NALP1 influences susceptibility to human congenital toxoplasmosis, proinflammatory cytokine response, and fate of Toxoplasma gondii-infected monocytic cells

William H. Witola, Ernest Mui, Aubrey Hargrave, Susan Liu, Magali Hypolite, Alexandre Montpetit, Pierre Cavailles, Cordelia Bisanz, Marie France Cesbron-Delauw, Gilbert J. Fournié, Rima McLeod

Research output: Research - peer-reviewArticle

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.

LanguageEnglish (US)
Pages756-766
Number of pages11
JournalInfection and Immunity
Volume79
Issue number2
DOIs
StatePublished - Feb 2011
Externally publishedYes

Fingerprint

Congenital Toxoplasmosis
Inflammasomes
Toxoplasma
Cytokines
Toxoplasmosis
Innate Immunity
Gene Knockdown Techniques
Interleukin-18
Interleukin-12
RNA Interference
Interleukin-1beta
Parasites
Cell Death
Up-Regulation
Alleles
Cell Line
Infection
Genes
Proteins
NLR Proteins

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

Cite this

NALP1 influences susceptibility to human congenital toxoplasmosis, proinflammatory cytokine response, and fate of Toxoplasma gondii-infected monocytic cells. / Witola, William H.; Mui, Ernest; Hargrave, Aubrey; Liu, Susan; Hypolite, Magali; Montpetit, Alexandre; Cavailles, Pierre; Bisanz, Cordelia; Cesbron-Delauw, Marie France; Fournié, Gilbert J.; McLeod, Rima.

In: Infection and Immunity, Vol. 79, No. 2, 02.2011, p. 756-766.

Research output: Research - peer-reviewArticle

Witola, WH, Mui, E, Hargrave, A, Liu, S, Hypolite, M, Montpetit, A, Cavailles, P, Bisanz, C, Cesbron-Delauw, MF, Fournié, GJ & McLeod, R 2011, 'NALP1 influences susceptibility to human congenital toxoplasmosis, proinflammatory cytokine response, and fate of Toxoplasma gondii-infected monocytic cells' Infection and Immunity, vol 79, no. 2, pp. 756-766. DOI: 10.1128/IAI.00898-10
Witola, William H. ; Mui, Ernest ; Hargrave, Aubrey ; Liu, Susan ; Hypolite, Magali ; Montpetit, Alexandre ; Cavailles, Pierre ; Bisanz, Cordelia ; Cesbron-Delauw, Marie France ; Fournié, Gilbert J. ; McLeod, Rima. / NALP1 influences susceptibility to human congenital toxoplasmosis, proinflammatory cytokine response, and fate of Toxoplasma gondii-infected monocytic cells. In: Infection and Immunity. 2011 ; Vol. 79, No. 2. pp. 756-766
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