Biological function and Vaccine Potential of Proteins from an M. tuberculosis secretion system

Mortensen, Rasmus J.

4. term

Nanotechnology, Master

2011

2011-07-07

69 pages

Det mycobakterielle ESX-3 secerneringssystem er involveret i tilegnelsen af værtens jern under en infektion med Mycobacterium tuberculosis (M.tb). Jern er en af de vigtigste virulensfaktoror for M.tb og ESX-3 er en forudsætning for mycobakteriel vækst. Proteinerne fra ESX-3 kan derfor tænkes at udgøre interessante drug targets eller nye vaccine antigener. I dette studie er proteininteractioner anført mellem tre strukturelle proteiner fra ESX-3. Det foreslås at disse proteiner danner et membranbundet transporterkompleks, der kan været et effektivt drug target til at kontrollere bakteriel vækst. De vacciner der i øjeblikket er i klinisk afprøvning, er baseret på immunodominante antigener, som er stærkt genkendt under en infektion. Dette studie viser betydelig beskyttende virkeevne af tre ikke-karakteriserede proteiner fra ESX-3, der ikke inducerer målelige immunresponser i inficerede dyr. Et af disse, giver højere beskyttelses niveauer end hvad der ses for andre velkendte antigener. Vaccination med denne type of 'subdominante antigener', tillader priming af nye beskyttende antigener oveni et allerede eksisterende immunsvar efter eksponering til M.tb. Det kan derfor tænkes at latent inficerede individer kan forhindres i at reaktivere til aktiv sygdom, hvis de tildeles dette antigen, hvilket fremsætter antigenet som en lovende kandidat til at udgøre backbonet i en ny generation af subunit vacciner mod M.tb.

The mycobacterial ESX-3 secretion system is involved in host iron sequestering during Mycobacterium tuberculosis (M.tb) infections. Iron is one of the most important virulence factors of M.tb and ESX-3 is a prerequisite for mycobacterial growth. The proteins of ESX-3 might therefore constitute interesting drug targets or new vaccine antigens. In here, protein interactions are indicated between three structural proteins of ESX-3. These proteins are suggested to form a membrane bound transporter complex that might be an efficient drug target to control bacterial growth. Vaccines currently in clinical trials are based on immunodominant antigens that are strongly recognized during infection. This study demonstrates substantial protective efficacy of three uncharacterized proteins from ESX-3 that do not induce detectable immune responses in infected animals. One of these, confer higher protection levels than what is observed for other well-known vaccine antigens. Vaccination with this kind of subdominant antigens, allows priming of new protective antigens on top of a pre-existing immune response after exposure to M.tb.. Administering this antigen to latently infected individuals can therefore be speculated to prevent disease reactivation which states this antigens as a promising candidate for making up the backbone in a new generation of subunit vaccines against M.tb.

tuberculosis ; vaccine ; secretion system ; immunology

Download
View record in AAU Student Projects