Six principal investigators within the LSI received funding via five grants from the Canadian Institutes for Health Research, in results announced this week for the 2021 Fall round.
Drs. Michael Gordon, Marc Horwitz, Kota Mizumoto, Edward Pryzdial, Natalie Strynadka and Hila Weidberg have been funded on five year projects. Congratulations to all for success in this highly competitive round!
Dr. Michael Gordon, (Zoology) and Co-Investigator Dr. Benjamin Matthews
The cellular and molecular mechanisms of lactic acid taste in flies and disease-vectoring mosquitoes
Sour taste is the detection of acid, yet different acids can taste distinct. Lactic acid is particularly notable because it imparts a relatively mild sour taste (and ‘sweet’ smell) to humans, but is also a metabolic product that carries important information for other animals. For example, the presence of lactic acid may tell a fly what types of bacteria are growing on some rotting fruit. It is also present in sweat and is a well-known attractant for blood-feeding mosquitoes. In this proposal, we use the well-established and powerful fruit fly model system to dissect the cells and molecules responsible for lactic acid taste. We then translate our findings into Aedes aegypti – mosquitoes that infect millions of people each year with deadly diseases like Dengue, yellow fever, Zika, and West Nile virus – with the goal of understanding how lactic acid influences blood feeding, thereby enabling new strategies for deterring mosquitoes from biting humans and reducing mosquito-borne disease transmission. Finally, we use the unique properties of acid taste in flies to investigate how the brain encodes the timing of taste information during feeding. Since the principles of sensory coding are similar between flies and mammals, and taste is critical in driving feeding, this will provide fundamental insight into how we decide what, and how much, we eat.
Dr. Kota Mizumoto (Zoology) and Co-Investigator Dr. Leigh A. Swayne
Elucidating the novel roles of gap junction and Zonula occludens (ZO) proteins as regulators of synapse number and position
In animals, cells exchange information with neighboring cells in order to coordinate numerous biological and cellular processes. This exchange occurs at multiple sites between the cells, including at ‘gap junctions’. Gap junctions are composed of a group of proteins called connexins in vertebrates and innexins in invertebrates; these proteins form a channel through which cells can exchange small molecules to communicate information. We recently discovered a new function for gap junction proteins in nerve cells that is independent of their role as channels. Nerve cells need to make specialized connections called synapses at very specific locations, to communicate properly with their target cells, such as muscle and nerve cells. We found that one function of gap junction proteins and their associated protein called Zonula occludens (ZO) protein is to control the position of these synapses. This is important because abnormal synapse positioning, resulting from a defective gap junction protein, could lead to serious neurological conditions. We aim to understand how gap junction and ZO proteins control the position of synapses using nerve cells in a model organism, the roundworm Caenorhabditis elegans. We also test our findings using roundworms can be applicable to mammals using mice. From our research, we will learn novel mechanisms by which nerve cells communicate, forming a neurocircuit to control the body.
Dr. Edward Pryzdial (Pathology and Laboratory Medicine) and Co-Investigator Dr. Marc Horwitz (Microbiology and Immunology)
Host cell-derived tissue factor as a broad-spectrum basis for viral pathology and infection
Well-balanced blood clotting is essential for health and has life-threatening impact when tipped off-balance. Many viruses are known to trigger an infected person’s blood clotting system and cause a wide range of clotting-related clinical problems; from heart disease to bleeding. The processes used by the virus to cause these diseases are poorly understood. Using the oral herpes virus (HSV1) as a model virus, our lab has shown that these germs hijack clotting activators to increase infection. To understand how, the current proposal focuses on our discovery that a protein called, tissue factor, is integrated into the virus’ surface. Tissue factor is found within our cell membranes and is essential for life. Many viruses are covered with a membrane, called an envelope, which is acquired from our infected cells and can therefore contain tissue factor. Why is tissue factor important? Because it is the initiator of blood clotting and it also alters the function of cells. Here we propose to expand our findings in HSV1 and extend our knowledge to HIV and dengue virus, both major global problems. We will take biochemical and animal approaches to test our ideas, which have already revealed possible strategies to treat these virus infections. In addition to these viruses, many others that burden
healthcare systems world-wide have an envelope, such as influenza, Ebola, hepatitis C and Zika viruses. The five virus types we have investigated to date all have tissue factor, suggesting that any virus with an envelope can acquire tissue factor. Since cells containing tissue factor are found throughout the body and are infected by many types of virus, we anticipate that targeting tissue factor found on the surface of viruses will allow us to treat a wide-range of viral infections and fill a serious deficiency in global healthcare.
Dr. Natalie Strynadka (Biochemistry and Molecular Biology)
Structure-guided in vitro and in situ analysis of virulence linked secretion systems in drug-resistant bacteria
Bacteria have evolved sophisticated assemblies to passage macromolecules essential to subsequent disease across their lipid membrane barriers. The Type III Secretion system “injectisome” is one prominent example, a syringe like complex that is essential for downstream pathogenesis of many health elated bacterial species in the clinic and community. This includes the causative agents of food and water borne disease, plague, hospital acquired infections, sexually transmitted disease and beyond. A remarkably sophisticated complex of two dozen highly oligomerized proteins spanning the 2 membranes of the bacteria as well as that of the human host cells they infect, the Strynadka laboratory has been a leader in the structure-guided study of the molecular underpinnings of how the injectisome works. Here her laboratory proposes to use a combination of sophisticated biophysical tools including xray crystallography and cryogenic electron microscopy (single particle/tomography) supported by cellular microbiology to study the atomic features and function of the injectisome in isolation and within the native context of the bacterial cells whose pathogenicity they promote. A related but distinct nanomachine, with many analogies to the Type III injectisome, is the “feeding tube” apparatus Clostridioides difficile mother cells use to passage essential molecules to the daughter cell, the latter which is destined to become a robust long-lived spore that allows this notorious hospital acquired pathogen to persist under even the harshest sanitization methods. The Strynadka laboratory propose to use a similar toolbox of biophysical and microbiology methods to study this fascinating system in vitro and in situ within C.difficile cells. Atomic information gleaned from these studies will drive essential understanding of how molecules are passaged across multiple membranes, and sets the foundation for design of antimicrobials to block their action and subsequent disease causing effects.
Dr. Hilla Weidberg (Cellular and Physiological Sciences)
Molecular mechanisms of sensing and repairing dysfunctional mitochondrial protein import
Mitochondria are essential factories within cells that manufacture energy and building blocks. A critical requirement for mitochondria to function properly is the ability to deliver proteins, the “factory manufacturing workers”, into the mitochondria. Defective mitochondrial protein delivery is a feature of aged cells and many human diseases, including heart and blood vessel diseases, and neurodegenerative diseases like Parkinson’s and Alzheimer’s. As these diseases affect a growing number of people in Canada, it is extremely important and timely to broaden our knowledge of how cells maintain mitochondrial and cellular health when mitochondrial protein delivery is impaired. I recently discovered a new monitoring (surveillance) pathway, called the mitochondrial compromised protein import response (mitoCPR), which promotes mitochondrial and cell recovery when protein delivery is not efficient. This work showed that problems in the delivery process lead to incomplete entry of proteins into the mitochondria, and to clogging of the protein entry sites. We aim to gain a deeper understanding of how the mitoCPR helps unclog and recover mitochondria under physiological and disease conditions. Using molecular biology and advanced technologies such as gene editing and proteomics, we will reveal how the cell keeps mitochondria healthy. This research holds potential for treatment strategies for neurodegenerative and other diseases where mitochondrial dysfunction plays a role.