The study of mast cell-mediated innate immune mechanisms in control of Francisella tularensis pulmonary infection

Mast cell innate immune response(s) to bacterial pathogens is a keystone in host defense against invading pathogens. These multifunctional cells express several toll-like receptors for pathogen recognition and subsequent relay of signals essential to alert the host immune system of attacking microbes. Studies have demonstrated that control and protection against pulmonary bacterial pathogens including Francisella tularensis, Mycobacterium tuberculosis and Pseudomonas aeruginosa require toll-like receptor 2 signaling. However, the primary mechanism of action has not been defined. In this study, an in vitro mast cell-macrophage co-culture system was designed to evaluate mast cell interactions and the mode of mast cell bacterial recognition and defense against two strains of Francisella tularensis, including the highly human virulent type A strain, SCHU S4 and the Live Vaccine Strain. Importantly, mice were challenged intranasally to further evaluate mast cell innate immune responses during pulmonary infection. This study provides novel insight into mast cell inhibition of replication of an important bacterial pathogen and select agent. Mast cell toll-like receptor 2 signaling and subsequent secreted interleukin-4 were critical for mast cell inhibition of Francisella replication. Importantly, lack of TLR2 signaling resulted in an abnormal upsurge of cathepsin L which may promote cellular destruction. Wild-type mast cell innate immune responses included enhanced accumulation of lysosomal associated membrane protein 2, phagosome maturation and acidification, which culminated in killing of the bacterial pathogens.