Global Assessment of <named-content content-type="genus-species">Mycobacterium avium</named-content> subsp. <italic toggle="yes">hominissuis</italic> Genetic Requirement for Growth and Virulence

ABSTRACT Nontuberculous mycobacterial infections caused by the opportunistic pathogen Mycobacterium avium subsp. hominissuis (MAH) are currently receiving renewed attention due to increased incidence combined with difficult treatment. Insights into the disease-causing mechanisms of this species have...

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Autores principales:	Marte S. Dragset, Thomas R. Ioerger, Maja Loevenich, Markus Haug, Niruja Sivakumar, Anne Marstad, Pere Joan Cardona, Geir Klinkenberg, Eric J. Rubin, Magnus Steigedal, Trude H. Flo
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	conditionally required genes Mycobacterium avium Mycobacterium tuberculosis transposon insertion sequencing virulence genes Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7001547c94cf460eb494a3b5fa7ce7b6
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spelling	oai:doaj.org-article:7001547c94cf460eb494a3b5fa7ce7b62021-12-02T19:46:17ZGlobal Assessment of <named-content content-type="genus-species">Mycobacterium avium</named-content> subsp. <italic toggle="yes">hominissuis</italic> Genetic Requirement for Growth and Virulence10.1128/mSystems.00402-192379-5077https://doaj.org/article/7001547c94cf460eb494a3b5fa7ce7b62019-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00402-19https://doaj.org/toc/2379-5077ABSTRACT Nontuberculous mycobacterial infections caused by the opportunistic pathogen Mycobacterium avium subsp. hominissuis (MAH) are currently receiving renewed attention due to increased incidence combined with difficult treatment. Insights into the disease-causing mechanisms of this species have been hampered by difficulties in genetic manipulation of the bacteria. Here, we identified and sequenced a highly transformable, virulent MAH clinical isolate susceptible to high-density transposon mutagenesis, facilitating global gene disruption and subsequent investigation of MAH gene function. By transposon insertion sequencing (TnSeq) of this strain, we defined the MAH genome-wide genetic requirement for virulence and in vitro growth and organized ∼3,500 identified transposon mutants for hypothesis-driven research. The majority (96%) of the genes we identified as essential for MAH in vitro had a mutual ortholog in the related and highly virulent Mycobacterium tuberculosis (Mtb). However, passaging our library through a mouse model of infection revealed a substantial number (54% of total hits) of novel virulence genes. More than 97% of the MAH virulence genes had a mutual ortholog in Mtb. Finally, we validated novel genes required for successful MAH infection: one encoding a probable major facilitator superfamily (MFS) transporter and another encoding a hypothetical protein located in the immediate vicinity of six other identified virulence genes. In summary, we provide new, fundamental insights into the underlying genetic requirement of MAH for growth and host infection. IMPORTANCE Pulmonary disease caused by nontuberculous mycobacteria is increasing worldwide. The majority of these infections are caused by the Mycobacterium avium complex (MAC), whereof >90% are due to Mycobacterium avium subsp. hominissuis (MAH). Treatment of MAH infections is currently difficult, with a combination of antibiotics given for at least 12 months. To control MAH by improved therapy, prevention, and diagnostics, we need to understand the underlying mechanisms of infection. Here, we provide crucial insights into MAH’s global genetic requirements for growth and infection. We find that the vast majority of genes required for MAH growth and virulence (96% and 97%, respectively) have mutual orthologs in the tuberculosis-causing pathogen M. tuberculosis (Mtb). However, we also find growth and virulence genes specific to MAC species. Finally, we validate novel mycobacterial virulence factors that might serve as future drug targets for MAH-specific treatment or translate to broader treatment of related mycobacterial diseases.Marte S. DragsetThomas R. IoergerMaja LoevenichMarkus HaugNiruja SivakumarAnne MarstadPere Joan CardonaGeir KlinkenbergEric J. RubinMagnus SteigedalTrude H. FloAmerican Society for Microbiologyarticleconditionally required genesMycobacterium aviumMycobacterium tuberculosistransposon insertion sequencingvirulence genesMicrobiologyQR1-502ENmSystems, Vol 4, Iss 6 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	conditionally required genes Mycobacterium avium Mycobacterium tuberculosis transposon insertion sequencing virulence genes Microbiology QR1-502
spellingShingle	conditionally required genes Mycobacterium avium Mycobacterium tuberculosis transposon insertion sequencing virulence genes Microbiology QR1-502 Marte S. Dragset Thomas R. Ioerger Maja Loevenich Markus Haug Niruja Sivakumar Anne Marstad Pere Joan Cardona Geir Klinkenberg Eric J. Rubin Magnus Steigedal Trude H. Flo Global Assessment of <named-content content-type="genus-species">Mycobacterium avium</named-content> subsp. <italic toggle="yes">hominissuis</italic> Genetic Requirement for Growth and Virulence
description	ABSTRACT Nontuberculous mycobacterial infections caused by the opportunistic pathogen Mycobacterium avium subsp. hominissuis (MAH) are currently receiving renewed attention due to increased incidence combined with difficult treatment. Insights into the disease-causing mechanisms of this species have been hampered by difficulties in genetic manipulation of the bacteria. Here, we identified and sequenced a highly transformable, virulent MAH clinical isolate susceptible to high-density transposon mutagenesis, facilitating global gene disruption and subsequent investigation of MAH gene function. By transposon insertion sequencing (TnSeq) of this strain, we defined the MAH genome-wide genetic requirement for virulence and in vitro growth and organized ∼3,500 identified transposon mutants for hypothesis-driven research. The majority (96%) of the genes we identified as essential for MAH in vitro had a mutual ortholog in the related and highly virulent Mycobacterium tuberculosis (Mtb). However, passaging our library through a mouse model of infection revealed a substantial number (54% of total hits) of novel virulence genes. More than 97% of the MAH virulence genes had a mutual ortholog in Mtb. Finally, we validated novel genes required for successful MAH infection: one encoding a probable major facilitator superfamily (MFS) transporter and another encoding a hypothetical protein located in the immediate vicinity of six other identified virulence genes. In summary, we provide new, fundamental insights into the underlying genetic requirement of MAH for growth and host infection. IMPORTANCE Pulmonary disease caused by nontuberculous mycobacteria is increasing worldwide. The majority of these infections are caused by the Mycobacterium avium complex (MAC), whereof >90% are due to Mycobacterium avium subsp. hominissuis (MAH). Treatment of MAH infections is currently difficult, with a combination of antibiotics given for at least 12 months. To control MAH by improved therapy, prevention, and diagnostics, we need to understand the underlying mechanisms of infection. Here, we provide crucial insights into MAH’s global genetic requirements for growth and infection. We find that the vast majority of genes required for MAH growth and virulence (96% and 97%, respectively) have mutual orthologs in the tuberculosis-causing pathogen M. tuberculosis (Mtb). However, we also find growth and virulence genes specific to MAC species. Finally, we validate novel mycobacterial virulence factors that might serve as future drug targets for MAH-specific treatment or translate to broader treatment of related mycobacterial diseases.
format	article
author	Marte S. Dragset Thomas R. Ioerger Maja Loevenich Markus Haug Niruja Sivakumar Anne Marstad Pere Joan Cardona Geir Klinkenberg Eric J. Rubin Magnus Steigedal Trude H. Flo
author_facet	Marte S. Dragset Thomas R. Ioerger Maja Loevenich Markus Haug Niruja Sivakumar Anne Marstad Pere Joan Cardona Geir Klinkenberg Eric J. Rubin Magnus Steigedal Trude H. Flo
author_sort	Marte S. Dragset
title	Global Assessment of <named-content content-type="genus-species">Mycobacterium avium</named-content> subsp. <italic toggle="yes">hominissuis</italic> Genetic Requirement for Growth and Virulence
title_short	Global Assessment of <named-content content-type="genus-species">Mycobacterium avium</named-content> subsp. <italic toggle="yes">hominissuis</italic> Genetic Requirement for Growth and Virulence
title_full	Global Assessment of <named-content content-type="genus-species">Mycobacterium avium</named-content> subsp. <italic toggle="yes">hominissuis</italic> Genetic Requirement for Growth and Virulence
title_fullStr	Global Assessment of <named-content content-type="genus-species">Mycobacterium avium</named-content> subsp. <italic toggle="yes">hominissuis</italic> Genetic Requirement for Growth and Virulence
title_full_unstemmed	Global Assessment of <named-content content-type="genus-species">Mycobacterium avium</named-content> subsp. <italic toggle="yes">hominissuis</italic> Genetic Requirement for Growth and Virulence
title_sort	global assessment of <named-content content-type="genus-species">mycobacterium avium</named-content> subsp. <italic toggle="yes">hominissuis</italic> genetic requirement for growth and virulence
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/7001547c94cf460eb494a3b5fa7ce7b6
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Global Assessment of <named-content content-type="genus-species">Mycobacterium avium</named-content> subsp. <italic toggle="yes">hominissuis</italic> Genetic Requirement for Growth and Virulence

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