Host adaptation of Mycobacterium tuberculosis and Mycobacterium bovis: a genomic and transcriptional approach
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Tipo de documento: | Tese |
Idioma: | eng |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da USP |
Texto Completo: | https://www.teses.usp.br/teses/disponiveis/10/10134/tde-30112022-110829/ |
Resumo: | Tuberculosis (TB) is caused by the Mycobacterium tuberculosis complex (MTBC), a bacterial group of clonally evolved pathogens that infect humans and animals. Despite a high genetic similarity, MTBC members demonstrate different host tropism and virulence. While Mycobacterium tuberculosis is the main causative agent of human TB and is highly adapted to this host species, Mycobacterium bovis has a broader host range with variable populational persistence. In order to provide insights into phenotypic differences between both pathogens, this four-chapter thesis was developed with two major aims: (i) to perform a phylogenomic analysis to understand the populational structure of M. bovis isolated from cattle and wildlife worldwide and to provide dating estimates for the origin of this pathogen; and (ii) to compare the global transcriptional profiles of M. bovis SP38 and M. tuberculosis H37Rv in vitro and identify their activated metabolic pathways using flux balance analysis (FBA) coupled with transcriptomics. First, the phylogenomic analysis, including approximately 2,000 M. genomes from 23 countries, identified at least four distinct lineages of M. bovis (Lb1, Lb2, Lb3, and Lb4) underlying the current disease distribution. These lineages clustered according to geographical origin and clonal complexes (CC), but not host species. Additionally, data divergence analysis indicates that extant M. bovis originated between 715- and 3,556-years BP (before present), with later emergence in the New World and Oceania, likely influenced by trades among countries. Next, RNA-seq from M. tuberculosis and M. bovis grown in vitro showed significant differences involving genes related to cell wall metabolism, with upregulation of PDIM (phthiocerol dimycocerosates) in M. bovis, and upregulation of SL-1 (sulfolipid), trehalose lipids, and glycolipids in M. tuberculosis. Among the top expressed genes, SigK regulon and secretion system ESX-1 were upregulated in M. bovis, while genes of the nitrate metabolism and toxin-antitoxin systems were upregulated in M. tuberculosis. Furthermore, FBA suggests major differences in central carbon metabolism between species, particularly in the use of glutamate to fuel the GABA shunt in M. tuberculosis, but cysteine production in M. bovis. We speculate that some of these differences occur because M. bovis is a microaerophile and M. tuberculosis an obligate aerobe. In conclusion, the studies reported herein greatly expanded our knowledge of the populational structure of M. bovis and its metabolism in comparison to the model organism M. tuberculosis. These results will serve as basis for further research related to the use of genomics to understand disease transmission and virulence, as well as to how these mycobacteria respond to microenvironmental conditions that can sustain their virulence and host tropism traits. |
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Host adaptation of Mycobacterium tuberculosis and Mycobacterium bovis: a genomic and transcriptional approachAdaptação de Mycobacterium tuberculosis e Mycobacterium bovis a hospedeiros: uma análise genômica e transcricionalMycobacterium bovisMycobacterium bovisMycobacterium tuberculosis complexMycobacterium tuberculosis complexAnálise de balance de fluxoFlux balance analysisGenômicaGenomicsTranscriptômicaTranscriptomicsTuberculosis (TB) is caused by the Mycobacterium tuberculosis complex (MTBC), a bacterial group of clonally evolved pathogens that infect humans and animals. Despite a high genetic similarity, MTBC members demonstrate different host tropism and virulence. While Mycobacterium tuberculosis is the main causative agent of human TB and is highly adapted to this host species, Mycobacterium bovis has a broader host range with variable populational persistence. In order to provide insights into phenotypic differences between both pathogens, this four-chapter thesis was developed with two major aims: (i) to perform a phylogenomic analysis to understand the populational structure of M. bovis isolated from cattle and wildlife worldwide and to provide dating estimates for the origin of this pathogen; and (ii) to compare the global transcriptional profiles of M. bovis SP38 and M. tuberculosis H37Rv in vitro and identify their activated metabolic pathways using flux balance analysis (FBA) coupled with transcriptomics. First, the phylogenomic analysis, including approximately 2,000 M. genomes from 23 countries, identified at least four distinct lineages of M. bovis (Lb1, Lb2, Lb3, and Lb4) underlying the current disease distribution. These lineages clustered according to geographical origin and clonal complexes (CC), but not host species. Additionally, data divergence analysis indicates that extant M. bovis originated between 715- and 3,556-years BP (before present), with later emergence in the New World and Oceania, likely influenced by trades among countries. Next, RNA-seq from M. tuberculosis and M. bovis grown in vitro showed significant differences involving genes related to cell wall metabolism, with upregulation of PDIM (phthiocerol dimycocerosates) in M. bovis, and upregulation of SL-1 (sulfolipid), trehalose lipids, and glycolipids in M. tuberculosis. Among the top expressed genes, SigK regulon and secretion system ESX-1 were upregulated in M. bovis, while genes of the nitrate metabolism and toxin-antitoxin systems were upregulated in M. tuberculosis. Furthermore, FBA suggests major differences in central carbon metabolism between species, particularly in the use of glutamate to fuel the GABA shunt in M. tuberculosis, but cysteine production in M. bovis. We speculate that some of these differences occur because M. bovis is a microaerophile and M. tuberculosis an obligate aerobe. In conclusion, the studies reported herein greatly expanded our knowledge of the populational structure of M. bovis and its metabolism in comparison to the model organism M. tuberculosis. These results will serve as basis for further research related to the use of genomics to understand disease transmission and virulence, as well as to how these mycobacteria respond to microenvironmental conditions that can sustain their virulence and host tropism traits.A tuberculose (TB) é uma doença causada por bactérias do complexo Mycobacterium tuberculosis (MTBC) que infectam humanos e animais. Membros do MTBC possuem evolução clonal, porém apesar da grande similaridade genômica demonstram diferenças em adaptabilidade hospedeira e grau de virulência. Enquanto Mycobacterium tuberculosis é o principal causador da TB humana, Mycobacterium bovis possui uma ampla gama de hospedeiros com persistência populacional variável. Para melhor compreender diferenças fenotípicas entre ambas as espécies, esta tese foi desenvolvida com dois objetivos: (i) avaliar filogenomicamente a população de M. bovis isolados de bovinos e animais selvagens distribuídos mundialmente, e prover estimativas de datação evolutiva da origem desse patógeno; (ii) comparar o perfil transcriptômico de M. bovis SP38 e M. tuberculosis H37Rv in vitro e identificar vias metabólicas ativas utilizando análise de balanço de fluxo (FBA) associada a transcriptoma. Primeiramente, a análise filogenômica, incluindo aproximadamente 2.000 genomas de M. bovis isolados de 23 países, identificou a existência de pelo menos quatro linhagens distintas (Lb1, Lb2, Lb3 e Lb4) abrangendo a distribuição atual da doença. Essas linhagens se agrupam de acordo com a localização geográfica e com complexos clonais (CC), mas não com espécie hospedeira. Além disso, análises evolutivas indicam possível origem de diversificação de M. bovis há 715 e 3.556 anos, com surgimento mais tardio no Novo Mundo e Oceania, provavelmente devido relações econômicas entre os países. Por seguinte, a análise de RNA-seq de M. tuberculosis e M. bovis a partir de culturas in vitro demonstrou diferenças significativas na expressão gênica envolvendo genes relacionados à metabolismo de parede celular, com regulação positiva de PDIM (phthiocerol dimycocerosates) em M. bovis e regulação positiva de SL-1 (sulfolipídio), lipídeos contendo trealose e glicolipídios em M. tuberculosis. Entre os genes mais expressos, M. bovis apresentou regulação positiva em genes relacionados ao regulon SigK e sistema de secreção ESX-1, por sua vez, M. tuberculosis demonstrou regulação positiva em genes associados a metabolismo de nitrato e sistemas toxina-antitoxina. Ainda, FBA sugere diferenças no metabolismo central de carbono, especialmente no uso de glutamato em direção ao GABA shunt em M. tuberculosis, ou à produção de cisteína em M. bovis. É possível que essas diferenças sejam observadas devido M. bovis ser classificado como um microaerófilo e M. tuberculosis um aeróbio obrigatório. Por fim, os estudos reportados expandem significativamente o conhecimento sobre a estrutura populacional de M. bovis e seu metabolismo, quando comparado ao organismo modelo, M. tuberculosis. Os resultados podem também servir como base para pesquisas futuras, relacionas ao uso de genômica para entender padrões de distribuição da doença e virulência, assim como entender como essas micobactérias respondem a condições ambientais que podem explicar suas características de virulência e adaptabilidade hospedeira.Biblioteca Digitais de Teses e Dissertações da USPGuimarães, Ana Marcia de SáZimpel, Cristina Kraemer2022-09-21info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttps://www.teses.usp.br/teses/disponiveis/10/10134/tde-30112022-110829/reponame:Biblioteca Digital de Teses e Dissertações da USPinstname:Universidade de São Paulo (USP)instacron:USPReter o conteúdo por motivos de patente, publicação e/ou direitos autoriais.info:eu-repo/semantics/openAccesseng2024-10-09T13:16:04Zoai:teses.usp.br:tde-30112022-110829Biblioteca Digital de Teses e Dissertaçõeshttp://www.teses.usp.br/PUBhttp://www.teses.usp.br/cgi-bin/mtd2br.plvirginia@if.usp.br|| atendimento@aguia.usp.br||virginia@if.usp.bropendoar:27212024-10-09T13:16:04Biblioteca Digital de Teses e Dissertações da USP - Universidade de São Paulo (USP)false |
dc.title.none.fl_str_mv |
Host adaptation of Mycobacterium tuberculosis and Mycobacterium bovis: a genomic and transcriptional approach Adaptação de Mycobacterium tuberculosis e Mycobacterium bovis a hospedeiros: uma análise genômica e transcricional |
title |
Host adaptation of Mycobacterium tuberculosis and Mycobacterium bovis: a genomic and transcriptional approach |
spellingShingle |
Host adaptation of Mycobacterium tuberculosis and Mycobacterium bovis: a genomic and transcriptional approach Zimpel, Cristina Kraemer Mycobacterium bovis Mycobacterium bovis Mycobacterium tuberculosis complex Mycobacterium tuberculosis complex Análise de balance de fluxo Flux balance analysis Genômica Genomics Transcriptômica Transcriptomics |
title_short |
Host adaptation of Mycobacterium tuberculosis and Mycobacterium bovis: a genomic and transcriptional approach |
title_full |
Host adaptation of Mycobacterium tuberculosis and Mycobacterium bovis: a genomic and transcriptional approach |
title_fullStr |
Host adaptation of Mycobacterium tuberculosis and Mycobacterium bovis: a genomic and transcriptional approach |
title_full_unstemmed |
Host adaptation of Mycobacterium tuberculosis and Mycobacterium bovis: a genomic and transcriptional approach |
title_sort |
Host adaptation of Mycobacterium tuberculosis and Mycobacterium bovis: a genomic and transcriptional approach |
author |
Zimpel, Cristina Kraemer |
author_facet |
Zimpel, Cristina Kraemer |
author_role |
author |
dc.contributor.none.fl_str_mv |
Guimarães, Ana Marcia de Sá |
dc.contributor.author.fl_str_mv |
Zimpel, Cristina Kraemer |
dc.subject.por.fl_str_mv |
Mycobacterium bovis Mycobacterium bovis Mycobacterium tuberculosis complex Mycobacterium tuberculosis complex Análise de balance de fluxo Flux balance analysis Genômica Genomics Transcriptômica Transcriptomics |
topic |
Mycobacterium bovis Mycobacterium bovis Mycobacterium tuberculosis complex Mycobacterium tuberculosis complex Análise de balance de fluxo Flux balance analysis Genômica Genomics Transcriptômica Transcriptomics |
description |
Tuberculosis (TB) is caused by the Mycobacterium tuberculosis complex (MTBC), a bacterial group of clonally evolved pathogens that infect humans and animals. Despite a high genetic similarity, MTBC members demonstrate different host tropism and virulence. While Mycobacterium tuberculosis is the main causative agent of human TB and is highly adapted to this host species, Mycobacterium bovis has a broader host range with variable populational persistence. In order to provide insights into phenotypic differences between both pathogens, this four-chapter thesis was developed with two major aims: (i) to perform a phylogenomic analysis to understand the populational structure of M. bovis isolated from cattle and wildlife worldwide and to provide dating estimates for the origin of this pathogen; and (ii) to compare the global transcriptional profiles of M. bovis SP38 and M. tuberculosis H37Rv in vitro and identify their activated metabolic pathways using flux balance analysis (FBA) coupled with transcriptomics. First, the phylogenomic analysis, including approximately 2,000 M. genomes from 23 countries, identified at least four distinct lineages of M. bovis (Lb1, Lb2, Lb3, and Lb4) underlying the current disease distribution. These lineages clustered according to geographical origin and clonal complexes (CC), but not host species. Additionally, data divergence analysis indicates that extant M. bovis originated between 715- and 3,556-years BP (before present), with later emergence in the New World and Oceania, likely influenced by trades among countries. Next, RNA-seq from M. tuberculosis and M. bovis grown in vitro showed significant differences involving genes related to cell wall metabolism, with upregulation of PDIM (phthiocerol dimycocerosates) in M. bovis, and upregulation of SL-1 (sulfolipid), trehalose lipids, and glycolipids in M. tuberculosis. Among the top expressed genes, SigK regulon and secretion system ESX-1 were upregulated in M. bovis, while genes of the nitrate metabolism and toxin-antitoxin systems were upregulated in M. tuberculosis. Furthermore, FBA suggests major differences in central carbon metabolism between species, particularly in the use of glutamate to fuel the GABA shunt in M. tuberculosis, but cysteine production in M. bovis. We speculate that some of these differences occur because M. bovis is a microaerophile and M. tuberculosis an obligate aerobe. In conclusion, the studies reported herein greatly expanded our knowledge of the populational structure of M. bovis and its metabolism in comparison to the model organism M. tuberculosis. These results will serve as basis for further research related to the use of genomics to understand disease transmission and virulence, as well as to how these mycobacteria respond to microenvironmental conditions that can sustain their virulence and host tropism traits. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-09-21 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://www.teses.usp.br/teses/disponiveis/10/10134/tde-30112022-110829/ |
url |
https://www.teses.usp.br/teses/disponiveis/10/10134/tde-30112022-110829/ |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
|
dc.rights.driver.fl_str_mv |
Reter o conteúdo por motivos de patente, publicação e/ou direitos autoriais. info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Reter o conteúdo por motivos de patente, publicação e/ou direitos autoriais. |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.coverage.none.fl_str_mv |
|
dc.publisher.none.fl_str_mv |
Biblioteca Digitais de Teses e Dissertações da USP |
publisher.none.fl_str_mv |
Biblioteca Digitais de Teses e Dissertações da USP |
dc.source.none.fl_str_mv |
reponame:Biblioteca Digital de Teses e Dissertações da USP instname:Universidade de São Paulo (USP) instacron:USP |
instname_str |
Universidade de São Paulo (USP) |
instacron_str |
USP |
institution |
USP |
reponame_str |
Biblioteca Digital de Teses e Dissertações da USP |
collection |
Biblioteca Digital de Teses e Dissertações da USP |
repository.name.fl_str_mv |
Biblioteca Digital de Teses e Dissertações da USP - Universidade de São Paulo (USP) |
repository.mail.fl_str_mv |
virginia@if.usp.br|| atendimento@aguia.usp.br||virginia@if.usp.br |
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1815256544703414272 |