Abstract
Different Francisella spp. produce five or six predicted acid phosphatases (AcpA, AcpB, AcpC, AcpD, HapA and HapB). The genes encoding the histidine acid phosphatases (hapA, hapB) and acpD of F. tularensis subsp. Schu S4 strain are truncated or disrupted. However, deletion of HapA (FTT1064) in F. tularensis Schu S4 resulted in a 33% reduction in acid phosphatase activity and loss of the four functional acid phosphatases in F. tularensis Schu S4 (ΔABCH) resulted in a>99% reduction in acid phosphatase activity compared to the wild type strain. All single, double and triple mutants tested, demonstrated a moderate decrease in mouse virulence and survival and growth within human and murine phagocytes, whereas the ΔABCH mutant showed >3.5-fold decrease in intramacrophage survival and 100% attenuation of virulence in mouse. While the Schu S4 ΔABCH strain was attenuated in the mouse model, it showed only limited protection against wild type challenge. F. tularensis Schu S4 failed to stimulate reactive oxygen species production in phagocytes, whereas infection by the ΔABCH strain stimulated 5- and 56-fold increase in reactive oxygen species production in neutrophils and human monocyte-derived macrophages, respectively. The ΔABCH mutant but not the wild type strain strongly co-localized with p47phox and replicated in macrophages isolated from p47phox knockout mice. Thus, F. tularensis Schu S4 acid phosphatases, including the truncated HapA, play a major role in intramacrophage survival and virulence of this human pathogen.
Highlights
Tularemia is a potentially fatal systemic disease of humans and animals caused by the bacterial pathogen Francisella tularensis subsp. tularensis (F. tularensis)
Construction of F. tularensis Schu S4 acid phosphatase gene deletions The comparative genome analysis of F. novicida and F. tularensis subsp. tularensis revealed that AcpA (FTT0221), AcpB (FTT0156) and AcpC (FTT0620) were highly conserved (98.05, 98.97, and 96.76% identity, respectively)
The genes encoding HapA, HapB, and AcpD are truncated/interrupted in F. tularensis subsp. tularensis Schu S4. This truncation has resulted in a lack of interest in HapA in Schu S4, driven by the fact that the predicted active site is in the C-terminal region that would be absent in the Schu S4 truncated protein. acpD and hapB are severely disrupted in Schu S4 [50] and were not further considered
Summary
Tularemia is a potentially fatal systemic disease of humans and animals caused by the bacterial pathogen Francisella tularensis subsp. tularensis (F. tularensis). Tularemia is a potentially fatal systemic disease of humans and animals caused by the bacterial pathogen Francisella tularensis subsp. Tularemia in humans is an acute febrile disease that shows cutaneous, oculoglandular, pneumonic, gastrointestinal or septic features depending upon the route of infection [7,8,9,10]. Two of the four subspecies of Francisella tularensis Tularensis, holarctica) cause significant disease in immuno-competent humans. Infections with Type A F. tularensis are associated with the highest mortality rates. All Francisella subspecies exhibit greater than 95% DNA identity [11]. An attenuated live vaccine strain (LVS) of F. holarctica was isolated and has been used extensively in humans, but has not achieved approval for use in the United States [12]
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