Author Archives: Dr. Dawn M. E. Bowdish

Dawn to talk at the Dept. of Chemical Engineering, Nov. 26, 2009

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I am looking forward to presenting some recent, unpublished data at the Department of Chemical Engineering at McMaster. This will be a very different audience than usual but I suspect that there will be many overlapping interests as macrophages are involved in biopolymer and nanoparticle recognition and detrimental host responses. Below is the title & abstract of the talk.

Macrophage scavenger receptors: role in adhesion, uptake & migration.
 Macrophages are tissue-resident white blood cells that are essential for detection of pathogens, clearance of modified host products and recognition of foreign bodies. Macrophages recognize both host and foreign ligands via surface expressed receptors. The result of this recognition may be a pro-inflammatory response, phagocytosis, or differentiation & adhesion. Although macrophage responses are essential for host defence and tissue homeostasis, they can also be detrimental when the macrophage is unable to clear foreign particles such as implants or environmental and synthetic particles. The scavenger receptors are macrophage receptors that have the unusual capacity of recognizing modified self proteins, pathogens and foreign particulates. We aim to determine how these receptors transmit signals to the cell and how this signaling affects macrophage adhesion, phagocytosis & endocytosis (uptake) and migration.

MARCO mediates macrophage responses to Mtb – publication now available.

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Dawn, in collaboration with Dr. Kaori Sakamoto (University of Georgia) andbowdish-plos-pathogens-paper-small Dr. David Russell (Cornell University), has demonstrated that the scavenger receptor MARCO is a receptor for Mycobacterium tuberculosis (Mtb). More specifically MARCO recognizes the major immunogenic mycobacterial lipid of Mtb, trehalose dimycolate (TDM).

Interestingly TDM was discovered to be a major immunogenic component of Mtb in the 50’s but attempts to find the macrophage receptor have been unsuccessful. This could well be because the scavenger receptors tend to be “sticky” (hence the nickname ‘molecular flypaper’) and bind with high avidity rather than affinity and for this reason many conventional assays (e.g.  pull-down) are not effective for finding ligands. Another interesting implication of this work is that MARCO is not expressed on all macrophages (for example it is on resident peritoneal macrophagesand alveolar but not bone marrow derived macrophages or cell lines) so this may explain why some macrophages are highly responsive to TDM while others are not.

Most importantly, however, this discovery has important implications for understanding Mtb pathogenesis, specifically with regard to how macrophages initiate (or fail to initiate) a pro-inflammatory response. TDM and deriviatives are potent adjuvants that show potential for eliciting strong and long-lasting immune responses and these data indicate that TDM mediated responses are due to both binding and signalling interactions with macrophages. Read the whole paper here.

Breaking News: Inimex Pharmaceuticals begins First Clinical Study of an Innate Defense Regulator

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During the course of Dr. Bowdish’s PhD she discovered that host defence peptides (formerly known as antimicrobial peptides) were not actually bactericidal under physiological conditions. Instead they worked by interacting with the leukocytes as “immunomodulators” altering cytokine responses and chemotaxis and altering the leukocyte’s pro-inflammatory response. This work was the basis of a patent which resulted in the creation of Inimex Pharmaceuticals. Recently Inimex has announced that they have successfully passed Phase I clinical trial for their IDR (Immune Defence Regulator), a new class of anti-infective drugs. Read the press release here.

The Bowdish lab has an ongoing interest in developing novel anti-infective agents.

Summer student Zhongyuan Tu wins IIDR studentship!

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The Bowdish lab’s first member, Zhongyuan Tu, has won a summer studentship award from the IIDR for his proposal called “How does the macrophage scavenger receptor MARCO signal?”. Zhongyuan will be starting in the lab in May and will continue on as a thesis student. During this time he will study the role of the macrophage scavenger receptor MARCO in adhesion, motility and phagocytosis. Congratulations Zhongyuan!

Dawn receives funding from the IIDR to study the role of macrophages in pneumococcal disease

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The IIDR has awarded the Bowdish lab seed money to study the role of macrophages in host response to colonization by Streptococcus pneumoniae. S. pneumoniae infections can range from treatable (respiratory tract infections, otitis) to life-threatening (meningitis, sepsis). The introduction of the pneumococcal conjugate vaccine (PCV) has shifted the epidemiology of S. pneumoniae infections but not eliminated them.  In humans, colonization of the upper respiratory tract is the initial step in pathogenesis. This is accompanied by a robust antibody response, which is generally believed to be required for clearance (and thus prevention of infection); however, data for this is not supported by clinical observations in which high levels of antibodies are not associated with clearance or in which immunodeficient patients susceptible to pneumococcal infections can produce robust anti-pneumococcal antibody responses while still being prone to recurrent systemic infections.  The aim of this project is to assess the importance of macrophages in the recognition and clearance of S. pneumoniae in the upper respiratory tract.   This work will be done in collaboration with Prof. Jeffrey Weiser at the University of Pennsylvania who is a world leader in the field of S. pneumoniae pathogenesis. Dawn will be travelling to his lab in July to learn from his lab members.  The Bowdish lab is currently recruiting graduate students and post-docs who are interested in the host response to S. pneumoniae infection and colonization.