Combined deletion of four Francisella novicida acid phosphatases attenuates virulence and macrophage vacuolar escape

Nrusingh P. Mohapatra, Shilpa Soni, Thomas J. Reilly, Jirong Liu, Karl E. Klose, John S. Gunn

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Francisella tularensis is a facultative intracellular pathogen and the etiologic agent of tularemia. It is capable of escape from macrophage phagosomes and replicates in the host cell cytosol. Bacterial acid phosphatases are thought to play a major role in the virulence and intracellular survival of a number of intracellular pathogens. The goal of this study was to delete the four primary acid phosphatases (Acps) from Francisella novicida and examine the interactions of mutant strains with macrophages, as well as the virulence of these strains in mice. We constructed F. novicida mutants with various combinations of acp deletions and showed that loss of the four Acps (AcpA, AcpB, AcpC, and histidine acid phosphatase [Hap]) in an F. novicida strain (ΔABCH) resulted in a 90% reduction in acid phosphatase activity. The ΔABCH mutant was defective for survival/growth within human and murine macrophage cell lines and was unable to escape from phagosome vacuoles. With accumulation of Acp deletions, a progressive loss of virulence in the mouse model was observed. The ΔABCH strain was dramatically attenuated and was an effective single-dose vaccine against homologous challenge. Furthermore, both acpA and hap were induced when the bacteria were within host macrophages. Thus, the Francisella acid phosphatases cumulatively play an important role in intracellular trafficking and virulence.

Original languageEnglish (US)
Pages (from-to)3690-3699
Number of pages10
JournalInfection and immunity
Volume76
Issue number8
DOIs
StatePublished - Aug 2008

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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