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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2020-04-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00097-20 |
| _version_ | 1828959561188376576 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-14T09:10:40Z |
| format | Article |
| id | doaj.art-658f04be6a784a3981f6642bfb460c8e |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-14T09:10:40Z |
| publishDate | 2020-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-658f04be6a784a3981f6642bfb460c8e2022-12-21T23:08:35ZengAmerican Society for MicrobiologymBio2150-75112020-04-0111210.1128/mBio.00097-20Collaborative Cross Mice Yield Genetic Modifiers for <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> Infection in Human Lung DiseaseNicola Ivan Lorè0Barbara Sipione1Gengming He2Lisa J. Strug3Hanifa J. Atamni4Alexandra Dorman5Richard Mott6Fuad A. Iraqi7Alessandra Bragonzi8Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, ItalyInfections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, ItalyProgram in Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, CanadaProgram in Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, CanadaDepartment of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelDepartment of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelGenetics Institute, University College London, London, United KingdomDepartment of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelInfections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, ItalyABSTRACT 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.https://journals.asm.org/doi/10.1128/mBio.00097-20Pseudomonas aeruginosagene modifiersrespiratory infectionmouse model |
| spellingShingle | 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 mBio Pseudomonas aeruginosa gene modifiers respiratory infection mouse model |
| title | 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_short | 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 |
| topic | Pseudomonas aeruginosa gene modifiers respiratory infection mouse model |
| url | https://journals.asm.org/doi/10.1128/mBio.00097-20 |
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