Bacterial toxins play an important role in the development of bacterial infection. Toxins secreted by bacteria may be transported by the vascular or lymphatic system and cause cytotoxic effects at tissue sites remote from the original point of invasion or growth. We focus on characterization of the pore-forming RTX (repeats in toxin) toxins from oral bacteria and human pathogens Aggregatibacter actinomycetemcomitans and Kingella kingae. The toxins of the RTX family are large proteins that contain glycine-rich repeats and are secreted from bacterial cells via type I secretion. Our work is aimed to understand the production, structure, and the mechanism of action on the host cells, and the role of the toxins in pathogenesis.
A. actinomycetemcomitans is an oral pathogen of Pasteurellaceae family and is the etiologic agent of localized aggressive periodontitis. As one of its virulence factors, A. actinomycetemcomitans produces leukotoxin RTX (LtxA) that known to lyse human leukocytes. LtxA interaction with human immune cells is a complex involving membrane cholesterol as well as membrane β2 integrin lymphocyte function-associated antigen 1 (LFA-1). Our recent results suggest that after entering the host cells by LFA-1 depended mechanism, LtxA induces lysosomal damage and cytosol acidification in immune cells. Our current research is to understand the mechanism of the toxin endocytic uptake and intracellular trafficking in human leukocytes.
K. kingae, a coccobacillus of the Nesseriaceae family, is a part of oral microflora n children. Recently, as the result of improved isolation and identification techniques, an increasing number of skeletal K. kingae infections have been reported throughout the world in pediatric patients. The bacterium produces RtxA, a toxin of RTX family, with a broad substrate specificity. Employing an infant rat model we demonstrated that RtxA is a key virulence factor for K. kingae. Further studies by our group showed that the toxin produces pores in artificial membranes inducing cation influx, which may lead to the host cell death. In our current investigation we explore the mechanisms of the cytotoxic action using a variety of biochemical and biophysical methods.