PMID- 32111888
OWN - NLM
STAT- MEDLINE
DCOM- 20201123
LR  - 20211214
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 10
IP  - 1
DP  - 2020 Feb 28
TI  - Genetic and pharmacological inhibition of inflammasomes reduces the survival of 
      Mycobacterium tuberculosis strains in macrophages.
PG  - 3709
LID - 10.1038/s41598-020-60560-y [doi]
LID - 3709
AB  - Mycobacterium tuberculosis infection causes high rates of morbidity and 
      mortality. Host-directed therapy may enhance the immune response, reduce tissue 
      damage and shorten treatment duration. The inflammasome is integral to innate 
      immune responses but over-activation has been described in tuberculosis (TB) 
      pathology and TB-immune reconstitution syndrome. Here we explore how clinical 
      isolates differentially activate the inflammasome and how inflammasome inhibition 
      can lead to enhanced bacterial clearance. Wild-type, Nlrp3(-/-)/Aim2(-/-), 
      Casp1/11(-/-) and Asc(-/-) murine bone-marrow derived macrophages (BMDMs) were 
      infected with laboratory strain M. tuberculosis H37Rv or clinical isolates from 
      various lineages. Inflammasome activation and bacterial numbers were measured, 
      and pharmacological inhibition of NLRP3 was achieved using MCC950. Clinical 
      isolates of M. tuberculosis differed in their ability to activate inflammasomes. 
      Beijing isolates had contrasting effects on IL-1beta and caspase-1 activation, but 
      all clinical isolates induced lower IL-1beta release than H37Rv. Our studies suggest 
      the involvement of NLRP3, AIM2 and an additional unknown sensor in IL-1beta 
      maturation. Pharmacological blockade of NLRP3 with MCC950 reduced bacterial 
      survival, and combined treatment with the antimycobacterial drug rifampicin 
      enhanced the effect. Modulating the inflammasome is an attractive adjunct to 
      current anti-mycobacterial therapy that warrants further investigation.
FAU - Subbarao, Sathyavani
AU  - Subbarao S
AD  - MRC Centre for Molecular Bacteriology and Infection, Department of Infectious 
      Disease, Flowers Building, Imperial College London, London, SW7 2AZ, UK.
FAU - Sanchez-Garrido, Julia
AU  - Sanchez-Garrido J
AD  - MRC Centre for Molecular Bacteriology and Infection, Department of Infectious 
      Disease, Flowers Building, Imperial College London, London, SW7 2AZ, UK.
FAU - Krishnan, Nitya
AU  - Krishnan N
AD  - MRC Centre for Molecular Bacteriology and Infection, Department of Infectious 
      Disease, Flowers Building, Imperial College London, London, SW7 2AZ, UK.
FAU - Shenoy, Avinash R
AU  - Shenoy AR
AUID- ORCID: 0000-0001-6228-9303
AD  - MRC Centre for Molecular Bacteriology and Infection, Department of Infectious 
      Disease, Flowers Building, Imperial College London, London, SW7 2AZ, UK. 
      a.shenoy@imperial.ac.uk.
FAU - Robertson, Brian D
AU  - Robertson BD
AUID- ORCID: 0000-0001-5785-5307
AD  - MRC Centre for Molecular Bacteriology and Infection, Department of Infectious 
      Disease, Flowers Building, Imperial College London, London, SW7 2AZ, UK. 
      b.robertson@imperial.ac.uk.
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
GR  - MR/P028225/1/RCUK | Medical Research Council (MRC)/International
GR  - 108246/Z/15/Z/Wellcome Trust (Wellcome)/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200228
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Aim2 protein, mouse)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Furans)
RN  - 0 (Heterocyclic Compounds, 4 or More Rings)
RN  - 0 (Indenes)
RN  - 0 (Inflammasomes)
RN  - 0 (Interleukin-1beta)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Sulfonamides)
RN  - 0 (Sulfones)
RN  - 6RS86E2BWQ 
      (N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide)
SB  - IM
MH  - Animals
MH  - DNA-Binding Proteins/genetics/immunology
MH  - Furans
MH  - Heterocyclic Compounds, 4 or More Rings/pharmacology
MH  - Humans
MH  - Indenes
MH  - Inflammasomes/drug effects/genetics/*immunology
MH  - Interleukin-1beta/genetics/immunology
MH  - Macrophages/*immunology/microbiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mycobacterium tuberculosis/drug effects/genetics/*growth & development
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/genetics/immunology
MH  - Sulfonamides
MH  - Sulfones/pharmacology
MH  - Tuberculosis/genetics/*immunology/microbiology
PMC - PMC7048741
COIS- The authors declare no competing interests.
EDAT- 2020/03/01 06:00
MHDA- 2020/11/24 06:00
PMCR- 2020/02/28
CRDT- 2020/03/01 06:00
PHST- 2019/05/29 00:00 [received]
PHST- 2020/02/13 00:00 [accepted]
PHST- 2020/03/01 06:00 [entrez]
PHST- 2020/03/01 06:00 [pubmed]
PHST- 2020/11/24 06:00 [medline]
PHST- 2020/02/28 00:00 [pmc-release]
AID - 10.1038/s41598-020-60560-y [pii]
AID - 60560 [pii]
AID - 10.1038/s41598-020-60560-y [doi]
PST - epublish
SO  - Sci Rep. 2020 Feb 28;10(1):3709. doi: 10.1038/s41598-020-60560-y.