Granuloma formation and host defense in chronic Mycobacterium tuberculosis infection requires PYCARD/ASC but not NLRP3 or caspase-1.
The NLR gene family mediates host immunity to various acute pathogenic stimuli, but its role in chronic infection is not known. This paper addressed the role of NLRP3 (NALP3), its adaptor protein PYCARD (ASC), and caspase-1 during infection with Mycobacterium tuberculosis (Mtb). Mtb infection of macrophages in culture induced IL-1beta secretion, and this requires the inflammasome components PYCARD, caspase-1, and NLRP3. However, in vivo Mtb aerosol infection of Nlrp3(-/-), Casp-1(-/-), and WT mice showed no differences in pulmonary IL-1beta production, bacterial burden, or long-term survival. In contrast, a significant role was observed for Pycard in host protection during chronic Mtb infection, as shown by an abrupt decrease in survival of Pycard(-/-) mice. Decreased survival of Pycard(-/-) animals was associated with defective granuloma formation. These data demonstrate that PYCARD exerts a novel inflammasome-independent role during chronic Mtb infection by containing the bacteria in granulomas.
McElvania Tekippe
Erin
E
Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Allen
Irving C
IC
Hulseberg
Paul D
PD
Sullivan
Jonathan T
JT
McCann
Jessica R
JR
Sandor
Matyas
M
Braunstein
Miriam
M
Ting
Jenny P-Y
JP
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D002478:Cells, Cultured; D002908:Chronic Disease; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000378:metabolism*; D005260:Female; D006099:Granuloma / Q000382:microbiology* / Q000473:pathology*; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity / Q000502:physiology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D014376:Tuberculosis / Q000276:immunology* / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D020170:Caspase 1
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