Brucella abortus bacA mutant induces greater pro-inflammatory cytokines than the wild-type parent strain

Michelle A. Parent, Radhika Goenka, Erin Murphy, Kristen LeVier, Nuno Carreiro, Basil Golding, Gail Patricia Ferguson, R. Martin Roop, Graham C. Walker, Cynthia L. Baldwin

Research output: Contribution to journalArticle

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Abstract

The inner-membrane protein BacA affects Brucella LPS structure. A bacA deletion mutant of Brucella abortus, known as KL7 (bacA(mut)-KL7), is attenuated in BALB/c mice and protects against challenge. Thus, bacA mutation was a candidate for incorporation into live attenuated vaccines. We assessed bacA(mut)-KL7 in 2 additional mouse strains: the more resistant C57BL/6 that produces interferon-gamma throughout the infection and the highly susceptible interferon-gamma-deficient C57BL/6 in which brucellae exhibit continual exponential growth. While it was hypothesized that bacA(mut)-KL7 would exhibit even greater attenuation relative to its parent strain B. abortus 2308 in C57BL/6 mice than it did in BALB/c mice, this was not the case. Moreover, it was more pathogenic in C57BL/6 interferon-gamma-deficient mice than 2308 causing abscesses and wasting even though the splenic loads of bacA(mut)-KL7 were significantly lower. These 2 observations were correlated, respectively, with an ability of IFNgamma-activated macrophages to equivalently control strains 2308 and bacA(mut)-KL7 and the ability of bacA(mut)-KL7 organism and its LPS to induce greater amounts of pro-inflammatory cytokines than 2308. We conclude that attenuation properties of bacA mutation are dependent upon the nature of the host but more importantly that bacterial gene deletion can result in increased host pathology without an increase in bacterial load, crucial considerations for vaccine design.
Original languageEnglish
Pages (from-to)55-62
Number of pages8
JournalMicrobes and Infection
Volume9
Issue number1
Early online date11 Dec 2006
DOIs
Publication statusPublished - Jan 2007

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Brucella abortus
Cytokines
Interferon-gamma
Brucella
Bacterial Genes
Attenuated Vaccines
Mutation
Bacterial Load
Gene Deletion
Inbred C57BL Mouse
Abscess
Membrane Proteins
Vaccines
Macrophages
Pathology
Growth
Infection

Keywords

  • animals
  • bacterial proteins
  • Brucella Vaccine
  • Brucella abortus
  • Brucellosis
  • complement system proteins
  • cytokines
  • gene deletion
  • interferon-gamma
  • lipopolysaccharides
  • macrophage Activation
  • macrophages
  • membrane transport proteins
  • mice
  • mice, inbred BALB C
  • mice, inbred C57BL
  • intracellular bacteria
  • bacA
  • Brucella

Cite this

Parent, M. A., Goenka, R., Murphy, E., LeVier, K., Carreiro, N., Golding, B., ... Baldwin, C. L. (2007). Brucella abortus bacA mutant induces greater pro-inflammatory cytokines than the wild-type parent strain. Microbes and Infection, 9(1), 55-62. https://doi.org/10.1016/j.micinf.2006.10.008

Brucella abortus bacA mutant induces greater pro-inflammatory cytokines than the wild-type parent strain. / Parent, Michelle A.; Goenka, Radhika; Murphy, Erin; LeVier, Kristen; Carreiro, Nuno; Golding, Basil; Ferguson, Gail Patricia; Roop, R. Martin; Walker, Graham C.; Baldwin, Cynthia L.

In: Microbes and Infection, Vol. 9, No. 1, 01.2007, p. 55-62.

Research output: Contribution to journalArticle

Parent, MA, Goenka, R, Murphy, E, LeVier, K, Carreiro, N, Golding, B, Ferguson, GP, Roop, RM, Walker, GC & Baldwin, CL 2007, 'Brucella abortus bacA mutant induces greater pro-inflammatory cytokines than the wild-type parent strain', Microbes and Infection, vol. 9, no. 1, pp. 55-62. https://doi.org/10.1016/j.micinf.2006.10.008
Parent, Michelle A. ; Goenka, Radhika ; Murphy, Erin ; LeVier, Kristen ; Carreiro, Nuno ; Golding, Basil ; Ferguson, Gail Patricia ; Roop, R. Martin ; Walker, Graham C. ; Baldwin, Cynthia L. / Brucella abortus bacA mutant induces greater pro-inflammatory cytokines than the wild-type parent strain. In: Microbes and Infection. 2007 ; Vol. 9, No. 1. pp. 55-62.
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abstract = "The inner-membrane protein BacA affects Brucella LPS structure. A bacA deletion mutant of Brucella abortus, known as KL7 (bacA(mut)-KL7), is attenuated in BALB/c mice and protects against challenge. Thus, bacA mutation was a candidate for incorporation into live attenuated vaccines. We assessed bacA(mut)-KL7 in 2 additional mouse strains: the more resistant C57BL/6 that produces interferon-gamma throughout the infection and the highly susceptible interferon-gamma-deficient C57BL/6 in which brucellae exhibit continual exponential growth. While it was hypothesized that bacA(mut)-KL7 would exhibit even greater attenuation relative to its parent strain B. abortus 2308 in C57BL/6 mice than it did in BALB/c mice, this was not the case. Moreover, it was more pathogenic in C57BL/6 interferon-gamma-deficient mice than 2308 causing abscesses and wasting even though the splenic loads of bacA(mut)-KL7 were significantly lower. These 2 observations were correlated, respectively, with an ability of IFNgamma-activated macrophages to equivalently control strains 2308 and bacA(mut)-KL7 and the ability of bacA(mut)-KL7 organism and its LPS to induce greater amounts of pro-inflammatory cytokines than 2308. We conclude that attenuation properties of bacA mutation are dependent upon the nature of the host but more importantly that bacterial gene deletion can result in increased host pathology without an increase in bacterial load, crucial considerations for vaccine design.",
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AU - Parent, Michelle A.

AU - Goenka, Radhika

AU - Murphy, Erin

AU - LeVier, Kristen

AU - Carreiro, Nuno

AU - Golding, Basil

AU - Ferguson, Gail Patricia

AU - Roop, R. Martin

AU - Walker, Graham C.

AU - Baldwin, Cynthia L.

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AB - The inner-membrane protein BacA affects Brucella LPS structure. A bacA deletion mutant of Brucella abortus, known as KL7 (bacA(mut)-KL7), is attenuated in BALB/c mice and protects against challenge. Thus, bacA mutation was a candidate for incorporation into live attenuated vaccines. We assessed bacA(mut)-KL7 in 2 additional mouse strains: the more resistant C57BL/6 that produces interferon-gamma throughout the infection and the highly susceptible interferon-gamma-deficient C57BL/6 in which brucellae exhibit continual exponential growth. While it was hypothesized that bacA(mut)-KL7 would exhibit even greater attenuation relative to its parent strain B. abortus 2308 in C57BL/6 mice than it did in BALB/c mice, this was not the case. Moreover, it was more pathogenic in C57BL/6 interferon-gamma-deficient mice than 2308 causing abscesses and wasting even though the splenic loads of bacA(mut)-KL7 were significantly lower. These 2 observations were correlated, respectively, with an ability of IFNgamma-activated macrophages to equivalently control strains 2308 and bacA(mut)-KL7 and the ability of bacA(mut)-KL7 organism and its LPS to induce greater amounts of pro-inflammatory cytokines than 2308. We conclude that attenuation properties of bacA mutation are dependent upon the nature of the host but more importantly that bacterial gene deletion can result in increased host pathology without an increase in bacterial load, crucial considerations for vaccine design.

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KW - lipopolysaccharides

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KW - membrane transport proteins

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KW - mice, inbred BALB C

KW - mice, inbred C57BL

KW - intracellular bacteria

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JO - Microbes and Infection

JF - Microbes and Infection

SN - 1286-4579

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ER -