title: Differential inflammasome activation signatures following intracellular infection of human macrophages with Mycobacterium bovis BCG or Trypanosoma cruzi.
abstract: Pathogens frequently exploit or evade inflammasome activation in order to survive and proliferate. Alternatively, inadequate inflammasome activation by attenuated microorganisms or adjuvanted subunit vaccines may contribute to poor longevity of protection. To further understand these pathways, we determined the differential inflammasome transcriptome of human THP monocyte-derived macrophages in response to Mycobacterium bovis BCG, as compared to LPS or Trypanosoma cruzi. The results identify the highly specific innate recognition programs associated with inflammasome activation by human macrophages exposed to these microbial stimuli. BCG, T. cruzi, and LPS strongly induced expression of both unique and overlapping genes downstream of TLR signaling pathways including cytokines and chemokines that mediate inflammation and regulate cell death pathways. Compared to LPS, BCG failed to directly activate anti-apoptotic molecules and multiple NLR and inflammasome complex components including caspase-1, and actively repressed important signaling intermediates in AP-1 and NFκB transcription factor pathways. Both BCG and T. cruzi repressed expression of TXNIP, an anti-oxidant inhibitor that recruits caspase-1 to the NLRP3 inflammasome, while T. cruzi infection uniquely failed to activate TNF-α. These results identify unique pathogen specific strategies to activate inflammation and modulate cell death that may drive inflammatory outcomes and suggest avenues of investigation to optimize host immunity.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Huante
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Thermo Fisher Scientific, Eugene, OR, USA.
authors.forename: V C
authors.initials: VC
authors.lastname: Calderon
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; Department of Pathology, UTMB, Galveston, TX, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Koo
authors.affiliation: Department of Pathology, UTMB, Galveston, TX, USA; Department of Preventative Medicine and Community Health, Office of Biostatistics, UTMB, Galveston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sinha
authors.affiliation: Department of Pathology, UTMB, Galveston, TX, USA; Department of Preventative Medicine and Community Health, Office of Biostatistics, UTMB, Galveston, TX, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Luxon
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Garg
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: jjendsle@utmb.edu.
authors.forename: J J
authors.initials: JJ
authors.lastname: Endsley
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001500:BCG Vaccine / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D058847:Inflammasomes / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000469:parasitology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051193:Toll-Like Receptors / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000276:immunology / Q000472:pathogenicity*
chemical_list: D051017:Apoptosis Regulatory Proteins; D001500:BCG Vaccine; D016207:Cytokines; D058847:Inflammasomes; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D051193:Toll-Like Receptors
keywords: Inflammasome; Inflammation; Mycobacteria; NLR; T. cruzi; TLR