The Q705K genetic variant in NLRP3 leads to inflammasome hyperactivation and contributes to invasive aspergillosis after stem cell transplantation
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1
University of Perugia, Department of Experimental Medicine and Biochemical Sciences, Italy
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2
University Of Parma, Department of Clinical And Experimental Medicine, Italy
The role of inflammasome stimulation, in particular NLRP3, in antifungal immunity has been the subject of many recent investigations in both mice and humans. Stimulation of the NLRP3 inflammasome has been demonstrated to occur in response to fungi, suggesting a crucial role in antifungal resistance. To understand the cellular and molecular immune pathways by which NLRP3 inflammasome activation might affect antifungal immunity, we have analyzed the association between genetic variants in the NLRP3 gene and susceptibility to invasive aspergillosis in hematopoietic stem cell transplanted patients. We found that a genetic variant in NLRP3 (rs35829419, Q705K) was associated with or tended to invasive aspergillosis when present in either donors, recipients or both. Moreover, this variant also led to poorer overall survival after transplantation. Functionally, the presence of the Q705K variant in human monocytes was correlated with an increased functional activity of the NLRP3 inflammasome, as revealed by increased levels of IL-1β and IL-18 upon stimulation with Aspergillus fumigatus. In conclusion, our results suggest that an hyperactivation of the NLRP3 inflammasome may be detrimental to antifungal immunity and therefore contribute to susceptibility to fungal infections in immunocompromised patients.
Acknowledgements
Cristina Cunha was supported by the Fundação para a Ciência e Tecnologia, Portugal (contract SFRH/BD/65962/2009)
Keywords:
Invasive Pulmonary Aspergillosis,
Hematopoietic Stem Cell Transplantation,
Single nucleotide polymorphisms (SNPs),
Inflammasome,
NLRP3
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Immune receptors and signaling
Citation:
Cunha
C,
Galosi
C,
Puccetti
M,
Aversa
F,
Romani
L and
Carvalho
A
(2013). The Q705K genetic variant in NLRP3 leads to inflammasome hyperactivation and contributes to invasive aspergillosis after stem cell transplantation.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.01022
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Received:
30 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Agostinho Carvalho, University of Perugia, Department of Experimental Medicine and Biochemical Sciences, Perugia, Italy, agostinhocarvalho@med.uminho.pt