Characterisation Of Cell-mediated Immune Responses In Burkholderia Pseudomallei Infection
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
The bacterium Burkholderia pseudomallei, causes a life threatening condition known as melioidosis. Melioidosis is emerging as an important infectious disease in tropical regions of Australia and South East Asia. Death rates following acute disease are extremely high. Despite the importance of B. pseudomallei in tropical public health, very little is known regarding how the body's defence mechanisms prevent the spread of infection. The wide distribution of melioidosis in tropical Australia and ot ....The bacterium Burkholderia pseudomallei, causes a life threatening condition known as melioidosis. Melioidosis is emerging as an important infectious disease in tropical regions of Australia and South East Asia. Death rates following acute disease are extremely high. Despite the importance of B. pseudomallei in tropical public health, very little is known regarding how the body's defence mechanisms prevent the spread of infection. The wide distribution of melioidosis in tropical Australia and other parts of the world, and the lack of basic scientific information regarding this disease, has prompted this study. The bacterium lives within the body's cells and therefore does not respond well to standard antibiotic treatment. Although some of the basic immune mechanisms have been identified, how protection to the organism develops remains unclear. In this project we will investigate the effect of B. pseudomallei on immune cells or lymphocytes. This study will determine the patients' immune responses to the bacteria causing the disease. Our research team has already successfully carried out work on several different aspects of melioidosis. The characterisation of the basic immune function determined in the proposed study will provide the scientific basis for improvement in treatment and the development of possible preventive strategies against melioidosis.Read moreRead less
Immune Regulation, Cellular Trafficking And Chemokine Receptors In Intestinal Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$204,750.00
Summary
The intestine is exposed to a vast array of foreign substances, or antigens, from food to the abundant bacteria that populate the gut. The gut immune system has developed elaborate and poorly understood mechanisms for preventing inflammation in response to these antigens. A breakdown in these control mechanisms may be partly responsible for the chronic intestinal diseases known as inflammatory bowel diseases, which cause abdominal pain, diarrhoea and bleeding. A recently described immune cell ty ....The intestine is exposed to a vast array of foreign substances, or antigens, from food to the abundant bacteria that populate the gut. The gut immune system has developed elaborate and poorly understood mechanisms for preventing inflammation in response to these antigens. A breakdown in these control mechanisms may be partly responsible for the chronic intestinal diseases known as inflammatory bowel diseases, which cause abdominal pain, diarrhoea and bleeding. A recently described immune cell type, known as a regulatory T cell (T reg), is a powerful candidate cell as a master controller of intestinal inflammation. We know that T cells move to various sites in the body under the influence of hormone-like proteins known as chemokines, but the existence of T reg cells in the intestine, their characteristics, their behaviour and their specific response to chemokines, are all unknown. These studies aim to examine the presence and nature of T reg cells in human and mouse intestine, in both health and inflammation, and to explore how these cells migrate into the gut under the influence of chemokines. This knowledge will help in our understanding of intestinal immunity and endogenous regulation of immune responses, and will provide new targets for treatment of inflammatory bowel disease, and potentially other inflammatory diseases.Read moreRead less
Host Resistance And Protection Against Oral Candidasis
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
Candida albicans is an important opportunistic pathogen, that is widely represented in general medical and dental practice, as well as in the hospital environment. Clinical observations indicate that defects in innate immunity predispose patients to disseminated infection, whereas a weakened cell-mediated immune response is commonly associated with chronic oral infections. Animal models of both chronic and acute oral candidiasis have been developed and characterised by the applicants, and these ....Candida albicans is an important opportunistic pathogen, that is widely represented in general medical and dental practice, as well as in the hospital environment. Clinical observations indicate that defects in innate immunity predispose patients to disseminated infection, whereas a weakened cell-mediated immune response is commonly associated with chronic oral infections. Animal models of both chronic and acute oral candidiasis have been developed and characterised by the applicants, and these have clearly implicated T cells in the process of recovery from primary infection. The models will now be used to analyse the effector mechanisms that lead to clearance of the yeast from the oral cavity, with a particular focus on the role of phagocytic cells, and their interaction with T cells. The acute model will be used to identify immunological variables that can act as markers of protection, and the effectiveness of therapeutic manipulations will be evaluated in the chronic model, with the ultimate aim of developing a protective vaccine for human infections.Read moreRead less
Comparative Effectiveness Of Vaccine-induced SIV-specific CD8 T Cells
Funder
National Health and Medical Research Council
Funding Amount
$607,797.00
Summary
A HIV vaccine remains elusive. Although killer T cell immunity can provide partial protection from HIV disease, we don't know the best type of killer T cells to induce by vaccination. This project compares multiple HIV vaccine strategies in macaques. We will carefully study the quality of killer T cell immunity induced using novel and cutting-edge assays. We will identify the requirements for effective killer T cell immunity to HIV.
The Effect Of Innate Immune Responses On The Induction Of Protective Immunity In Murine Typhoid Fever
Funder
National Health and Medical Research Council
Funding Amount
$136,500.00
Summary
Salmonella are important pathogens of humans causing diseases ranging from gastroenteritis, typhoid fever to arthritis. Like most if not all infections, the early interaction between the host and the bacterium is characterised by very non-specific symptoms. These non-specific symptoms arise because the so-called innate immune system is activated by the infection. The purpose of this grant is to establish whether these non-specific symptoms, caused by the release of immunological homrones called ....Salmonella are important pathogens of humans causing diseases ranging from gastroenteritis, typhoid fever to arthritis. Like most if not all infections, the early interaction between the host and the bacterium is characterised by very non-specific symptoms. These non-specific symptoms arise because the so-called innate immune system is activated by the infection. The purpose of this grant is to establish whether these non-specific symptoms, caused by the release of immunological homrones called cytokines, are essential to the development of an effective immune response which can protect against subsequent re-infection. This study has important implications for vaccines, of our understanding of how bacteria cause disease, and the role-capacity of the innate immune system in the development of immunity.Read moreRead less
Effector And Memory CD8+ T Cell Responses To Engineered Influenza A Escape Mutants
Funder
National Health and Medical Research Council
Funding Amount
$465,210.00
Summary
T cells are a critical component of the immune system after infection with viruses. In particular, virus-specific CD8+ T cells can clear viral infections by killing virally-infected cells and the release of immunomodulators. These are called effector T cells. After the viral infection is cleared, a small proportion of T cells (around 5 to 10%) survives for many years and constitute a memory pool of virus-specific T cells. Memory T cells provide a rapid and effective protection in case of a repea ....T cells are a critical component of the immune system after infection with viruses. In particular, virus-specific CD8+ T cells can clear viral infections by killing virally-infected cells and the release of immunomodulators. These are called effector T cells. After the viral infection is cleared, a small proportion of T cells (around 5 to 10%) survives for many years and constitute a memory pool of virus-specific T cells. Memory T cells provide a rapid and effective protection in case of a repeated infection with the same virus, and hence result in a less severe disease. However, viruses often mutate their genes to escape such efficient T cell responses. In this study, we will investigate T cell responses after infection with mutated strains of influenza viruses. We will engineer a panel of mutant influenza viruses, which alter the nature and characteristics of T cells. We will analyse how efficient are these T cells and whether they can protect against a normal strain of influenza A. Subsequently, we will characterise quantitative and qualitative aspects of memory T cell pools after infection with mutant influenza viruses. Since a number of viruses such as influenza, HIV and HCV rapidly mutate their genes, our study will not only address the question of T cell responses to mutated influenza viruses, but also will provide an excellent model for investigating protective T cell responses to other viral infections.Read moreRead less
Antigen Dose And TCR Repertoire In CD8+ T Cell Immunodominance Hierarchies
Funder
National Health and Medical Research Council
Funding Amount
$558,920.00
Summary
The CD8+, or killer , T lymphocytes (white blood cells) are the hit men of immunity, recirculating continually around the body to eliminate other cells that are dangerous because they are cancerous or infected with a virus. A major difficulty is that killer T cells also exert selective pressures that cause viruses and tumours to mutate and thus avoid immune control. This is a particularly serious problem for RNA viruses that readily mutate as they divide. These include the human immunodeficiency ....The CD8+, or killer , T lymphocytes (white blood cells) are the hit men of immunity, recirculating continually around the body to eliminate other cells that are dangerous because they are cancerous or infected with a virus. A major difficulty is that killer T cells also exert selective pressures that cause viruses and tumours to mutate and thus avoid immune control. This is a particularly serious problem for RNA viruses that readily mutate as they divide. These include the human immunodeficiency virus (HIV) that causes AIDS and, while the mutations that are most important with influenza viruses are those that modify viral surface proteins recognized by antibodies, such T cell escape mutants can also be a problem with influenza. The other reason why there is particular interest in promoting CD8+ T cell-mediated immunity to influenza is that the killer T cells are very cross-reactive. We have shown that vaccination approaches that prime mouse CD8+ T cells to resist influenza A viruses circulating currently in humans will also protect against the highly lethal, and dangerous H5N1 bird 'flu. The present flu vaccines only stimulate antibodies, so there is interest in the possibility of a major re-design. The CD8+ T cells recognize tiny elements (peptides) of the virus or tumour bound in the tip of our own transplantation, or class I major histocompatibility complex (MHCI) molecules. These pMHCI complexes are called epitopes. The focus here is on the use of novel genetic engineering strategies to find out how, when the virus mutates to disrupt the major epitopes seen by killer T cells, other minor epitopes can be abnormally emphasized in a way that promotes effective immune control. As we work on this with the relatively simple and safe influenza model we will concurrently develop strategies that may be of value in HIV and tumour immunity. Solving this problem could prove to be a substantial advance in the design of vaccines and immunotherapy approaches.Read moreRead less
Argonaute Proteins In The Mammalian Antiviral Response
Funder
National Health and Medical Research Council
Summary
Viruses are the most abundant infectious agents on earth, and the diseases caused by them are a constant threat and cause of mortality worldwide. Awarded the Nobel Prize for Medicine in 2006, RNA interference (RNAi) is a natural process that plants use to attack viruses. Humans possess all of the tools for RNAi, but whether it is used for antiviral defense is unknown. This study aims to uncover this immune process which will open new avenues to treat virus infections, such as influenza and HIV.
Interaction Of Anti-viral IDO And NOS2 In Vivo In A Novel Murine STD Model.
Funder
National Health and Medical Research Council
Funding Amount
$573,629.00
Summary
Sexually transmitted viral diseases (STD) are increasing globally, but we know little of how virus is controlled early in infection. We have shown for the first time in vivo, in our STD model, that during an antiviral immune response, soluble factors turn on an enzyme, indoleamine 2,3-dioxygenase (IDO), to break down and deplete the amino acid, L-tryptophan, starving virus to reduce growth early in STDs. Our project will further define the action and control of IDO in STD.