Collaborative Cross Mice Yield Genetic Modifiers for <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Infection in Human Lung Disease

ABSTRACT Human genetics influence a range of pathological and clinical phenotypes in respiratory infections; however, the contributions of disease modifiers remain underappreciated. We exploited the Collaborative Cross (CC) mouse genetic-reference population to map genetic modifiers that affect the...

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Autores principales:	Nicola Ivan Lorè, Barbara Sipione, Gengming He, Lisa J. Strug, Hanifa J. Atamni, Alexandra Dorman, Richard Mott, Fuad A. Iraqi, Alessandra Bragonzi
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Pseudomonas aeruginosa gene modifiers respiratory infection mouse model Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/658f04be6a784a3981f6642bfb460c8e
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spelling	oai:doaj.org-article:658f04be6a784a3981f6642bfb460c8e2021-11-15T15:57:01ZCollaborative Cross Mice Yield Genetic Modifiers for <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Infection in Human Lung Disease10.1128/mBio.00097-202150-7511https://doaj.org/article/658f04be6a784a3981f6642bfb460c8e2020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00097-20https://doaj.org/toc/2150-7511ABSTRACT Human genetics influence a range of pathological and clinical phenotypes in respiratory infections; however, the contributions of disease modifiers remain underappreciated. We exploited the Collaborative Cross (CC) mouse genetic-reference population to map genetic modifiers that affect the severity of Pseudomonas aeruginosa lung infection. Screening for P. aeruginosa respiratory infection in a cohort of 39 CC lines exhibits distinct disease phenotypes ranging from complete resistance to lethal disease. Based on major changes in the survival times, a quantitative-trait locus (QTL) was mapped on murine chromosome 3 to the genomic interval of Mb 110.4 to 120.5. Within this locus, composed of 31 protein-coding genes, two candidate genes, namely, dihydropyrimidine dehydrogenase (Dpyd) and sphingosine-1-phosphate receptor 1 (S1pr1), were identified according to the level of genome-wide significance and disease gene prioritization. Functional validation of the S1pr1 gene by pharmacological targeting in C57BL/6NCrl mice confirmed its relevance in P. aeruginosa pathophysiology. However, in a cohort of Canadian patients with cystic fibrosis (CF) disease, regional genetic-association analysis of the syntenic human locus on chromosome 1 (Mb 97.0 to 105.0) identified two single-nucleotide polymorphisms (rs10875080 and rs11582736) annotated to the Dpyd gene that were significantly associated with age at first P. aeruginosa infection. Thus, there is evidence that both genes might be implicated in this disease. Our results demonstrate that the discovery of murine modifier loci may generate information that is relevant to human disease progression. IMPORTANCE Respiratory infection caused by P. aeruginosa is one of the most critical health burdens worldwide. People affected by P. aeruginosa infection include patients with a weakened immune system, such as those with cystic fibrosis (CF) genetic disease or non-CF bronchiectasis. Disease outcomes range from fatal pneumonia to chronic life-threatening infection and inflammation leading to the progressive deterioration of pulmonary function. The development of these respiratory infections is mediated by multiple causes. However, the genetic factors underlying infection susceptibility are poorly known and difficult to predict. Our study employed novel approaches and improved mouse disease models to identify genetic modifiers that affect the severity of P. aeruginosa lung infection. We identified candidate genes to enhance our understanding of P. aeruginosa infection in humans and provide a proof of concept that could be exploited for other human pathologies mediated by bacterial infection.Nicola Ivan LorèBarbara SipioneGengming HeLisa J. StrugHanifa J. AtamniAlexandra DormanRichard MottFuad A. IraqiAlessandra BragonziAmerican Society for MicrobiologyarticlePseudomonas aeruginosagene modifiersrespiratory infectionmouse modelMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Pseudomonas aeruginosa gene modifiers respiratory infection mouse model Microbiology QR1-502
spellingShingle	Pseudomonas aeruginosa gene modifiers respiratory infection mouse model Microbiology QR1-502 Nicola Ivan Lorè Barbara Sipione Gengming He Lisa J. Strug Hanifa J. Atamni Alexandra Dorman Richard Mott Fuad A. Iraqi Alessandra Bragonzi Collaborative Cross Mice Yield Genetic Modifiers for <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Infection in Human Lung Disease
description	ABSTRACT Human genetics influence a range of pathological and clinical phenotypes in respiratory infections; however, the contributions of disease modifiers remain underappreciated. We exploited the Collaborative Cross (CC) mouse genetic-reference population to map genetic modifiers that affect the severity of Pseudomonas aeruginosa lung infection. Screening for P. aeruginosa respiratory infection in a cohort of 39 CC lines exhibits distinct disease phenotypes ranging from complete resistance to lethal disease. Based on major changes in the survival times, a quantitative-trait locus (QTL) was mapped on murine chromosome 3 to the genomic interval of Mb 110.4 to 120.5. Within this locus, composed of 31 protein-coding genes, two candidate genes, namely, dihydropyrimidine dehydrogenase (Dpyd) and sphingosine-1-phosphate receptor 1 (S1pr1), were identified according to the level of genome-wide significance and disease gene prioritization. Functional validation of the S1pr1 gene by pharmacological targeting in C57BL/6NCrl mice confirmed its relevance in P. aeruginosa pathophysiology. However, in a cohort of Canadian patients with cystic fibrosis (CF) disease, regional genetic-association analysis of the syntenic human locus on chromosome 1 (Mb 97.0 to 105.0) identified two single-nucleotide polymorphisms (rs10875080 and rs11582736) annotated to the Dpyd gene that were significantly associated with age at first P. aeruginosa infection. Thus, there is evidence that both genes might be implicated in this disease. Our results demonstrate that the discovery of murine modifier loci may generate information that is relevant to human disease progression. IMPORTANCE Respiratory infection caused by P. aeruginosa is one of the most critical health burdens worldwide. People affected by P. aeruginosa infection include patients with a weakened immune system, such as those with cystic fibrosis (CF) genetic disease or non-CF bronchiectasis. Disease outcomes range from fatal pneumonia to chronic life-threatening infection and inflammation leading to the progressive deterioration of pulmonary function. The development of these respiratory infections is mediated by multiple causes. However, the genetic factors underlying infection susceptibility are poorly known and difficult to predict. Our study employed novel approaches and improved mouse disease models to identify genetic modifiers that affect the severity of P. aeruginosa lung infection. We identified candidate genes to enhance our understanding of P. aeruginosa infection in humans and provide a proof of concept that could be exploited for other human pathologies mediated by bacterial infection.
format	article
author	Nicola Ivan Lorè Barbara Sipione Gengming He Lisa J. Strug Hanifa J. Atamni Alexandra Dorman Richard Mott Fuad A. Iraqi Alessandra Bragonzi
author_facet	Nicola Ivan Lorè Barbara Sipione Gengming He Lisa J. Strug Hanifa J. Atamni Alexandra Dorman Richard Mott Fuad A. Iraqi Alessandra Bragonzi
author_sort	Nicola Ivan Lorè
title	Collaborative Cross Mice Yield Genetic Modifiers for <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Infection in Human Lung Disease
title_short	Collaborative Cross Mice Yield Genetic Modifiers for <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Infection in Human Lung Disease
title_full	Collaborative Cross Mice Yield Genetic Modifiers for <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Infection in Human Lung Disease
title_fullStr	Collaborative Cross Mice Yield Genetic Modifiers for <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Infection in Human Lung Disease
title_full_unstemmed	Collaborative Cross Mice Yield Genetic Modifiers for <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Infection in Human Lung Disease
title_sort	collaborative cross mice yield genetic modifiers for <named-content content-type="genus-species">pseudomonas aeruginosa</named-content> infection in human lung disease
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/658f04be6a784a3981f6642bfb460c8e
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Collaborative Cross Mice Yield Genetic Modifiers for <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Infection in Human Lung Disease

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