Kyle Novakowski successfully defended his thesis “IDENTIFICATION AND FUNCTIONAL CHARACTERIZATION OF CONSERVED RESIDUES AND DOMAINS IN THE MACROPHAGE SCAVENGER RECEPTOR MARCO” to become the Bowdish lab’s 4th PhD student. He’ll be joining Turnstone Biologics as a PhD scientist. We wish him very well in his future endeavours. Congratulations Dr. Novakowski!
First author on the publication, PhD student Kyle Novakowski of Dr. Dawn Bowdish’s lab.
A common element that links ancient fish that dwell in the darkest depths of the oceans to land mammals, Neanderthals, and humans is the necessity to defend against pathogens. Hundreds of millions of years of evolution have shaped how our innate immune cells, such as macrophages, detect and destroy microorganisms.
In a new study led by Dr. Dawn Bowdish (in collaboration with Dr. Brian Golding) and her PhD student Kyle Novakowski, the team identified novel sites within a macrophage receptor, MARCO, that are under positive selection and are human-specific. The team demonstrated the importance of these sites by site-directed mutation and showed a reduction in cellular binding and uptake of pathogens. These findings demonstrate how small genetic changes in humans can influence how we defend ourselves against pathogens.
Read the full publication in Oxford University Press.
Human-specific mutations and positively-selected sites in MARCO confer functional changes. Novakowski KE, Yap NVL, Yin C, Sakamoto K, Heit B, Golding GB, Bowdish DME. Mol Biol Evol. 2017 Nov 20. doi: 10.1093/molbev/msx298.
Dawn, in collaboration with Dr. Kaori Sakamoto (University of Georgia) and 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.
Dawn will be visiting her alma mater & speaking on her recent work.
If you missed the talk, check out http://www.fejes.ca/ (link) for a synopsis.