Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation

Cristina Cunha, Franco Aversa, João F. Lacerda, Alessandro Busca, Oliver Kurzai, Matthias Grube, Jürgen Löffler, Johan A. Maertens, Alain S. Bell, Antonio Inforzato, Elisa Barbati, Bruno Almeida, Pedro Santos E Sousa, Anna Barbui, Leonardo Potenza, Morena Caira, Fernando Rodrigues, Giovanni Salvatori, Livio Pagano, Mario LuppiAlberto Mantovani, Andrea Velardi, Luigina Romani, Agostinho Carvalho

Research output: Contribution to journalArticle

Abstract

BACKGROUND: The soluble pattern-recognition receptor known as long pentraxin 3 (PTX3) has a nonredundant role in antifungal immunity. The contribution of single-nucleotide polymorphisms (SNPs) in PTX3 to the development of invasive aspergillosis is unknown. METHODS: We screened an initial cohort of 268 patients undergoing hematopoietic stem-cell transplantation (HSCT) and their donors for PTX3 SNPs modifying the risk of invasive aspergillosis. The analysis was also performed in a multicenter study involving 107 patients with invasive aspergillosis and 223 matched controls. The functional consequences of PTX3 SNPs were investigated in vitro and in lung specimens from transplant recipients. RESULTS: Receipt of a transplant from a donor with a homozygous haplotype (h2/h2) in PTX3 was associated with an increased risk of infection, in both the discovery study (cumulative incidence, 37% vs. 15%; adjusted hazard ratio, 3.08; P = 0.003) and the confirmation study (adjusted odds ratio, 2.78; P = 0.03), as well as with defective expression of PTX3. Functionally, PTX3 deficiency in h2/h2 neutrophils, presumably due to messenger RNA instability, led to impaired phagocytosis and clearance of the fungus. CONCLUSIONS: Genetic deficiency of PTX3 affects the antifungal capacity of neutrophils and may contribute to the risk of invasive aspergillosis in patients treated with HSCT.

Original languageEnglish
Pages (from-to)421-432
Number of pages12
JournalNew England Journal of Medicine
Volume370
Issue number5
DOIs
Publication statusPublished - 2014

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Aspergillosis
Stem Cell Transplantation
Single Nucleotide Polymorphism
Hematopoietic Stem Cell Transplantation
Neutrophils
Tissue Donors
Pattern Recognition Receptors
PTX3 protein
RNA Stability
Phagocytosis
Haplotypes
Multicenter Studies
Immunity
Cohort Studies
Fungi
Odds Ratio
Transplants
Lung
Messenger RNA
Infection

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cunha, C., Aversa, F., Lacerda, J. F., Busca, A., Kurzai, O., Grube, M., ... Carvalho, A. (2014). Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. New England Journal of Medicine, 370(5), 421-432. https://doi.org/10.1056/NEJMoa1211161

Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. / Cunha, Cristina; Aversa, Franco; Lacerda, João F.; Busca, Alessandro; Kurzai, Oliver; Grube, Matthias; Löffler, Jürgen; Maertens, Johan A.; Bell, Alain S.; Inforzato, Antonio; Barbati, Elisa; Almeida, Bruno; Santos E Sousa, Pedro; Barbui, Anna; Potenza, Leonardo; Caira, Morena; Rodrigues, Fernando; Salvatori, Giovanni; Pagano, Livio; Luppi, Mario; Mantovani, Alberto; Velardi, Andrea; Romani, Luigina; Carvalho, Agostinho.

In: New England Journal of Medicine, Vol. 370, No. 5, 2014, p. 421-432.

Research output: Contribution to journalArticle

Cunha, C, Aversa, F, Lacerda, JF, Busca, A, Kurzai, O, Grube, M, Löffler, J, Maertens, JA, Bell, AS, Inforzato, A, Barbati, E, Almeida, B, Santos E Sousa, P, Barbui, A, Potenza, L, Caira, M, Rodrigues, F, Salvatori, G, Pagano, L, Luppi, M, Mantovani, A, Velardi, A, Romani, L & Carvalho, A 2014, 'Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation', New England Journal of Medicine, vol. 370, no. 5, pp. 421-432. https://doi.org/10.1056/NEJMoa1211161
Cunha, Cristina ; Aversa, Franco ; Lacerda, João F. ; Busca, Alessandro ; Kurzai, Oliver ; Grube, Matthias ; Löffler, Jürgen ; Maertens, Johan A. ; Bell, Alain S. ; Inforzato, Antonio ; Barbati, Elisa ; Almeida, Bruno ; Santos E Sousa, Pedro ; Barbui, Anna ; Potenza, Leonardo ; Caira, Morena ; Rodrigues, Fernando ; Salvatori, Giovanni ; Pagano, Livio ; Luppi, Mario ; Mantovani, Alberto ; Velardi, Andrea ; Romani, Luigina ; Carvalho, Agostinho. / Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. In: New England Journal of Medicine. 2014 ; Vol. 370, No. 5. pp. 421-432.
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abstract = "BACKGROUND: The soluble pattern-recognition receptor known as long pentraxin 3 (PTX3) has a nonredundant role in antifungal immunity. The contribution of single-nucleotide polymorphisms (SNPs) in PTX3 to the development of invasive aspergillosis is unknown. METHODS: We screened an initial cohort of 268 patients undergoing hematopoietic stem-cell transplantation (HSCT) and their donors for PTX3 SNPs modifying the risk of invasive aspergillosis. The analysis was also performed in a multicenter study involving 107 patients with invasive aspergillosis and 223 matched controls. The functional consequences of PTX3 SNPs were investigated in vitro and in lung specimens from transplant recipients. RESULTS: Receipt of a transplant from a donor with a homozygous haplotype (h2/h2) in PTX3 was associated with an increased risk of infection, in both the discovery study (cumulative incidence, 37{\%} vs. 15{\%}; adjusted hazard ratio, 3.08; P = 0.003) and the confirmation study (adjusted odds ratio, 2.78; P = 0.03), as well as with defective expression of PTX3. Functionally, PTX3 deficiency in h2/h2 neutrophils, presumably due to messenger RNA instability, led to impaired phagocytosis and clearance of the fungus. CONCLUSIONS: Genetic deficiency of PTX3 affects the antifungal capacity of neutrophils and may contribute to the risk of invasive aspergillosis in patients treated with HSCT.",
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AU - Cunha, Cristina

AU - Aversa, Franco

AU - Lacerda, João F.

AU - Busca, Alessandro

AU - Kurzai, Oliver

AU - Grube, Matthias

AU - Löffler, Jürgen

AU - Maertens, Johan A.

AU - Bell, Alain S.

AU - Inforzato, Antonio

AU - Barbati, Elisa

AU - Almeida, Bruno

AU - Santos E Sousa, Pedro

AU - Barbui, Anna

AU - Potenza, Leonardo

AU - Caira, Morena

AU - Rodrigues, Fernando

AU - Salvatori, Giovanni

AU - Pagano, Livio

AU - Luppi, Mario

AU - Mantovani, Alberto

AU - Velardi, Andrea

AU - Romani, Luigina

AU - Carvalho, Agostinho

PY - 2014

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N2 - BACKGROUND: The soluble pattern-recognition receptor known as long pentraxin 3 (PTX3) has a nonredundant role in antifungal immunity. The contribution of single-nucleotide polymorphisms (SNPs) in PTX3 to the development of invasive aspergillosis is unknown. METHODS: We screened an initial cohort of 268 patients undergoing hematopoietic stem-cell transplantation (HSCT) and their donors for PTX3 SNPs modifying the risk of invasive aspergillosis. The analysis was also performed in a multicenter study involving 107 patients with invasive aspergillosis and 223 matched controls. The functional consequences of PTX3 SNPs were investigated in vitro and in lung specimens from transplant recipients. RESULTS: Receipt of a transplant from a donor with a homozygous haplotype (h2/h2) in PTX3 was associated with an increased risk of infection, in both the discovery study (cumulative incidence, 37% vs. 15%; adjusted hazard ratio, 3.08; P = 0.003) and the confirmation study (adjusted odds ratio, 2.78; P = 0.03), as well as with defective expression of PTX3. Functionally, PTX3 deficiency in h2/h2 neutrophils, presumably due to messenger RNA instability, led to impaired phagocytosis and clearance of the fungus. CONCLUSIONS: Genetic deficiency of PTX3 affects the antifungal capacity of neutrophils and may contribute to the risk of invasive aspergillosis in patients treated with HSCT.

AB - BACKGROUND: The soluble pattern-recognition receptor known as long pentraxin 3 (PTX3) has a nonredundant role in antifungal immunity. The contribution of single-nucleotide polymorphisms (SNPs) in PTX3 to the development of invasive aspergillosis is unknown. METHODS: We screened an initial cohort of 268 patients undergoing hematopoietic stem-cell transplantation (HSCT) and their donors for PTX3 SNPs modifying the risk of invasive aspergillosis. The analysis was also performed in a multicenter study involving 107 patients with invasive aspergillosis and 223 matched controls. The functional consequences of PTX3 SNPs were investigated in vitro and in lung specimens from transplant recipients. RESULTS: Receipt of a transplant from a donor with a homozygous haplotype (h2/h2) in PTX3 was associated with an increased risk of infection, in both the discovery study (cumulative incidence, 37% vs. 15%; adjusted hazard ratio, 3.08; P = 0.003) and the confirmation study (adjusted odds ratio, 2.78; P = 0.03), as well as with defective expression of PTX3. Functionally, PTX3 deficiency in h2/h2 neutrophils, presumably due to messenger RNA instability, led to impaired phagocytosis and clearance of the fungus. CONCLUSIONS: Genetic deficiency of PTX3 affects the antifungal capacity of neutrophils and may contribute to the risk of invasive aspergillosis in patients treated with HSCT.

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