Bowdish lab research on the evolution of MARCO featured in the New York Times

Our research on the scavenger receptor MARCO was featured in an article “Air Pollution, Evolution, and the Fate of Billions of Humans” by Carl Zimmer in the New York Times. In this manuscript we collaborated with Dr. Brian Golding, an expert in evolutionary biology in order to understand the evolution of this macrophage receptor. MARCO (or macrophage receptor with collagenous structure) is expressed on macrophages where it binds bacteria and particles such as those found in dust and air pollution. We had hypothesized that because it is the receptor for two pathogens, Streptococcus pneumoniae and Mycobacterium tuberculosis, that have played a major part in driving human evolution, that we might find evidence of areas of the receptor that were undergoing rapid evolution to protect us from this pathogen.

In order to determine which regions of the protein were changing we performed a phylogenetic analysis of the sequence of MARCO from humans, our close ancestors, the Denisovians and Neanderthals, and primates. We found a few interesting things. There was one mutation, which we call F282S (282 refers to the 282nd amino acid in the protein, the F = phenylalanine and the S= serine), had changed very rapidly. All our primate, Denisovian and Neanderthal relatives had a serine residue in that position but fully 83% of the human genomes we analyzed had a phenylalanine. The fact that this mutation spread so quickly through the population means that there must have been very strong selection pressure. We cloned both variants and found that the human specific variant was indeed better at binding inert particles and bacteria. There were a few other interesting mutations we characterized (see article below) but the take home message is that some of the evolutionary adaptations we have made to deal with pathogens may have influenced our ability to handle air pollution or, since the savannah was predicted to be a dry and dusty place, the adaptations we’ve made to deal with particulates in the air may have changed our response to pathogens.

To read the full article, see below.

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.
PMID: 2916561

Kyle Novakowski is the Bowdish lab’s newest PhD!

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!

Publication: Human-specific mutations and positively-selected sites in MARCO confer functional changes.

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.
PMID: 2916561

MARCO mediates macrophage responses to Mtb – publication now available.

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.