Divergent roles of Toll-like receptor 2 in response to lipoteichoic acid and Staphylococcus aureus in vivo.

The response of leukocytes to lipoteichoic acid (LTA), a TLR2-dependent major cell wall component of Staphylococcus aureus, is linked to the outcome of an infection. In this study we investigated the role of nonhematopoietic TLR2 in response to LTA and S. aureus by creating bone marrow chimeras. Significant leukocyte recruitment in response to LTA required IFN-gamma priming in WT C57BL/6 and TLR2(-/-)-->WT mice, but was not observed in TLR2(-/-) or WT-->TLR2(-/-) animals. LTA also induced a proinflammatory response in IFN-gamma primed primary human microvascular endothelial cells leading to leukocyte recruitment in vitro. When mice were infected with S. aureus, the most profound elevation of TNF-alpha and IL-6 was seen in TLR2(-/-) and TLR2(-/-)-->WT mice. TLR2(-/-), but not chimeric mice, demonstrated increased IL-17, blood leukocytosis and pulmonary neutrophilia compared to WT mice. Collectively, the results suggest an essential role for IFN-gamma and nonhematopoietic TLR2 for leukocyte recruitment in response to LTA. In contrast, TLR2 on both hematopoietic and nonhematopoietic cells appears to orchestrate an inhibitory response to S. aureus such that in complete TLR2 deficiency, there is an exaggerated proinflammatory response and/or skewing of the immune response towards a Th17 phenotype that may contribute to the decreased survival of TLR2(-/-) mice.

The use of immunohistochemistry to determine oncolytic reovirus distribution and replication in-human tumors.

An oncolytic virus is considered a targeted cancer therapy due to its ability to specifically target, replicate in and lyse cancer cells while leaving normal cells unharmed. Over the last few years several tumor selective oncolytic viruses have been developed. These include certain DNA viruses such as adenovirus that have been genetically manipulated to target specific cancer cells by exerting restrictions on the virus at the level of cell entry, viral gene transcription and viral protein translation. There are a variety of RNA viruses being studied as possible cancer therapies including reovirus. Reovirus is intrinsically oncolytic without the need for any genetic manipulation. The inherent oncolytic properties of this virus are derived from the fact that it specifically targets cells with an activated Ras pathway found in many cancer cells. REOLYSIN® is a proprietary formulation of human reovirus type 3 Dearing developed by Oncolytics Biotech Inc. and is the only therapeutic reovirus in clinical development. This review provides an overview of the development of REOLYSIN as a potential cancer therapeutic and the growing role of in situ based molecular pathology methods in providing clinical proof of concept and in guiding clinical development.