Infection with francisella tularensis lvs clpb leads to an altered yet protective immune response

Lydia M. Barrigan, Shraddha Tuladhar, Jason C. Brunton, Matthew D. Woolard, Ching ju Chen, Divey Saini, Richard Frothingham, Gregory D. Sempowski, Thomas H. Kawula, Jeffrey A Frelinger

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Bacterial attenuation is typically thought of as reduced bacterial growth in the presence of constant immune pressure. Infection with Francisella tularensis elicits innate and adaptive immune responses. Several in vivo screens have identified F. tularensis genes necessary for virulence. Many of these mutations render F. tularensis defective for intracellular growth. However, some mutations have no impact on intracellular growth, leading us to hypothesize that these F. tularensis mutants are attenuated because they induce an altered host immune response. We were particularly interested in the F. tularensis LVS (live vaccine strain) clpB (FTL_0094) mutant because this strain was attenuated in pneumonic tularemia yet induced a protective immune response. The attenuation of LVS clpB was not due to an intracellular growth defect, as LVS clpB grew similarly to LVS in primary bone marrow-derived macrophages and a variety of cell lines. We therefore determined whether LVS clpB induced an altered immune response compared to that induced by LVS in vivo. We found that LVS clpB induced proinflammatory cytokine production in the lung early after infection, a process not observed during LVS infection. LVS clpB provoked a robust adaptive immune response similar in magnitude to that provoked by LVS but with increased gamma interferon (IFN-γ) and interleukin-17A (IL- 17A) production, as measured by mean fluorescence intensity. Altogether, our results indicate that LVS clpB is attenuated due to altered host immunity and not an intrinsic growth defect. These results also indicate that disruption of a nonessential gene(s) that is involved in bacterial immune evasion, like F. tularensis clpB, can serve as a model for the rational design of attenuated vaccines.

Original languageEnglish (US)
Pages (from-to)2028-2042
Number of pages15
JournalInfection and Immunity
Volume81
Issue number6
DOIs
StatePublished - Jun 2013

Fingerprint

Tularemia
Vaccines
Francisella tularensis
Growth
Adaptive Immunity
Immune Evasion
Lung
Attenuated Vaccines
Mutation
Interleukin-17
Infection
Innate Immunity
Genes
Interferon-gamma
Virulence
Immunity
Fluorescence
Macrophages

ASJC Scopus subject areas

  • Immunology
  • Microbiology
  • Parasitology
  • Infectious Diseases

Cite this

Infection with francisella tularensis lvs clpb leads to an altered yet protective immune response. / Barrigan, Lydia M.; Tuladhar, Shraddha; Brunton, Jason C.; Woolard, Matthew D.; Chen, Ching ju; Saini, Divey; Frothingham, Richard; Sempowski, Gregory D.; Kawula, Thomas H.; Frelinger, Jeffrey A.

In: Infection and Immunity, Vol. 81, No. 6, 06.2013, p. 2028-2042.

Research output: Contribution to journalArticle

Barrigan, LM, Tuladhar, S, Brunton, JC, Woolard, MD, Chen, CJ, Saini, D, Frothingham, R, Sempowski, GD, Kawula, TH & Frelinger, JA 2013, 'Infection with francisella tularensis lvs clpb leads to an altered yet protective immune response', Infection and Immunity, vol. 81, no. 6, pp. 2028-2042. https://doi.org/10.1128/IAI.00207-13
Barrigan, Lydia M. ; Tuladhar, Shraddha ; Brunton, Jason C. ; Woolard, Matthew D. ; Chen, Ching ju ; Saini, Divey ; Frothingham, Richard ; Sempowski, Gregory D. ; Kawula, Thomas H. ; Frelinger, Jeffrey A. / Infection with francisella tularensis lvs clpb leads to an altered yet protective immune response. In: Infection and Immunity. 2013 ; Vol. 81, No. 6. pp. 2028-2042.
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AU - Tuladhar, Shraddha

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AU - Woolard, Matthew D.

AU - Chen, Ching ju

AU - Saini, Divey

AU - Frothingham, Richard

AU - Sempowski, Gregory D.

AU - Kawula, Thomas H.

AU - Frelinger, Jeffrey A

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AB - Bacterial attenuation is typically thought of as reduced bacterial growth in the presence of constant immune pressure. Infection with Francisella tularensis elicits innate and adaptive immune responses. Several in vivo screens have identified F. tularensis genes necessary for virulence. Many of these mutations render F. tularensis defective for intracellular growth. However, some mutations have no impact on intracellular growth, leading us to hypothesize that these F. tularensis mutants are attenuated because they induce an altered host immune response. We were particularly interested in the F. tularensis LVS (live vaccine strain) clpB (FTL_0094) mutant because this strain was attenuated in pneumonic tularemia yet induced a protective immune response. The attenuation of LVS clpB was not due to an intracellular growth defect, as LVS clpB grew similarly to LVS in primary bone marrow-derived macrophages and a variety of cell lines. We therefore determined whether LVS clpB induced an altered immune response compared to that induced by LVS in vivo. We found that LVS clpB induced proinflammatory cytokine production in the lung early after infection, a process not observed during LVS infection. LVS clpB provoked a robust adaptive immune response similar in magnitude to that provoked by LVS but with increased gamma interferon (IFN-γ) and interleukin-17A (IL- 17A) production, as measured by mean fluorescence intensity. Altogether, our results indicate that LVS clpB is attenuated due to altered host immunity and not an intrinsic growth defect. These results also indicate that disruption of a nonessential gene(s) that is involved in bacterial immune evasion, like F. tularensis clpB, can serve as a model for the rational design of attenuated vaccines.

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