Roles Of Virus-integrin Interactions And Rotavirus Modulation Of Host Cell Responses In Viral Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$474,000.00
Summary
Rotaviruses are the main cause of severe gastroenteritis in children, and cause 1 in 27 Australian children under the age of 5 years to spend time in hospital. There is currently no rotavirus vaccine available. We aim to discover how rotavirus interacts with host cells. This information is necessary to formulate a safe and effective vaccine, or a therapeutic agent that can block virus growth in host cells. Previously, we showed that rotavirus attaches to cells and enters them using several membe ....Rotaviruses are the main cause of severe gastroenteritis in children, and cause 1 in 27 Australian children under the age of 5 years to spend time in hospital. There is currently no rotavirus vaccine available. We aim to discover how rotavirus interacts with host cells. This information is necessary to formulate a safe and effective vaccine, or a therapeutic agent that can block virus growth in host cells. Previously, we showed that rotavirus attaches to cells and enters them using several members of the integrin protein family that are present on the surface of the cells. Integrins are critical for cell adhesion, survival and communication. In this project, we will identify how rotavirus usage of integrins modulates cell functions. This will help us understand how rotavirus causes disease, how virus spreads in the body and how the immune response defends us from rotavirus. Rotavirus binds integrins using particular stretches of protein sequence that we have shown are also present in other human viral pathogens that cause hepatitis, AIDS and measles. We will determine if these other viruses also recognize integrins.Read moreRead less
Analysis Of The Role Of Rotavirus Infection In Development Of Type 1 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$348,875.00
Summary
Our earlier studies in children with a family history of type 1 diabetes have shown that infection with a common virus, rotavirus, may be one factor contributing to their progression to diabetes. Rotavirus is the most common cause of diarrhoea, vomiting and dehydration in young children, and it was thought that rotavirus infection is usually confined to the intestine. To understand how rotavirus infection might promote diabetes, my group has developed a mouse model. Using mice for these studies ....Our earlier studies in children with a family history of type 1 diabetes have shown that infection with a common virus, rotavirus, may be one factor contributing to their progression to diabetes. Rotavirus is the most common cause of diarrhoea, vomiting and dehydration in young children, and it was thought that rotavirus infection is usually confined to the intestine. To understand how rotavirus infection might promote diabetes, my group has developed a mouse model. Using mice for these studies allows us to control infection and completely analyse the results of infection, which we cannot do in humans. A type of mouse that is very likely to develop type 1 diabetes in its first 6 months of life is infected by mouth with rotavirus. We have shown that these mice develop diabetes 7 weeks faster than the same type of mice that are not given virus. In this project, we will determine the effects of mouse age, virus strain, the number of times infection occurs, and levels of virus growth in the intestine or pancreas on virus-induced diabetes acceleration. The ability of treatments for rotavirus infection, and vaccination against rotavirus, to block this accelerated diabetes also will be tested. We expect that rotavirus will be found growing in the pancreas, that virus growth is necessary for diabetes acceleration, and that prevention of rotavirus infection will also prevent the rapid diabetes onset. This model could prove to be suitable for testing the effectiveness and safety of new drugs and vaccines against both rotavirus and type 1 diabetes. Our studies will be crucial in determining the importance of rotavirus infection in the development of type 1 diabetes.Read moreRead less
Envelope Glycoprotein Determinants Of Pathogenic, Macrophage-tropic HIV-1 And Their Role In HIV-1 Disease Progression
Funder
National Health and Medical Research Council
Funding Amount
$442,500.00
Summary
Human immunodeficiency virus type 1 (HIV-1) causes AIDS and, to date, has infected 20 thousand people in Australia and 40 million worldwide. In addition to T-cells of the immune system, HIV-1 can also infect cells of the monocyte-macrophage lineage found in blood, brain, lymph node, lungs, bone marrow, skin and brain. HIV-1 strains that can infect these cells are called macrophage-tropic (M-tropic) strains. Infected macrophages are a major source of new HIV-1 produced in the body, and they compl ....Human immunodeficiency virus type 1 (HIV-1) causes AIDS and, to date, has infected 20 thousand people in Australia and 40 million worldwide. In addition to T-cells of the immune system, HIV-1 can also infect cells of the monocyte-macrophage lineage found in blood, brain, lymph node, lungs, bone marrow, skin and brain. HIV-1 strains that can infect these cells are called macrophage-tropic (M-tropic) strains. Infected macrophages are a major source of new HIV-1 produced in the body, and they complicate therapy by the current drugs used to treat HIV-1 infection because infection is often latent (or dormant) and, unlike T-cells, they are long lived and may continue to produce new virus for the duration of their normal life span. HIV-1 virus from patients with advanced disease (i.e. AIDS) can infect macrophages better than virus from patients at early stages of disease (i.e. just after infection, or during the asymptomatic or healthy period). Therefore, the increased ability of HIV-1 to infect macrophages, i.e., enhanced M-tropism, is an important factor contributing to the development of AIDS in people with HIV-1 infection. However, what causes HIV-1 to increase it's ability to infect macrophages and cause AIDS is unknown. This proposal aims to identify features of HIV-1 that are important for enhanced M-tropism and HIV-1 disease progression. We expect to find that the virus gradually changes during the course of infection to forms that can bind to receptor molecules on the cell more tightly, and to forms that need fewer receptors on the cell surface for infection. We believe that these forms of HIV-1 virus are now better able to infect macrophages, which naturally only have small amounts of receptors on their surface, and also can infect and kill T-cells better, leading to AIDS. This study will contribute to a greater understanding of how HIV-1 causes AIDS, which is necessary for the development of new drugs to treat HIV-1 infection.Read moreRead less