Identification of Mycobacterium tuberculosis counterimmune (cim) mutants in immunodeficient mice by differential screening

Katherine B. Hisert, Meghan A. Kirksey, James E. Gomez, Alexandra O. Sousa, Jeffery S. Cox, William R. Jacobs, Carl F. Nathan, John D. McKinney

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Tuberculosis (TB) is characterized by lifetime persistence of Mycobacterium tuberculosis. Despite the induction of a vigorous host immune response that curtails disease progression in the majority of cases, the organism is not eliminated. Subsequent immunosuppression can lead to reactivation after a prolonged period of clinical latency. Thus, while it is clear that protective immune mechanisms are engaged during M. tuberculosis infection, it also appears that the pathogen has evolved effective countermechanisms. Genetic studies with animal infection models and with patients have revealed a key role for the cytokine gamma interferon (IFN-γ) in resistance to TB. IFN-γ activates a large number of antimicrobial pathways. Three of these IFN-γ-dependent mechanisms have been implicated in defense against M. tuberculosis: inducible nitric oxide syntliase (iNOS), phagosome oxidase (phox), and the phagosome-associated GTPase LRG-47. In order to identify bacterial genes that provide protection against specific host immune pathways, we have developed the strategy of differential signature-tagged transposon mutagenesis. Using this approach we liave identified three M. tuberculosis genes that are essential for progressive M. tuberculosis growth and rapid lethality in iNOS-deficient mice but not in IFN-γ-deficient mice. We propose that these genes are involved in pathways that allow M. tuberculosis to counter IFN-γ-dependent immune mechanisms other than iNOS.

Original languageEnglish (US)
Pages (from-to)5315-5321
Number of pages7
JournalInfection and Immunity
Volume72
Issue number9
DOIs
StatePublished - Sep 1 2004

Fingerprint

Mycobacterium tuberculosis
Interferons
Phagosomes
Nitric Oxide
Interferon-gamma
Tuberculosis
Bacterial Genes
Mycobacterium Infections
GTP Phosphohydrolases
Essential Genes
Mutagenesis
Immunosuppression
Disease Progression
Oxidoreductases
Animal Models
Cytokines
Growth
Infection
Genes

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

Cite this

Identification of Mycobacterium tuberculosis counterimmune (cim) mutants in immunodeficient mice by differential screening. / Hisert, Katherine B.; Kirksey, Meghan A.; Gomez, James E.; Sousa, Alexandra O.; Cox, Jeffery S.; Jacobs, William R.; Nathan, Carl F.; McKinney, John D.

In: Infection and Immunity, Vol. 72, No. 9, 01.09.2004, p. 5315-5321.

Research output: Contribution to journalArticle

Hisert, Katherine B. ; Kirksey, Meghan A. ; Gomez, James E. ; Sousa, Alexandra O. ; Cox, Jeffery S. ; Jacobs, William R. ; Nathan, Carl F. ; McKinney, John D. / Identification of Mycobacterium tuberculosis counterimmune (cim) mutants in immunodeficient mice by differential screening. In: Infection and Immunity. 2004 ; Vol. 72, No. 9. pp. 5315-5321.
@article{237b3651de514c11a0b2cb3db246b575,
title = "Identification of Mycobacterium tuberculosis counterimmune (cim) mutants in immunodeficient mice by differential screening",
abstract = "Tuberculosis (TB) is characterized by lifetime persistence of Mycobacterium tuberculosis. Despite the induction of a vigorous host immune response that curtails disease progression in the majority of cases, the organism is not eliminated. Subsequent immunosuppression can lead to reactivation after a prolonged period of clinical latency. Thus, while it is clear that protective immune mechanisms are engaged during M. tuberculosis infection, it also appears that the pathogen has evolved effective countermechanisms. Genetic studies with animal infection models and with patients have revealed a key role for the cytokine gamma interferon (IFN-γ) in resistance to TB. IFN-γ activates a large number of antimicrobial pathways. Three of these IFN-γ-dependent mechanisms have been implicated in defense against M. tuberculosis: inducible nitric oxide syntliase (iNOS), phagosome oxidase (phox), and the phagosome-associated GTPase LRG-47. In order to identify bacterial genes that provide protection against specific host immune pathways, we have developed the strategy of differential signature-tagged transposon mutagenesis. Using this approach we liave identified three M. tuberculosis genes that are essential for progressive M. tuberculosis growth and rapid lethality in iNOS-deficient mice but not in IFN-γ-deficient mice. We propose that these genes are involved in pathways that allow M. tuberculosis to counter IFN-γ-dependent immune mechanisms other than iNOS.",
author = "Hisert, {Katherine B.} and Kirksey, {Meghan A.} and Gomez, {James E.} and Sousa, {Alexandra O.} and Cox, {Jeffery S.} and Jacobs, {William R.} and Nathan, {Carl F.} and McKinney, {John D.}",
year = "2004",
month = "9",
day = "1",
doi = "10.1128/IAI.72.9.5315-5321.2004",
language = "English (US)",
volume = "72",
pages = "5315--5321",
journal = "Infection and Immunity",
issn = "0019-9567",
publisher = "American Society for Microbiology",
number = "9",

}

TY - JOUR

T1 - Identification of Mycobacterium tuberculosis counterimmune (cim) mutants in immunodeficient mice by differential screening

AU - Hisert, Katherine B.

AU - Kirksey, Meghan A.

AU - Gomez, James E.

AU - Sousa, Alexandra O.

AU - Cox, Jeffery S.

AU - Jacobs, William R.

AU - Nathan, Carl F.

AU - McKinney, John D.

PY - 2004/9/1

Y1 - 2004/9/1

N2 - Tuberculosis (TB) is characterized by lifetime persistence of Mycobacterium tuberculosis. Despite the induction of a vigorous host immune response that curtails disease progression in the majority of cases, the organism is not eliminated. Subsequent immunosuppression can lead to reactivation after a prolonged period of clinical latency. Thus, while it is clear that protective immune mechanisms are engaged during M. tuberculosis infection, it also appears that the pathogen has evolved effective countermechanisms. Genetic studies with animal infection models and with patients have revealed a key role for the cytokine gamma interferon (IFN-γ) in resistance to TB. IFN-γ activates a large number of antimicrobial pathways. Three of these IFN-γ-dependent mechanisms have been implicated in defense against M. tuberculosis: inducible nitric oxide syntliase (iNOS), phagosome oxidase (phox), and the phagosome-associated GTPase LRG-47. In order to identify bacterial genes that provide protection against specific host immune pathways, we have developed the strategy of differential signature-tagged transposon mutagenesis. Using this approach we liave identified three M. tuberculosis genes that are essential for progressive M. tuberculosis growth and rapid lethality in iNOS-deficient mice but not in IFN-γ-deficient mice. We propose that these genes are involved in pathways that allow M. tuberculosis to counter IFN-γ-dependent immune mechanisms other than iNOS.

AB - Tuberculosis (TB) is characterized by lifetime persistence of Mycobacterium tuberculosis. Despite the induction of a vigorous host immune response that curtails disease progression in the majority of cases, the organism is not eliminated. Subsequent immunosuppression can lead to reactivation after a prolonged period of clinical latency. Thus, while it is clear that protective immune mechanisms are engaged during M. tuberculosis infection, it also appears that the pathogen has evolved effective countermechanisms. Genetic studies with animal infection models and with patients have revealed a key role for the cytokine gamma interferon (IFN-γ) in resistance to TB. IFN-γ activates a large number of antimicrobial pathways. Three of these IFN-γ-dependent mechanisms have been implicated in defense against M. tuberculosis: inducible nitric oxide syntliase (iNOS), phagosome oxidase (phox), and the phagosome-associated GTPase LRG-47. In order to identify bacterial genes that provide protection against specific host immune pathways, we have developed the strategy of differential signature-tagged transposon mutagenesis. Using this approach we liave identified three M. tuberculosis genes that are essential for progressive M. tuberculosis growth and rapid lethality in iNOS-deficient mice but not in IFN-γ-deficient mice. We propose that these genes are involved in pathways that allow M. tuberculosis to counter IFN-γ-dependent immune mechanisms other than iNOS.

UR - http://www.scopus.com/inward/record.url?scp=4544245973&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=4544245973&partnerID=8YFLogxK

U2 - 10.1128/IAI.72.9.5315-5321.2004

DO - 10.1128/IAI.72.9.5315-5321.2004

M3 - Article

C2 - 15322028

AN - SCOPUS:4544245973

VL - 72

SP - 5315

EP - 5321

JO - Infection and Immunity

JF - Infection and Immunity

SN - 0019-9567

IS - 9

ER -