IAI Accepts, published online ahead of print on 19 October 2009

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Infect. Immun. doi:10.1128/IAI.00750-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Presence of CD14 overcomes evasion of innate immune responses by virulent Francisella tularensis in human dendritic cells in vitro and pulmonary cells in vivo.

Jennifer C. Chase and Catharine M. Bosio^*

Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA 59840

^* To whom correspondence should be addressed. Email: bosioc{at}niaid.nih.gov.

Francisella tularensis is a Gram negative bacterium that causes acute, lethal, disease following inhalation. We have previously shown that viable F. tularensis fails to stimulate secretion of pro-inflammatory cytokines following infection of human DC (hDC) in vitro and pulmonary cells in vivo. Here we demonstrate that presence of the receptor CD14 is critical for detection of virulent F. tularensis strain SchuS4 by dendritic cells, monocytes and pulmonary cells. Addition of soluble CD14 (sCD14) to hDC restored cytokine production following infection with SchuS4. In contrast, addition of anti-CD14 to monocyte cultures inhibited the ability of these cells to respond to SchuS4. Addition or blocking CD14 following SchuS4 infection in dendritic cells and monocytes, respectively, was not due to alterations in phagocytosis or replication of the bacterium in these cells. Administration of sCD14 in vivo also restored cytokine production following infection with SchuS4, as assessed by increased concentrations of TNF-, IL-1, IL-12p70 and IL-6 in the lungs of mice receiving sCD14 compared to mock treated controls. In contrast to homogenous cultures of monocytes or dendritic cells infected in vitro, mice treated with sCD14 in vivo also controlled bacterial replication and dissemination compared to mock treated controls. Interestingly, animals that lacked CD14 were not more susceptible or resistant to pulmonary infection with SchuS4. Together, these data support the hypothesis that absence or low abundance, of CD14 on hDC and in the lung contributes to evasion of innate immunity by virulent F. tularensis. However, CD14 is not required for development of inflammation during the last 24-48 hours of SchuS4 infection. Thus, presence of this receptor may aid in control of virulent F. tularensis infections at early, but not late, stages of infection.