NALP1 Influences Susceptibility to Human Congenital Toxoplasmosis, Pro-Inflammatory Cytokine Response and Fate of T. gondii-Infected Monocytic Cells

Infect Immun. 2010 Nov 22. [Epub ahead of print]

NALP1 Influences Susceptibility to Human Congenital Toxoplasmosis, Pro-Inflammatory Cytokine Response and Fate of T. gondii-Infected Monocytic Cells

Witola WH, Mui E, Hargrave A, Liu S, Hypolite M, Montpetit A, Cavailles P, Bisanz C, Cesbron-Delauw MF, Fournié GJ, McLeod R.

Departments of Surgery (Ophthalmology) and Pediatrics (Infectious Disease), The University of Chicago, Chicago, Illinois 60637, USA; Laboratoire Adaptation et Pathogénie des Micro-organismes, CNRS UMR 5163, Université Joseph Fourier GRENOBLE 1, Institut Jean Roget, BP 170, 38042 Grenoble cedex 9, France; Centre d'Innovation, Génome Québec, Montréal, Québec H3A 1A4, Canada; INSERM, U563, F-31000 Toulouse, France and University Toulouse III Paul Sabatier, F-31000 Toulouse, France.

Abstract
NALP1 is a member of the NOD-like receptor (NLR) family proteins that form inflammasomes. Upon cellular infection or stress, inflammasomes are activated, triggering maturation of pro-inflammatory cytokines and downstream cellular signaling mediated through the MyD88 adaptor. Toxoplasma gondii is an obligate intracellular parasite that stimulates production of high levels of pro-inflammatory cytokines important in innate immunity. Herein, susceptibility alleles for human congenital toxoplasmosis in NALP1 gene were identified. 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, up-regulation of pro-inflammatory cytokines IL-1β, IL-18 and IL-12 with 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, to our knowledge, this is the first report on the crucial role of NALP1 inflammasome in the pathogenesis of T. gondii infections in humans.

PMID: 21098108 [PubMed - as supplied by publisher]