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Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer.

Buffen K, Oosting M, Quintin J, Ng A, Kleinnijenhuis J, Kumar V, van de Vosse E, Wijmenga C, van Crevel R, Oosterwijk E, Grotenhuis AJ, Vermeulen SH, Kiemeney LA, van de Veerdonk FL, Chamilos G, Xavier RJ, van der Meer JW, Netea MG, Joosten LA - PLoS Pathog. (2014)

Bottom Line: It has been recently proposed that the non-specific effects of BCG are mediated through epigenetic reprogramming of monocytes, a process called trained immunity.Single nucleotide polymorphisms (SNPs) in the autophagy genes ATG2B (rs3759601) and ATG5 (rs2245214) influenced both the in vitro and in vivo training effect of BCG upon restimulation with unrelated bacterial or fungal stimuli.These findings identify a key role of autophagy for the nonspecific protective effects of BCG.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.

ABSTRACT
The anti-tuberculosis-vaccine Bacillus Calmette-Guérin (BCG) is the most widely used vaccine in the world. In addition to its effects against tuberculosis, BCG vaccination also induces non-specific beneficial effects against certain forms of malignancy and against infections with unrelated pathogens. It has been recently proposed that the non-specific effects of BCG are mediated through epigenetic reprogramming of monocytes, a process called trained immunity. In the present study we demonstrate that autophagy contributes to trained immunity induced by BCG. Pharmacologic inhibition of autophagy blocked trained immunity induced in vitro by stimuli such as β-glucans or BCG. Single nucleotide polymorphisms (SNPs) in the autophagy genes ATG2B (rs3759601) and ATG5 (rs2245214) influenced both the in vitro and in vivo training effect of BCG upon restimulation with unrelated bacterial or fungal stimuli. Furthermore, pharmacologic or genetic inhibition of autophagy blocked epigenetic reprogramming of monocytes at the level of H3K4 trimethylation. Finally, we demonstrate that rs3759601 in ATG2B correlates with progression and recurrence of bladder cancer after BCG intravesical instillation therapy. These findings identify a key role of autophagy for the nonspecific protective effects of BCG.

No MeSH data available.


Related in: MedlinePlus

Autophagy affected by SNP in ATG2B.(a–b) Monocytes genotyped for ATG2B rs3759601 were seeded on coverslips, and stimulated with BCG. After 1 hour of stimulation, cells were fixed and stained with an antibody against LC3. Slides were analyzed by confocal microscopy. Data are representative for 3 experiments.
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ppat-1004485-g003: Autophagy affected by SNP in ATG2B.(a–b) Monocytes genotyped for ATG2B rs3759601 were seeded on coverslips, and stimulated with BCG. After 1 hour of stimulation, cells were fixed and stained with an antibody against LC3. Slides were analyzed by confocal microscopy. Data are representative for 3 experiments.

Mentions: To identify the effect of rs3759601 in ATG2B on autophagy, the amount of LC3+ vesicles in BCG stimulated monocytes of individuals carrying the major or minor variant of the SNP have been compared. A decrease in autophagosome formation of individuals carrying the CC genotype can be seen as demonstrated by a lower percentage of LC3+ monocytes (Figure 3a–b).


Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer.

Buffen K, Oosting M, Quintin J, Ng A, Kleinnijenhuis J, Kumar V, van de Vosse E, Wijmenga C, van Crevel R, Oosterwijk E, Grotenhuis AJ, Vermeulen SH, Kiemeney LA, van de Veerdonk FL, Chamilos G, Xavier RJ, van der Meer JW, Netea MG, Joosten LA - PLoS Pathog. (2014)

Autophagy affected by SNP in ATG2B.(a–b) Monocytes genotyped for ATG2B rs3759601 were seeded on coverslips, and stimulated with BCG. After 1 hour of stimulation, cells were fixed and stained with an antibody against LC3. Slides were analyzed by confocal microscopy. Data are representative for 3 experiments.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214925&req=5

ppat-1004485-g003: Autophagy affected by SNP in ATG2B.(a–b) Monocytes genotyped for ATG2B rs3759601 were seeded on coverslips, and stimulated with BCG. After 1 hour of stimulation, cells were fixed and stained with an antibody against LC3. Slides were analyzed by confocal microscopy. Data are representative for 3 experiments.
Mentions: To identify the effect of rs3759601 in ATG2B on autophagy, the amount of LC3+ vesicles in BCG stimulated monocytes of individuals carrying the major or minor variant of the SNP have been compared. A decrease in autophagosome formation of individuals carrying the CC genotype can be seen as demonstrated by a lower percentage of LC3+ monocytes (Figure 3a–b).

Bottom Line: It has been recently proposed that the non-specific effects of BCG are mediated through epigenetic reprogramming of monocytes, a process called trained immunity.Single nucleotide polymorphisms (SNPs) in the autophagy genes ATG2B (rs3759601) and ATG5 (rs2245214) influenced both the in vitro and in vivo training effect of BCG upon restimulation with unrelated bacterial or fungal stimuli.These findings identify a key role of autophagy for the nonspecific protective effects of BCG.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.

ABSTRACT
The anti-tuberculosis-vaccine Bacillus Calmette-Guérin (BCG) is the most widely used vaccine in the world. In addition to its effects against tuberculosis, BCG vaccination also induces non-specific beneficial effects against certain forms of malignancy and against infections with unrelated pathogens. It has been recently proposed that the non-specific effects of BCG are mediated through epigenetic reprogramming of monocytes, a process called trained immunity. In the present study we demonstrate that autophagy contributes to trained immunity induced by BCG. Pharmacologic inhibition of autophagy blocked trained immunity induced in vitro by stimuli such as β-glucans or BCG. Single nucleotide polymorphisms (SNPs) in the autophagy genes ATG2B (rs3759601) and ATG5 (rs2245214) influenced both the in vitro and in vivo training effect of BCG upon restimulation with unrelated bacterial or fungal stimuli. Furthermore, pharmacologic or genetic inhibition of autophagy blocked epigenetic reprogramming of monocytes at the level of H3K4 trimethylation. Finally, we demonstrate that rs3759601 in ATG2B correlates with progression and recurrence of bladder cancer after BCG intravesical instillation therapy. These findings identify a key role of autophagy for the nonspecific protective effects of BCG.

No MeSH data available.


Related in: MedlinePlus