On this edition of Focus In Sound, we meet a young investigator who is making significant contributions to our basic knowledge of cell signaling pathways, cell death mechanisms, innate immunity, infectious diseases and autoimmune disorders. Dr. Maya Saleh of McGill University was named an Investigator in the Pathogenesis of Infectious Disease by the Burroughs Wellcome Fund in 2009. Maya received her Ph.D. at McGill in 2001, served post-docs at Merck and the La Jolla Institute, and in 2005 returned to McGill to join the faculty. She is an Associate Professor in the Departments of Medicine and Biochemistry and Director of the Inflammation and Cancer Program. She is also an Associate Member in the Department of Microbiology and Immunology, an Associate Member of the Goodman Cancer Centre, and a member of the Center for the Study of Host Resistance and the Division of Critical Care of the McGill University Health Centre Research Institute.
Transcription of “Interview with Maya Saleh”
00;00;07;25 – 00;00;44;21
Ernie Hood
Welcome to Focus In Sound, the podcast series from the Focus newsletter published by the Burroughs Wellcome Fund. I’m your host, science writer Ernie Hood. On this edition of Focus In Sound, we meet a young investigator who is making significant contributions to our basic knowledge of cell signaling pathways, cell death mechanisms, innate immunity, infectious diseases and autoimmune disorders. Dr. Maya Saleh of McGill University was named an investigator in the pathogenesis of infectious disease by the Burroughs Wellcome Fund in 2009.
00;00;45;11 – 00;01;21;20
Ernie Hood
Maya received her Ph.D. at McGill in 2001, served postdocs at Merck and the La Hoya Institute and in 2005 returned to McGill to join the faculty. She is an associate professor in the Department of Medicine and Biochemistry and director of the Inflammation and Cancer Program. She is also an associate member in the Department of Microbiology and Immunology, an associate member of the Goodman Cancer Center and a member of the Center for the Study of Host Resistance and the Division of Critical Care of the McGill University Health Center Research Institute.
00;01;22;16 – 00;01;24;23
Ernie Hood
Maya Saleh welcome to Focus In Sound.
00;01;25;27 – 00;01;27;02
Maya Saleh
Thank you for having me.
00;01;27;22 – 00;01;39;29
Ernie Hood
My, I’m sure our listeners could tell just from that introduction that your laboratory’s research really touches a variety of different areas. Is there one central focus from which everything else emanates?
00;01;41;17 – 00;02;12;28
Maya Saleh
Yes, absolutely. It seems that we are researching a variety of different areas that in fact, they’re all interrelated, and that’s what’s fascinating for us. So we’re investigating specifically immune mediated, inflammatory diseases, including infectious diseases, inflammatory bowel disease. Starting to look at metabolic diseases and cancer and the common link between all of these is inflammation. So our interest at the cellular and molecular level is to understand how the inflammatory response is triggered and executed.
00;02;13;22 – 00;02;41;08
Maya Saleh
So this has directed our focus to studying how the host initially senses the presence of microbes, both comments and questioning or that of stress and linear transformation, as in cancer or metabolic perturbation. And as you know, this early detection is a function of specific receptors of our innate immune system, which is our first line of defense. Now, these receptors are termed pattern recognition receptors.
00;02;41;10 – 00;03;12;11
Maya Saleh
They’re highly conserved from plants to humans and have evolved to confer host resistance of infection, injury or stress. So the way they function is that when they sense the presence of microbial motifs or endogenous themes or signal such as those produced in the cancer microenvironment or during metabolic stress, these receptors activate a plethora of effector mechanisms that initiate the inflammatory response.
00;03;12;17 – 00;03;37;18
Maya Saleh
And there are a number of these receptors in the innate immune system, different families and a number of numbers for families and excitement in the field right now is to understand the specific role of each of these in health and disease. So in the last few years, my lab has studied subfamily of these receptors known as analogs or not like receptors along with their associated inflammasomes.
00;03;38;08 – 00;03;58;04
Maya Saleh
And these analogs are mutated or deregulated in multiple diseases like IBD, inflammatory bowel disease, cancers. I hated it to read periodic fevers syndromes, which is Alzheimer’s and so on. And our goal is to understand how they operate in physiological and pathological condition.
00;03;58;12 – 00;04;15;17
Ernie Hood
Maya, your group recently published an important paper in Nature, illuminating the coevolution of pathways involving apoptosis or programed cell death and innate immunity. Those would seem to be very different or even opposing phenomena. Can you tell us more about what you’ve discovered?
00;04;16;08 – 00;04;47;06
Maya Saleh
In this context, we’ve been particularly interested in understanding how the host’s innate immune system, in particular these microbial sensors dialog with the microbiota in the intestine. So it’s now clear from our work and that of many other labs that animals are necessary to maintain intestinal homeostasis and immune tolerance towards these comments and micro-organisms and consequently their deregulation is at the basis of this inflammatory bowel disease, this like Crohn’s disease and the threat of colitis.
00;04;47;27 – 00;05;15;10
Maya Saleh
In particular, we focused on two receptors that sense bacterial peptidoglycan specifically, namely not one and the two, as these have been genetically linked to these inflammatory bowel disorders. And yet, although we know these two receptors are necessary in the intestine, we still lack information on how they function in the gut and how they translate the bacterial sensing signals to induction of homeostatic responses.
00;05;15;21 – 00;05;45;05
Maya Saleh
So in this particular paper, we’ve decided to take a functional genomic approach to define the key molecules and pathways required for not functioning intestinal epithelial cells following bacterial patches of like glycan sensing via these receptors. So our rationale was to refine the molecular portrait of not signaling first to understand the function of these receptors at the fundamental level, and second, to identify therapeutic targets for energy.
00;05;45;29 – 00;06;12;08
Maya Saleh
So the approach we’ve used was to systemically, systematically silence every druggable gene in the genome and question which of these is needed to either stimulate or inhibit the inflammatory response following activation by bacterial peptidoglycan? Now, one interesting facet that emerged from this work was the finding of an enrichment of Epoc ptosis effector proteins in this innate immunity pathway.
00;06;12;22 – 00;06;49;12
Maya Saleh
In other words, as you’ve mentioned, it appears that proteins that were thought to primarily function in the process of programed cell death might have evolved additional vital functions in innate immunity. So on the surface, these functions appear contradictory, but in the big scheme of host resistance, they’re actually not. If you think about it, in primitive organisms, cell death is the main host defense strategy against vessel genic infection whereby an infected cell commits suicide to destroy the microorganism and prevent it spread to neighboring cells in more complex organism like ours.
00;06;49;12 – 00;07;19;04
Maya Saleh
Other innate immunity mechanisms, including the inflammatory process, were essentially grafted to this primitive cell death response. But of course, when these fail the last resort, she means cell death. And in fact, there are a multitude of parallels between the cell death message machinery and the analog pathways. First, both are activated by molecules released from the mitochondria, which, as you can imagine, is reminiscent of an intracellular bacterium.
00;07;19;27 – 00;07;53;06
Maya Saleh
Second, these NLRB sectors are very similar structurally to the molecule that triggers apoptosis or the process activating factor. Thirdly, the inflammasome complex that forms when these animals are activated again resembles structurally the apoptosis complex. And finally the proteases or the enzymes that are engaged engage in bush complexes known as guess pieces that are necessary to execute cell death or regulate inflammation belong to the same family.
00;07;53;15 – 00;07;57;10
Maya Saleh
Thus, in theory, have evolved from the same ancestral gene.
00;07;57;15 – 00;08;00;11
Ernie Hood
So these are actually complementary functions then?
00;08;01;03 – 00;08;02;04
Maya Saleh
Yes, we think so.
00;08;02;28 – 00;08;18;23
Ernie Hood
I understand from what you said already, Maya, that this particular work may well have clinical implications as well, perhaps helping to identify new targets for therapy in disorders that you’ve mentioned, such as inflammatory bowel disease. How would that work?
00;08;19;14 – 00;08;46;27
Maya Saleh
Yeah, absolutely. By knowing the key players that the director and a lot of responses one could design not to RepuTex to target these proteins in pathological conditions. So in this nature, people we’ve characterized specifically one such molecule known as vent, and we know exactly which domain is involved in interaction with an illness. And we know that without this molecule the analysis are unable to transduced inflammatory signaling.
00;08;46;28 – 00;08;56;00
Maya Saleh
So one can now design therapeutic approaches around targeting the crosstalk between this protein and analog receptors.
00;08;56;02 – 00;09;05;06
Ernie Hood
So is that a direction that you will continue to pursue you and your group, or would that development of new therapies fall through others?
00;09;05;25 – 00;09;22;21
Maya Saleh
No, we are of course interested in that and we’re now refining the region in the big molecule that can interfere with the notch function and we have at McGill actually programs that would allow us to translate our basic science finding further into the clinic.
00;09;23;16 – 00;09;45;13
Ernie Hood
Terrific. Well, we will certainly look forward to your results from that work. My, you’ve already touched on this, but I’d like to get you to elaborate just a little bit. You and your colleagues have also made great strides in characterizing what’s going on in the gut in terms of innate immunity, which you’ve already touched on briefly as we’ve learned so much recently about the role of the gut microbiota.
00;09;45;25 – 00;10;14;16
Ernie Hood
Obviously, the gut epithelial cells have a way to recognize the benign or so-called commensal microorganisms that colonize the gut, while also being able to sense and attack pathological microbes that might invade. I’m sure that’s a very simplistic explanation, but please tell us about the insights you’ve provided into both gut homeostasis and disease causing dysfunctions in this very complex but vital biological system.
00;10;15;10 – 00;10;41;21
Maya Saleh
Last year we published a report in the journal Immunity examining the role of the Inflammasome in investment homeostasis, colitis and colitis associated with colorectal cancer. So as I mentioned, when GIS and alarm receptors are activated, they assemble a large complex referred to as the Inflammasome that recruits and activates this protease enzyme named Caspase one. Now this enzyme is inflammatory.
00;10;41;21 – 00;11;06;29
Maya Saleh
It processes some dormant cytokines, such as interleukin one, beta and interleukin 18 into the active forms and enables the release from the cell. So we’ve asked a simple question of whether the Islamism this inflammatory entity, contributes to the inflammatory pathology that occurs in IBD and colorectal cancer, or whether it’s, on the contrary, protective. And what we found was that the latter is correct.
00;11;07;06 – 00;11;34;22
Maya Saleh
So it seems that the crosstalk between the microbiota and the inflammasome in intestinal epithelial cells is necessary to induce a physiological level of inflammation, which we’ve characterized to be specifically mediated by the cytokine and the inflammatory dependance type account. Interleukin 18. And that is needed first to maintain that impurity barrier intact or to induce its repair following either a physical, chemical or microbial insult.
00;11;35;04 – 00;12;14;02
Maya Saleh
Second, to maintain a symbiotic microbial ecology. Indeed, what we’ve shown is that this in inflammasomes signaling and lack of the steady state production of interleukin 18 leads to colitis and colitis associated colorectal cancer. And we were able to reverse this pathology through the administration of interleukin 18 two called lytic elements and others have shown that defects in inflammasome signaling also lead to this biotic expansion of skeletal genic bacteria in the gut that further fuels the vicious cycle of chronic inflammation, such as what occurs in IBD.
00;12;14;21 – 00;12;23;11
Maya Saleh
So this works argues against full inhibition of caspase one or total internalization of interleukin 18. As therapeutic approaches in IBD.
00;12;23;19 – 00;12;46;14
Ernie Hood
I see. Well, I’m sure you’ll be continuing to to develop that work as well. The work you do, Meyer seems to be really kind of unique in that it is on a very basic level in terms of gaining new biological knowledge, but at the same time, it also seems to have great translational potential. Is that a part of your approach to always keep that in mind?
00;12;47;06 – 00;13;23;00
Maya Saleh
Yeah, indeed. I believe that my training path has greatly contributed to the translation and approach of my research. So I’m a basic scientist who has trained in both academia and in the industry. And and that’s part of, I would say, a rare group of individuals try to constantly translate basic scientific discoveries into potential therapeutic treatments. And academically, I have a diversified background in genetics, biochemistry and immunology, which I think is an asset to pursuing complex disease mechanisms and tackling relevant research questions.
00;13;23;24 – 00;13;28;29
Ernie Hood
Well, it must keep you very engaged. On a daily basis, I imagine.
00;13;29;05 – 00;13;29;28
Maya Saleh
Absolutely. Yeah.
00;13;30;23 – 00;13;35;08
Ernie Hood
Well, my. How did you happen to pursue this particular type of research?
00;13;35;20 – 00;14;08;17
Maya Saleh
We were talking about this translational aspect. I always had an attraction towards interacting with patients and clinical research. So during my master studies at the American University of Beirut, my work focused on the genetic basis of beta thalassemia, which is a severe anemia clotting disorder endemic to the Mediterranean region. So at the time I identified the spectrum of the beta cells, mutations in Lebanon, and this had a direct impact on the development of the first prenatal screening and counseling facility in the country.
00;14;09;05 – 00;14;34;27
Maya Saleh
And then from there, I moved to my doctor of studies at McGill, where I investigated embryonic development, specifically biochemical events that switch on or off of transcription and program required for embryogenesis. So all this is very far from what I’m doing right now. However, during my postdoc, I joined the laboratory of Dr. Donald Nicholson at Merck, first in Montreal, then in San Diego.
00;14;35;15 – 00;15;14;02
Maya Saleh
And I think this unique training experience in the industry contributed to this translational approach of my research. So my work at Merck focused on understanding the biology of these enzymes as we talked about the diseases. However, first the focus was on understanding the role in cell death and neurodegenerative diseases. Then in 2004, I have cloned a new test based gene termed Test 12 and have identified a mutation in this gene that confines its expression to the African population and African descendants, but not to other ethnicities in the human population.
00;15;14;22 – 00;15;49;27
Maya Saleh
In addition, which demonstrated that African American individuals that expressed test results once were predisposed to infection and that this test, this was a little was associated with severe sepsis in in the clinic. And so this discovery was published in Nature in 2004 and led me to embark on a second postdoctoral fellowship now in the laboratory of Dr. Douglas GREENE, then at De La Hoya Institute of Allergy and Immunology, to dissect the mechanism by which this protein infected inflammation and the innate immune response.
00;15;50;21 – 00;16;20;00
Maya Saleh
My work in that lab, which I completed as an independent spy at McGill, resulted in a second publication also in Nature in 2006, where we characterized the mechanism by which it was inhibited the generation of a necessary inflammatory response during infection. And then identified that at the molecular level, the way this protein function is by antagonizing or acting as an inhibitor to the INFLAMMASOME complex that we’ve discussed.
00;16;20;00 – 00;16;34;25
Maya Saleh
Our work was among the first to emphasize the key role of the inflammasome in host defense during bacterial infection and sepsis. And this has been directed at our efforts to further contribute to this emerging field of analog mediated innate immunity.
00;16;35;06 – 00;16;51;11
Ernie Hood
Well, you’ve already made some really significant contributions and had some very important publications as you’ve shared with us, and congratulations for all that. So where is your research headed from here? What are the burning questions that remain to be answered?
00;16;52;08 – 00;17;30;05
Maya Saleh
Yeah. So first the burning questions now are first to understand whether these innate immunity receptors have distinct or overlapping functions in different physiological or pathological contexts. And to understand what agonist they recognize both during infection, but also in sterile inflammatory diseases such as in metabolic diseases or cancer. And then to understand their predominant effector mechanisms, how do they function following, sensing of either the danger signals produced in sterile conditions or during infection.
00;17;30;14 – 00;17;54;27
Maya Saleh
And this would provide therapeutic opportunities, as we’ve discussed. But we’re also very interested in understanding the role of the microbiota and sensing of the microbiota by these receptors, not only in the intestine, but also in relatively sterile tissues such as the lungs or in the mammary gland, and understand their contribution to diseases at this site.
00;17;55;09 – 00;17;59;06
Ernie Hood
Terrific. Well, it sounds like you have plenty to keep you busy for years to come.
00;17;59;26 – 00;18;00;04
Maya Saleh
Yes.
00;18;00;29 – 00;18;18;19
Ernie Hood
Well, my, it’s been a great pleasure for us to get to know you and your work, which is shedding so much light on basic cellular mechanisms while illuminating a path toward improved treatments and outcomes. We wish you the best of luck for continued success. And thanks so much for joining us today on Focus In Sound.
00;18;18;21 – 00;18;19;23
Maya Saleh
Thank you for having me.
00;18;21;01 – 00;18;36;23
Ernie Hood
We hope you’ve enjoyed listening to this edition of the Focus In Sound Podcast. Until next time. This is Ernie Hood. Thanks for listening.
