title: NALP1 influences susceptibility to human congenital toxoplasmosis, proinflammatory cytokine response, and fate of Toxoplasma gondii-infected monocytic cells.
abstract: NALP1 is a member of the NOD-like receptor (NLR) family of proteins that form inflammasomes. Upon cellular infection or stress, inflammasomes are activated, triggering maturation of proinflammatory cytokines and downstream cellular signaling mediated through the MyD88 adaptor. Toxoplasma gondii is an obligate intracellular parasite that stimulates production of high levels of proinflammatory cytokines that are important in innate immunity. In this study, susceptibility alleles for human congenital toxoplasmosis were identified in the NALP1 gene. To investigate the role of the NALP1 inflammasome during infection with T. gondii, we genetically engineered a human monocytic cell line for NALP1 gene knockdown by RNA interference. NALP1 silencing attenuated progression of T. gondii infection, with accelerated host cell death and eventual cell disintegration. In line with this observation, upregulation of the proinflammatory cytokines interleukin-1β (IL-1β), IL-18, and IL-12 upon T. gondii infection was not observed in monocytic cells with NALP1 knockdown. These findings suggest that the NALP1 inflammasome is critical for mediating innate immune responses to T. gondii infection and pathogenesis. Although there have been recent advances in understanding the potent activity of inflammasomes in directing innate immune responses to disease, this is the first report, to our knowledge, on the crucial role of the NALP1 inflammasome in the pathogenesis of T. gondii infections in humans.
authors.affiliation: Department of Surgery (Ophthalmology), The University of Chicago, Chicago, IL 60637, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Witola
authors.forename: Ernest
authors.initials: E
authors.lastname: Mui
authors.forename: Aubrey
authors.initials: A
authors.lastname: Hargrave
authors.forename: Susan
authors.initials: S
authors.lastname: Liu
authors.forename: Magali
authors.initials: M
authors.lastname: Hypolite
authors.forename: Alexandre
authors.initials: A
authors.lastname: Montpetit
authors.forename: Pierre
authors.initials: P
authors.lastname: Cavailles
authors.forename: Cordelia
authors.initials: C
authors.lastname: Bisanz
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Cesbron-Delauw
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Fournié
authors.forename: Rima
authors.initials: R
authors.lastname: McLeod
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D002648:Child; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007113:Immunity, Innate; D018445:Infectious Disease Transmission, Vertical; D009000:Monocytes / Q000166:cytology / Q000378:metabolism / Q000469:parasitology*; D000070576:NLR Proteins; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D034622:RNA Interference; D013997:Time Factors; D014122:Toxoplasma / Q000502:physiology*; D014125:Toxoplasmosis, Congenital / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D000070576:NLR Proteins; C427903:NLRP1 protein, human