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. (Funded by the European Society of Clinical Microbiology and Infectious Diseases and others.).

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. - ISSN 0028-4793. - STAMPA. - 370(2014), pp. 421-432. [10.1056/NEJMoa1211161]

Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation

POTENZA, Leonardo;LUPPI, Mario;
2014

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. (Funded by the European Society of Clinical Microbiology and Infectious Diseases and others.).
370
421
432
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. - ISSN 0028-4793. - STAMPA. - 370(2014), pp. 421-432. [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
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