Pathology – Dr. Sakamoto’s Lab
The overall mission of our lab is to study the mechanisms used by pathogens to manipulate the host immune system.
Resident peritoneal macrophages.
In collaboration with the Bowdish laboratory at McMaster University, we are studying the role of the class A scavenger receptor, MARCO, in tuberculosis. Scavenger receptors are expressed on the surface of macrophages and are involved in the non-specific binding and uptake of a variety of endogenous and exogenous proteins and lipids, most notably, low-density lipoprotein (LDL). We have shown that macrophage pro-inflammatory cytokine responses to TDM are mediated via a collaborative effort between MARCO, TLR2, and CD14. MARCO-deficient macrophages also show markedly reduced pro-inflammatory cytokine responses to infection with M. tuberculosis. We have also discovered that certain single nucleotide polymorphisms in the MARCO gene are associated with either susceptibility or resistance to TB. This project aims to understand the role of MARCO in TB pathogenesis through the use of murine models, histopathology, and cell biological, biochemical, molecular biological, and immunological techniques.
Trehalose dimycolate Project
The cording phenotype exhibited by virulent mycobacteria is caused by trehalose 6,6’-dimycolate (TDM).
Trehalose 6,6’-dimycolate (TDM) is a primary immunostimulatory component of the cell wall of Mycobacterium tuberculosis (TB) and Complete Freund’s Adjuvant. It has been shown to individually reproduce many of the lesions associated with tuberculosis, to both stimulate or inhibit macrophage activity, to cause both necrosis and apoptosis, and has recently been shown to prevent phagosomal-lysosomal fusion in macrophages. This last effect is key to the persistence of TB in macrophages and the success of this pathogen. What is intriguing about this glycolipid is that these effects vary depending on how the molecule is presented. For example, if TDM is coated onto a “bacteria-sized” latex particle, it does not stimulate macrophages. Whereas if TDM is presented on a larger particle (i.e., greater than 10 mm in diameter) or as a monolayer or an emulsion, it stimulates Toll-like receptor signaling, MAPK pathway activation, and cytokine production. This project aims to identify how TDM inhibits macrophage activity in some forms while stimulating activity in other forms, through a combination of cell biological, molecular biological, immunological, and biochemical techniques.
Mycobacterial-helminth Co-infection Project
In collaboration with the Ezenwa laboratory in the Odum School of Ecology, we are studying the effects of co-infection with mycobacterial and intestinal helminth species, on both the host and the respective pathogens. In the African buffalo, deworming was associated with increased IFN-gamma levels and reduced incidence of TB. In a mouse model of co-infection, we found that co-infection influenced parasite survival and reproduction via the host immune response; however, this relationship was dependent upon the protein content of the diet.
Blood sampling of an African buffalo at Kruger National Park in South Africa.