A conserved and immunodominant lipoprotein of Francisella tularensis is proinflammatory but not essential for virulence

Abstract

Francisella tularensis is a highly virulent bacterium that causes tularemia, a disease that is often fatal if untreated. A live vaccine strain (LVS) of this bacterium is attenuated for virulence in humans but produces lethal disease in mice. F. tularensis has been classified as a Category A agent of bioterrorism. Despite this categorization, little is known about the components of the organism that are responsible for causing disease in its hosts. Here, we report the deletion of a well-characterized lipoprotein of F. tularensis, designated LpnA (also known as Tul4), in the LVS. An LpnA deletion mutant was comparable to the wild-type strain in its ability to grow intracellularly and cause lethal disease in mice. Additionally, mice inoculated with a sublethal dose of the mutant strain were afforded the same protection against a subsequent lethal challenge with the LVS as were mice initially administered a sublethal dose of the wild-type bacterium. The LpnA-deficient strain showed an equivalent ability to promote secretion of chemokines by human monocyte-derived macrophages as its wild-type counterpart. However, recombinant LpnA potently stimulated primary cultures of human macrophages in a Toll-like receptor 2-dependent manner. Although human endothelial cells also were activated by recombinant LpnA, their response was relatively modest. LpnA is clearly unnecessary for multiple functions of the LVS, but its inflammatory capacity implicates it and other Francisella lipoproteins as potentially important to the pathogenesis of tularemia.

Francisella tularensisInfection-Derived Monoclonal Antibodies Provide Detection, Protection, and Therapy

“…Each protein was unambiguously identified based on having a Mowse score of Ͼ300, with the exception of LpnA. However, the identity of LpnA as the cognate antigen to MAb 164 was confirmed by Western blotting against an LpnA knockout strain of F. tularensis LVS (17). Consistent with previous reports, the predominant isotype of these MAbs is IgG2a (45).…”

Subversion of Host Recognition and Defense Systems by Francisella spp

“…TLR2 is the primary TLR involved in the inflammatory response to Francisella infection (1). Known Francisella TLR2 agonists include the uncharacterized lipoproteins LpnA/Tul4 and FTT_1103 (86,220). To our knowledge, TLR2 recognition of Francisella PGN has not been reported, and the status of PGN as a TLR2 ligand is still under debate (12,73,222).…”

GroEL and Lipopolysaccharide fromFrancisella tularensisLive Vaccine Strain Synergistically Activate Human Macrophages

“…It is likely, then, that F. tularensis elicits inflammation via components other than LPS. Recently, it has been shown that two lipoproteins of F. tularensis, LpnA and FTT1103, stimulate expression of chemokines by human and murine cells of innate immunity (24,60). As shown herein, the heat shock protein GroEL from F. tularensis also provokes changes in host cells.…”