Mycobacterium tuberculosis prevents inflammasome activation.
Mycobacterium tuberculosis (Mtb) parasitizes host macrophages and subverts host innate and adaptive immunity. Several cytokines elicited by Mtb are mediators of mycobacterial clearance or are involved in tuberculosis pathology. Surprisingly, interleukin-1beta (IL-1beta), a major proinflammatory cytokine, has not been implicated in host-Mtb interactions. IL-1beta is activated by processing upon assembly of the inflammasome, a specialized inflammatory caspase-activating protein complex. Here, we show that Mtb prevents inflammasome activation and IL-1beta processing. An Mtb gene, zmp1, which encodes a putative Zn(2+) metalloprotease, is required for this process. Infection of macrophages with zmp1-deleted Mtb triggered activation of the inflammasome, resulting in increased IL-1beta secretion, enhanced maturation of Mtb containing phagosomes, improved mycobacterial clearance by macrophages, and lower bacterial burden in the lungs of aerosol-infected mice. Thus, we uncovered a previously masked role for IL-1beta in the control of Mtb and a mycobacterial system that prevents inflammasome and, therefore, IL-1beta activation.
Master
Sharon S
SS
Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
Rampini
Silvana K
SK
Davis
Alexander S
AS
Keller
Christine
C
Ehlers
Stefan
S
Springer
Burkhard
B
Timmins
Graham S
GS
Sander
Peter
P
Deretic
Vojo
V
D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D015536:Down-Regulation; D005798:Genes, Bacterial / Q000502:physiology; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000096:biosynthesis; D008168:Lung / Q000382:microbiology; D008262:Macrophage Activation; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D045726:Metalloproteases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000472:pathogenicity; D010588:Phagosomes / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D014774:Virulence
D003598:Cytoskeletal Proteins; D053583:Interleukin-1beta; D046912:Multiprotein Complexes; D045726:Metalloproteases; D020170:Caspase 1