Publication: A naturally occurring transcript variant of MARCO reveals the SRCR domain is critical for function

Macrophages play a critical role in innate immunity by detecting, engulfing and destroying pathogenic bacteria and alerting neighbouring immune cells to join the fight against infection. They have many different receptors on their cell surface that allow them to carry out these important processes. A particular group of receptors called Scavenger Receptors are vital to this response. A recent study published in Immunology and Cell Biology by PhD student Kyle Novakowski from the laboratory of Dr. Dawn Bowdish has uncovered a mechanism by which a specific scavenger receptor contributes to macrophage-specific antibacterial immunity.

Scavenger Receptors are evolutionarily ancient and have evolved to recognize a wide array of pathogens by detecting ligands that are common across many pathogenic organisms. A particularly important Scavenger Receptor is Macrophage Receptor with Collagenous Structure, or MARCO. MARCO has been shown to significantly contribute to the clearance of Streptococcus pneumoniae colonization of the nose and in models of pneumococcal pneumonia. The NSERC-funded study took a unique approach to functionally characterizing how MARCO contributes to innate immunity by studying a naturally-occurring variant of the receptor. The study highlighted the importance of a particular domain of the receptor that is required for macrophages to bind and internalize ligands. The study also showed that the domain is necessary to enhance the pro-inflammatory response to pathogenic Streptococcus pneumoniae and can enhance cellular adhesion; both vital to proper macrophage functions.

To read the article, please click here.

Manuscript: The evolution of the scavenger receptor cysteine-rich domain of the class A scavenger receptors

Do you work out? Cause you’re built like a rock! A rock like Dwayne “The Rock” Johnson! You have an impenetrable body thanks to your complex immune system. So how did you get such a sophisticated immune system?

In the Bowdish lab, we do more than just macrophage biology; we also study the evolution of the immune system! The scavenger receptors are a group of receptors that play an important role in your immune system by binding harmful bacteria. Our most recent publication by Yap et al., looks at how these receptors evolved and how evolution has changed their function. These receptors are found in various forms of life such as sharks, frogs, and mammals, but the function and appearance of these receptors has changed over time. Check out the open access….

MARCO is required for TLR2- and NOD2-mediated resonses to Streptococcus pneumoniae and clearance of pneumococcal colonization in the murine nasopharnyx. 2013. Dorrington et al. J. Immunol.

Click image for .pdf of paper.

Dorrington JI

Despite having multiple vaccines against Streptococcus pneumoniae available today, over a million people die each year due to pneumococcal infections. Mike Dorrington, a Ph.D. candidate in the Bowdish lab, is attempting to understand how to produce better vaccines by gaining a better grasp on how the immune system fights these bacteria. Mike has recently published a manuscript entitled “MARCO is required for TLR2- and NOD2-mediated responses to Streptococcus pneumoniae and clearance of pneumococcal colonization in the murine nasopharynx” in the Journal of Immunology. Mike’s work focuses on the importance of macrophage scavenger receptors in immune protection against S. pneumoniae, the most common cause of bacterial pneumonia. This manuscript provides us with evidence that Macrophage Receptor with Collagenous structure (MARCO), a class A scavenger receptor, plays an integral role in establishing and maintaining the appropriate innate immune response to the bacteria in its preferred niche, the nasal passage.

     S. pneumoniae is a very common pathogen that causes fatal disease in children under the age of 5 (where it often causes meningitis) and adults over the age of 65 (where it most often presents in pneumonia). Before infectious disease occurs, bacteria colonize the nasal passages of individuals where they replicate. If the bacteria are able to persist for long enough, they will then move to the lungs, blood, or meninges and cause potentially life-threatening disease. It has previously been shown that the clearance of the bacteria from the nasal passages was dependent on an influx of macrophages to the site. These cells are able to internalize and kill the bacteria efficiently. MARCO is expressed by these active macrophages and has been shown to play a role in the recognition of the bacteria.

Mike’s work shows that mice who lack MARCO expression are unable to clear bacterial colonization in a timely fashion. This is due to a decrease in a number of innate immune functions. First, MARCO-deficient mice have significantly less recruitment of innate immune cells such as neutrophils and macrophages to the site of colonization. Without these cells, the bacteria are free to thrive and replicate in the nasal passage, increasing the chance that they will travel to further tissues and cause disease. MARCO-deficient mice also present with less inflammation than they’re wild-type counterparts, as seen by a paucity of pro-inflammatory cytokines and chemokines including, surprisingly, type I interferons (cytokines associated with antiviral immunity). These data are supported by experiments performed in vitro using macrophage populations from MARCO-deficient and wild-type mice. When these cells are stimulated with S. pneumoniae, the MARCO-deficient macrophages produce less cytokines and chemokines. These cells are also less able to internalize the bacteria, a key step in the destruction of the pathogens.

A potentially ground-breaking finding that comes from Mike’s work is that MARCO is able to modulate the activity of other important innate immune receptors. Mike has shown that NF-kB activation in S. pneumoniae-stimulated cells expressing MARCO along with TLR2 and its co-receptor CD14 is much higher than cells not expressing MARCO. This is also true of cells expressing MARCO as well as NOD2 when compared to those expressing just NOD2. As NF-kB is a central regulator of immune function, this represents a very important step in our understanding of antibacterial innate immune responses in the nose.

Mike’s work on MARCO will continue as he attempts to uncover the mechanism by which MARCO increases NF-kB activation by these other receptors. It is his hope to be able to apply these advances in the basic science to vaccine development in order to generate an effective strain-independent vaccine against S. pneumoniae infection.

Mike Dorrington (PhD candidate) discovers that MARCO is required for recognition and removal of S. pneumoniae in the sinuses.

Despite having multiple vaccines against Streptococcus pneumoniae available today, over a million people die each year due to pneumococcal infections. Mike Dorrington, a Ph.D. candidate in the Bowdish lab, is attempting to understand how to produce better vaccines by gaining a better grasp on how the immune system fights these bacteria. Mike has recently published a manuscript entitled “MARCO is required for TLR2- and NOD2-mediated responses to Streptococcus pneumoniae and clearance of pneumococcal colonization in the murine nasopharynx” in the Journal of Immunology. Mike’s work focuses on the importance of macrophage scavenger receptors in immune protection against S. pneumoniae, the most common cause of bacterial pneumonia. This manuscript provides us with evidence that Macrophage Receptor with Collagenous structure (MARCO), a class A scavenger receptor, plays an integral role in establishing and maintaining the appropriate innate immune response to the bacteria in its preferred niche, the nasal passage.

At the celebration of Mike’s first first author publication. Although Dawn is mostly happy for Mike, she is also slightly nervous that she might be about to lose an eye when the champagne is opened.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

     S. pneumoniae is a very common pathogen that causes fatal disease in children under the age of 5 (where it often causes meningitis) and adults over the age of 65 (where it most often presents in pneumonia). Before infectious disease occurs, bacteria colonize the nasal passages of individuals where they replicate. If the bacteria are able to persist for long enough, they will then move to the lungs, blood, or meninges and cause potentially life-threatening disease. It has previously been shown that the clearance of the bacteria from the nasal passages was dependent on an influx of macrophages to the site. These cells are able to internalize and kill the bacteria efficiently. MARCO is expressed by these active macrophages and has been shown to play a role in the recognition of the bacteria.

Mike’s work shows that mice who lack MARCO expression are unable to clear bacterial colonization in a timely fashion. This is due to a decrease in a number of innate immune functions. First, MARCO-deficient mice have significantly less recruitment of innate immune cells such as neutrophils and macrophages to the site of colonization. Without these cells, the bacteria are free to thrive and replicate in the nasal passage, increasing the chance that they will travel to further tissues and cause disease. MARCO-deficient mice also present with less inflammation than they’re wild-type counterparts, as seen by a paucity of pro-inflammatory cytokines and chemokines including, surprisingly, type I interferons (cytokines associated with antiviral immunity). These data are supported by experiments performed in vitro using macrophage populations from MARCO-deficient and wild-type mice. When these cells are stimulated with S. pneumoniae, the MARCO-deficient macrophages produce less cytokines and chemokines. These cells are also less able to internalize the bacteria, a key step in the destruction of the pathogens.

A potentially ground-breaking finding that comes from Mike’s work is that MARCO is able to modulate the activity of other important innate immune receptors. Mike has shown that NF-kB activation in S. pneumoniae-stimulated cells expressing MARCO along with TLR2 and its co-receptor CD14 is much higher than cells not expressing MARCO. This is also true of cells expressing MARCO as well as NOD2 when compared to those expressing just NOD2. As NF-kB is a central regulator of immune function, this represents a very important step in our understanding of antibacterial innate immune responses in the nose.

Mike’s work on MARCO will continue as he attempts to uncover the mechanism by which MARCO increases NF-kB activation by these other receptors. It is his hope to be able to apply these advances in the basic science to vaccine development in order to generate an effective strain-independent vaccine against S. pneumoniae infection.

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.

Summer student Zhongyuan Tu wins IIDR studentship!

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!