Autophagy Controls BCG-Induced Trained Immunity and the Response to Intravesical BCG Therapy for Bladder Cancer

被引：206

作者：

Buffen, Kathrin ^{[1
,2
]}

Oosting, Marije ^{[1
,2
]}

Quintin, Jessica ^{[1
,2
]}

Ng, Aylwin ^{[3
,4
,5
]}

Kleinnijenhuis, Johanneke ^{[1
,2
]}

Kumar, Vinod ^{[6
]}

van de Vosse, Esther ^{[7
]}

Wijmenga, Cisca ^{[6
]}

van Crevel, Reinout ^{[1
,2
]}

Oosterwijk, Egbert ^{[8
]}

Grotenhuis, Anne J. ^{[9
,10
]}

Vermeulen, Sita H. ^{[9
,10
,11
]}

Kiemeney, Lambertus A. ^{[8
,9
,10
]}

van de Veerdonk, Frank L. ^{[1
,2
]}

Chamilos, Georgios ^{[12
]}

Xavier, Ramnik J. ^{[3
,4
,5
]}

van der Meer, Jos W. M. ^{[1
,2
]}

Netea, Mihai G. ^{[1
,2
]}

Joosten, Leo A. B. ^{[1
,2
]}

机构：

[1] Radboud Univ Nijmegen, Dept Internal Med, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, RIMLS, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[3] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA USA

[4] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA

[5] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA USA

[6] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[7] Leiden Univ, Dept Infect Dis, Med Ctr, Leiden, Netherlands

[8] Radboud Univ Nijmegen, Dept Urol, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[9] Radboud Univ Nijmegen, Dept Hlth Evidence, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[10] Radboud Univ Nijmegen, RIHS, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[11] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[12] Univ Crete, Dept Med, Iraklion, Crete, Greece

来源：

PLOS PATHOGENS | 2014年 / 10卷 / 10期

基金：

欧洲研究理事会;

关键词：

NATURAL-KILLER-CELLS; CANDIDA-ALBICANS; RANDOMIZED-TRIAL; DENDRITIC CELLS; CHILD SURVIVAL; HOST-DEFENSE; WEST-AFRICA; VACCINATION; MONOCYTES; IMMUNOTHERAPY;

D O I：

10.1371/journal.ppat.1004485

中图分类号：

Q93 [微生物学];

学科分类号：

071005 [微生物学];

摘要：

The anti-tuberculosis-vaccine Bacillus Calmette-Guerin (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 beta-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.

引用

页数：10

共 29 条

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