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Published online before print August 14, 2006

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(Journal of Leukocyte Biology. 2006;80:1224-1230.)
© 2006 by Society for Leukocyte Biology

Francisella tularensis LVS evades killing by human neutrophils via inhibition of the respiratory burst and phagosome escape

Ramona L. McCaffrey^*, and Lee-Ann H. Allen^*,,,1

^* Inflammation Program and Departments of
Medicine and
Microbiology, University of Iowa and the VA Medical Center, Iowa City, Iowa, USA

¹ Correspondence: Inflammation Program, University of Iowa, 2501 Crosspark Rd., MTF-D154, Coralville, IA 52241, USA. E-mail: lee-ann-allen{at}uiowa.edu

ABSTRACT

Francisella tularensis is a Gram-negative bacterium and the causative agent of tularemia. Recent data indicate that F. tularensis replicates inside macrophages, but its fate in other cell types, including human neutrophils, is unclear. We now show that F. tularensis live vaccine strain (LVS), opsonized with normal human serum, was rapidly ingested by neutrophils but was not eliminated. Moreover, evasion of intracellular killing can be explained, in part, by disruption of the respiratory burst. As judged by luminol-enhanced chemiluminescence and nitroblue tetrazolium staining, neutrophils infected with live F. tularensis did not generate reactive oxygen species. Confocal microscopy demonstrated that NADPH oxidase assembly was disrupted, and LVS phagosomes did not acquire gp91/p22^phox or p47/p67^phox. At the same time, F. tularensis also impaired neutrophil activation by heterologous stimuli such as phorbol esters and opsonized zymosan particles. Later in infection, LVS escaped the phagosome, and live organisms persisted in the neutrophil cytosol for at least 12 h. To our knowledge, our data are the first demonstration of a facultative intracellular pathogen, which disrupts the oxidative burst and escapes the phagosome to evade elimination inside neutrophils, and as such, our data define a novel mechanism of virulence.

Key Words: NADPH oxidase • tularemia • superoxide • pathogenesis

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