Many bacterial pathogens invade host cells to replicate and avoid detection by the host. These pathogens interact with the host and by manipulating it to its benefit they establish an environment to survive in. A detailed understanding of the targeted hosts pathways and which are essential for pathogen survival is knowledge that will allow future development of therapeutic intervention strategies.
Cytokine-driven Allergic Inflammation: Characterization Of Two Isoform-specific Modes Of IL-3 Receptor Activation And Investigation Of New Receptor-associated Signalling Partners.
Funder
National Health and Medical Research Council
Funding Amount
$620,716.00
Summary
In asthma, the symptoms are caused by an allergic reaction in the lung orchestrated by immune cells which produce small proteins called cytokines thus stimulating inflammatory cell production. The cytokine IL-3 is critical for the production of basophils which have an important role in the inflammation. The project will investigate the molecular details of how the IL-3 binds to its receptor and stimulates basophil production and reveal new targets for controlling inflammation in asthma.
Immunodominance And Protective Immunity In The Context Of A Complex Host-pathogen System.
Funder
National Health and Medical Research Council
Funding Amount
$899,832.00
Summary
In experimental infection models with simple organisms, pathogen-specific immune responses recognize only a small fraction of potential epitopes encoded by the genome. This phenomenon is termed immunodominance. We propose the first comprehensive study of immunodominance in humans in response to a complex pathogen, the Plasmodium parasite that causes malaria. This will provide valuable new knowledge of host-pathogen immunity and facilitate rational vaccine design.
Characterization Of A Novel IFNbeta Signaling Axis Mediated Via IFNAR1
Funder
National Health and Medical Research Council
Funding Amount
$353,754.00
Summary
Type I interferons (IFNs) play an important role in regulating immune responses to pathogens and tumors and are used therapeutically. This project will investigate a novel IFN signaling axis that we have recently characterized that is mediated via the low affinity IFN receptor, IFNAR1. This signaling axis occurs independently of the high affinity IFN receptor IFNAR2 and contributes to lethality in a model of septic shock.
Molecular Mechanisms Of G Protein-Coupled Receptor Cross Talk
Funder
National Health and Medical Research Council
Funding Amount
$256,980.00
Summary
The normal function of all living cells depends on how they respond to the multitude of physical and chemical stimuli to which they are constantly exposed. The majority of chemical stimuli acting on cells do so not by directly entering the cell, but rather by acting on specific types of receiver proteins on the cell's surface called receptors. One important family of receptors transmit their message to the inside of the cell by coupling to yet another type of protein known as the G protein. Aber ....The normal function of all living cells depends on how they respond to the multitude of physical and chemical stimuli to which they are constantly exposed. The majority of chemical stimuli acting on cells do so not by directly entering the cell, but rather by acting on specific types of receiver proteins on the cell's surface called receptors. One important family of receptors transmit their message to the inside of the cell by coupling to yet another type of protein known as the G protein. Aberrations in the normal function of these G protein-coupled receptors have been implicated in a wide variety of disorders, such as schizophrenia, pain and dementia. To date, most therapeutic approaches to treating these disorders have targeted individual types of G protein-coupled receptors thought to play a role in each disease state, but this has met with mixed success. One of the reasons for this is that each disorder actually involves more than one type of G protein-coupled receptor communicating with other types in a complex way. Our current proposal specifically focuses on some of the newer mechanisms that have been suggested to play an important role in the communication between different types of G protein-coupled receptors located in the same type of cell. An understanding of how such receptor proteins can communicate with one another in this situation is absolutely vital in unravelling processes involved in the maintenance of health, abnormalities that lead to disease and in the development of more effective treatments.Read moreRead less
Determination Of The Mechanisms Of Action Of A Cytomegalovirus Chemokine Receptor Homologue In Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$251,341.00
Summary
A number of herpesviruses encode proteins that are similar to proteins of our immune system. These pirated proteins are exploited by the virus to enable it to replicate and persist in the infected individual, usually by evading or gaining advantage from the normal immune response. This project will investigate the role of one such protein found in both human and animal herpesviruses (specifically cytomegaloviruses (CMV)) that is conserved with cellular cell surface proteins (receptors) that bind ....A number of herpesviruses encode proteins that are similar to proteins of our immune system. These pirated proteins are exploited by the virus to enable it to replicate and persist in the infected individual, usually by evading or gaining advantage from the normal immune response. This project will investigate the role of one such protein found in both human and animal herpesviruses (specifically cytomegaloviruses (CMV)) that is conserved with cellular cell surface proteins (receptors) that bind immune signaling molecules (chemokines). Chemokines are important proteins in the early response to infection. Binding of chemokines to their receptors initiates a cascade of signals within the cell that has profound effects on cellular responses to environmental stimuli. Thus, it is believed that herpesviruses have acquired chemokine receptors to modify or react to the immune response, causing infected cells to behave abnormally either despite or in response to chemokine signals. This project will determine how this CMV specific protein affects the function of cells that CMV infects and how this may promote virus replication, dissemination and persistence in infected hosts. We will also engineer CMVs where the activity of the target protein can be inhibited by administration of prototype antiviral drugs. If inhibition of the activity of the protein is found to reduce virus replication, dissemination or persistence, then this will demonstrate that this type of protein would be a suitable target for the development of novel drugs active against CMV infections. CMV can cause serious (potentially life threatening) disease in newborn children (following infection in the uterus) and immunosuppressed people (eg. organ transplant recipients and people with HIV-AIDS). Our studies will improve our understanding of the contribution of a specific CMV protein to disease, thereby assisting efforts to reduce the impact of CMV infections.Read moreRead less
The Role Of Ryk/AF6/Eph Complexes In Neuronal Pathfinding/fasciculation
Funder
National Health and Medical Research Council
Funding Amount
$422,036.00
Summary
During embryonic development nerve cells in the central nervous system have to find the right connections to make with other nerve cells. The process by which nerve cells find the right partners to make connections with is called neuronal pathfinding. Once some nerve cells have made the right connections, other nerve cells attach to these cells and form bundles of nerve fibres. This process is called fasciculation or bundling. This whole process is vital to the normal development and function of ....During embryonic development nerve cells in the central nervous system have to find the right connections to make with other nerve cells. The process by which nerve cells find the right partners to make connections with is called neuronal pathfinding. Once some nerve cells have made the right connections, other nerve cells attach to these cells and form bundles of nerve fibres. This process is called fasciculation or bundling. This whole process is vital to the normal development and function of the central nervous system and the brain. Without the right connections between nerves, information could not be received, processed or sent to organs in the body. We are now starting to discover some of the molecules which control the process of nerve cell pathfinding during development. It has been known for some time that proteins called Eph receptors play an important role in neuronal pathfinding and development of the head region in mice. We have now discovered that two other proteins called Ryk and AF-6 are able to bind to Eph receptors. We have very recently created mice which lack the Ryk protein and these mice have defects in their head deveopment strikingly similarto the head defects seen in mice that lack Eph receptors. We now wish to see whether Ryk mice have defects in neuronal pathfinding and fasciculation as do mice lacking Eph receptors. We also think that Ryk, Af-6 and Eph receptors form a protein complex which can modify cell function. We now wish to explore how this protein complex can do this.Read moreRead less