Hypervirulent mutant of Mycobacterium tuberculosis resulting from disruption of the mce1 operon

Nobuyuki Shimono, Lisa Morici, Nicola Casali, Sally Cantrell, Ben Sidders, Sabine Ehrt, Lee W. Riley

Research output: Contribution to journalArticle

141 Citations (Scopus)

Abstract

An estimated one-third of the world's population is latently infected with Mycobacterium tuberculosis, the etiologic agent of tuberculosis. Here, we demonstrate that, unlike wild-type M. tuberculosis, a strain of M. tuberculosis disrupted in the mce1 operon was unable to enter a stable persistent state of infection in mouse lungs. Instead, the mutant continued to replicate and killed the mice more rapidly than did the wild-type strain. Histological examination of mouse lungs infected with the mutant strain revealed diffusely organized granulomas with aberrant inflammatory cell migration. Murine macrophages infected ex vivo with the mutant strain were reduced in their ability to produce tumor necrosis factor α, IL-6, monocyte chemoattractant protein 1, and nitric oxide (NO), but not IL-4. The mce1 mutant strain complemented with the mce1 genes stimulated tumor necrosis factor α and NO production by murine macrophages at levels stimulated by the wild-type strain. These observations indicate that the mce1 operon mutant is unable to stimulate T helper 1-type immunity in mice. The hypervirulence of the mutant strain may have resulted from its inability to stimulate a proinflammatory response that would otherwise induce organized granuloma formation and control the infection without killing the organism. The mce1 operon of M. tuberculosis may be involved in modulating the host inflammatory response in such a way that the bacterium can enter a persistent state without being eliminated or causing disease in the host.

Original languageEnglish
Pages (from-to)15918-15923
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number26
DOIs
Publication statusPublished - Dec 23 2003

Fingerprint

Operon
Mycobacterium tuberculosis
Granuloma
Nitric Oxide
Tumor Necrosis Factor-alpha
Macrophages
Lung
Chemokine CCL2
Infection Control
Interleukin-4
Cell Movement
Immunity
Interleukin-6
Tuberculosis
Bacteria
Infection
Population
Genes

All Science Journal Classification (ASJC) codes

  • General

Cite this

Hypervirulent mutant of Mycobacterium tuberculosis resulting from disruption of the mce1 operon. / Shimono, Nobuyuki; Morici, Lisa; Casali, Nicola; Cantrell, Sally; Sidders, Ben; Ehrt, Sabine; Riley, Lee W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 26, 23.12.2003, p. 15918-15923.

Research output: Contribution to journalArticle

Shimono, Nobuyuki ; Morici, Lisa ; Casali, Nicola ; Cantrell, Sally ; Sidders, Ben ; Ehrt, Sabine ; Riley, Lee W. / Hypervirulent mutant of Mycobacterium tuberculosis resulting from disruption of the mce1 operon. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 26. pp. 15918-15923.
@article{19ec1def4e7341acb457a0612b03dad0,
title = "Hypervirulent mutant of Mycobacterium tuberculosis resulting from disruption of the mce1 operon",
abstract = "An estimated one-third of the world's population is latently infected with Mycobacterium tuberculosis, the etiologic agent of tuberculosis. Here, we demonstrate that, unlike wild-type M. tuberculosis, a strain of M. tuberculosis disrupted in the mce1 operon was unable to enter a stable persistent state of infection in mouse lungs. Instead, the mutant continued to replicate and killed the mice more rapidly than did the wild-type strain. Histological examination of mouse lungs infected with the mutant strain revealed diffusely organized granulomas with aberrant inflammatory cell migration. Murine macrophages infected ex vivo with the mutant strain were reduced in their ability to produce tumor necrosis factor α, IL-6, monocyte chemoattractant protein 1, and nitric oxide (NO), but not IL-4. The mce1 mutant strain complemented with the mce1 genes stimulated tumor necrosis factor α and NO production by murine macrophages at levels stimulated by the wild-type strain. These observations indicate that the mce1 operon mutant is unable to stimulate T helper 1-type immunity in mice. The hypervirulence of the mutant strain may have resulted from its inability to stimulate a proinflammatory response that would otherwise induce organized granuloma formation and control the infection without killing the organism. The mce1 operon of M. tuberculosis may be involved in modulating the host inflammatory response in such a way that the bacterium can enter a persistent state without being eliminated or causing disease in the host.",
author = "Nobuyuki Shimono and Lisa Morici and Nicola Casali and Sally Cantrell and Ben Sidders and Sabine Ehrt and Riley, {Lee W.}",
year = "2003",
month = "12",
day = "23",
doi = "10.1073/pnas.2433882100",
language = "English",
volume = "100",
pages = "15918--15923",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "26",

}

TY - JOUR

T1 - Hypervirulent mutant of Mycobacterium tuberculosis resulting from disruption of the mce1 operon

AU - Shimono, Nobuyuki

AU - Morici, Lisa

AU - Casali, Nicola

AU - Cantrell, Sally

AU - Sidders, Ben

AU - Ehrt, Sabine

AU - Riley, Lee W.

PY - 2003/12/23

Y1 - 2003/12/23

N2 - An estimated one-third of the world's population is latently infected with Mycobacterium tuberculosis, the etiologic agent of tuberculosis. Here, we demonstrate that, unlike wild-type M. tuberculosis, a strain of M. tuberculosis disrupted in the mce1 operon was unable to enter a stable persistent state of infection in mouse lungs. Instead, the mutant continued to replicate and killed the mice more rapidly than did the wild-type strain. Histological examination of mouse lungs infected with the mutant strain revealed diffusely organized granulomas with aberrant inflammatory cell migration. Murine macrophages infected ex vivo with the mutant strain were reduced in their ability to produce tumor necrosis factor α, IL-6, monocyte chemoattractant protein 1, and nitric oxide (NO), but not IL-4. The mce1 mutant strain complemented with the mce1 genes stimulated tumor necrosis factor α and NO production by murine macrophages at levels stimulated by the wild-type strain. These observations indicate that the mce1 operon mutant is unable to stimulate T helper 1-type immunity in mice. The hypervirulence of the mutant strain may have resulted from its inability to stimulate a proinflammatory response that would otherwise induce organized granuloma formation and control the infection without killing the organism. The mce1 operon of M. tuberculosis may be involved in modulating the host inflammatory response in such a way that the bacterium can enter a persistent state without being eliminated or causing disease in the host.

AB - An estimated one-third of the world's population is latently infected with Mycobacterium tuberculosis, the etiologic agent of tuberculosis. Here, we demonstrate that, unlike wild-type M. tuberculosis, a strain of M. tuberculosis disrupted in the mce1 operon was unable to enter a stable persistent state of infection in mouse lungs. Instead, the mutant continued to replicate and killed the mice more rapidly than did the wild-type strain. Histological examination of mouse lungs infected with the mutant strain revealed diffusely organized granulomas with aberrant inflammatory cell migration. Murine macrophages infected ex vivo with the mutant strain were reduced in their ability to produce tumor necrosis factor α, IL-6, monocyte chemoattractant protein 1, and nitric oxide (NO), but not IL-4. The mce1 mutant strain complemented with the mce1 genes stimulated tumor necrosis factor α and NO production by murine macrophages at levels stimulated by the wild-type strain. These observations indicate that the mce1 operon mutant is unable to stimulate T helper 1-type immunity in mice. The hypervirulence of the mutant strain may have resulted from its inability to stimulate a proinflammatory response that would otherwise induce organized granuloma formation and control the infection without killing the organism. The mce1 operon of M. tuberculosis may be involved in modulating the host inflammatory response in such a way that the bacterium can enter a persistent state without being eliminated or causing disease in the host.

UR - http://www.scopus.com/inward/record.url?scp=0346734118&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0346734118&partnerID=8YFLogxK

U2 - 10.1073/pnas.2433882100

DO - 10.1073/pnas.2433882100

M3 - Article

C2 - 14663145

AN - SCOPUS:0346734118

VL - 100

SP - 15918

EP - 15923

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 26

ER -