vaccine Potential of Proteins from an M. tuberculosis secretion system
Author
Mortensen, Rasmus J.
Term
4. term
Education
Publication year
2011
Submitted on
2011-07-07
Pages
69
Abstract
Tuberkulosebakterien Mycobacterium tuberculosis (M.tb) er stærkt afhængig af jern for at vokse. ESX-3-sekretionssystemet hjælper bakterien med at skaffe jern i værten og er nødvendigt for mykobakteriers vækst. Derfor kan ESX-3-proteiner være interessante mål for lægemidler eller som vaccineantigener. I denne undersøgelse påvises interaktioner mellem tre strukturelle ESX-3-proteiner, som tyder på, at de danner et membranbundet transportkompleks. Et sådant kompleks kan være et effektivt lægemiddelmål til at begrænse bakterievækst. Mange TB-vacciner i kliniske forsøg fokuserer på immunodominante antigener (proteiner, som immunforsvaret naturligt genkender stærkt under infektion). Her viser vi, at tre hidtil ukarakteriserede ESX-3-proteiner, som ikke udløser målbare immunresponser hos inficerede dyr, alligevel giver betydelig beskyttelse ved vaccination. Ét af disse gav endda højere beskyttelse end nogle velkendte vaccineantigener. Vaccination med sådanne subdominante antigener (mindre naturligt fremtrædende for immunforsvaret) kan primere nye beskyttende responser oven på en eksisterende immunitet efter eksponering for M.tb. At give dette antigen til personer med latent TB-infektion kan potentielt forebygge reaktivering af sygdommen, hvilket gør det til en lovende kandidat som rygrad i næste generations subunitvacciner (vacciner baseret på udvalgte dele af bakterien) mod M.tb.
The tuberculosis bacterium Mycobacterium tuberculosis (M.tb) relies heavily on iron to grow. The ESX-3 secretion system helps the bacterium obtain iron in the host and is essential for mycobacterial growth. ESX-3 proteins are therefore potential targets for drugs or vaccine antigens. This study identifies interactions among three structural ESX-3 proteins, suggesting they form a membrane-bound transporter complex. Such a complex could be an effective drug target to limit bacterial growth. Many TB vaccines in clinical trials focus on immunodominant antigens (proteins that the immune system naturally recognizes strongly during infection). Here, we show that three previously uncharacterized ESX-3 proteins that do not elicit detectable immune responses in infected animals nonetheless provide substantial protection when used for vaccination. One of these even confers higher protection than some well-known vaccine antigens. Vaccinating with such subdominant antigens (less naturally prominent to the immune system) can prime new protective responses on top of pre-existing immunity after exposure to M.tb. Administering this antigen to individuals with latent TB infection could potentially prevent disease reactivation, making it a promising candidate for the backbone of next-generation subunit vaccines (vaccines based on selected parts of the bacterium) against M.tb.
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