Clinical Impact Of Clonal Pseudomonas Aeruginosa In Cystic Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$547,238.00
Summary
In patients with cystic fibrosis (CF), the normal defence mechanisms are compromised by an inherent genetic fault which results in an extremely sticky and dehydrated mucus. The respiratory system is unable to eradicate microbes (infection) from the lungs of patients with CF which begin to multiply and cause infection and inflammation. Recurring infections are treated with multiple courses of antibiotics and frequent hospitalisation and eventually result in premature death. This study focuses on ....In patients with cystic fibrosis (CF), the normal defence mechanisms are compromised by an inherent genetic fault which results in an extremely sticky and dehydrated mucus. The respiratory system is unable to eradicate microbes (infection) from the lungs of patients with CF which begin to multiply and cause infection and inflammation. Recurring infections are treated with multiple courses of antibiotics and frequent hospitalisation and eventually result in premature death. This study focuses on the major bacterial problem, Pseudomonas aeruginosa. Several studies from Australia and the UK, including our own have shown that about 30% to 45% of patients share the same strain of Pseudomonas aeruginosa within a centre. We know that two dominant strains of Pseudomonas aeruginosa are found in CF centres on the eastern board of Australia. This is unexpected as this bacterium is usually acquired from the environment. The emergence of these clonal strains is causing increasing anxiety in the CF community. This study is designed to provide vitally needed information on the clinical implications of being infected by an clonal strain of Pseudomonas aeruginosa and the risk factors for the acquisition of an clonal strain. This new information will provide a rationale basis for the need for changes to infection control policies (including patient segregation), better outcome predictors for patients infected with clonal strain of Pseudomonas aeruginosa.Read moreRead less
Treatment Of Cerebral Palsy - An Experimental Approach
Funder
National Health and Medical Research Council
Funding Amount
$589,544.00
Summary
Cerebral palsy is characterised by disordered movement evident early in life leading to lifelong disability. The motor disorder arises from an abnormality within the white-matter of the brain that is non-progressive and is identifiable soon after birth. In humans and experimental models of fetal infection there is an increase in markers of inflammation. We will use induce ovine fetal infection and white matter injury to examine if anti-inflammatory treatments can prevent fetal brain damage.
Mechanisms Regulating Establishment Of Persistent Herpesvirus Infection
Funder
National Health and Medical Research Council
Funding Amount
$511,446.00
Summary
Herpesviruses are a major cause of disease worldwide and are amongst the most successful human pathogens, with some viruses infecting more than 80% of the world's population. This group of viruses persist and reactivate in hosts and induce immunosuppression.The control of herpesviruses infections thus represents an important clinical goal. Understanding the mechanisms involved in the induction of viral persistence and immunosuppression is a crucial step towards developing better therapies.
Determinants Of Cytomegalovirus Salivary Gland Persistence
Funder
National Health and Medical Research Council
Funding Amount
$566,308.00
Summary
Human cytomegalovirus (HCMV) persists for extended periods in the salivary gland, an organ of viral transmission. It is not clear how the virus avoids immune mediated control in this tissue. This aspect of viral pathology will be assessed in a mouse model using two strains of murine CMV which exhibit marked differences in salivary gland persistence. The role of tissue tropism (inhibition of apoptosis), viral immune evasion and host immunity in salivary gland persistence will be studied.
Defining The Mechanisms That Regulate Effective Long-term Anti-viral Immunity
Funder
National Health and Medical Research Council
Funding Amount
$547,315.00
Summary
Human cytomegalovirus (HCMV) is a common human pathogen which normally causes a mild or even asymptomatic infection. However, in immunocompromised individuals, HCMV causes severe disease whose manifestations include chorioretinitis, interstitial pneumonia and hepatitis. Similarly, in neonates lacking a fully mature immune system, HCMV causes severe morbidity. Vaccines that protect against HCMV induced cytomegalic inclusion disease have been designated Level I (most favourable) due to the predict ....Human cytomegalovirus (HCMV) is a common human pathogen which normally causes a mild or even asymptomatic infection. However, in immunocompromised individuals, HCMV causes severe disease whose manifestations include chorioretinitis, interstitial pneumonia and hepatitis. Similarly, in neonates lacking a fully mature immune system, HCMV causes severe morbidity. Vaccines that protect against HCMV induced cytomegalic inclusion disease have been designated Level I (most favourable) due to the prediction that they could save lives and prevent life-long disability. Similarly, therapies that prevent and-or reduce HCMV reactivation will significantly improve the prognosis of transplant and AIDS patients. The murine CMV (MCMV) infection model has provided important insights as to how the immune system controls infection, and the mechanisms utilized by the virus to circumvent these processes. The design of effective therapies and vaccines requires a thorough understanding of the mechanisms required to generate and maintain long-lasting anti-viral responses. The studies outlined in this proposal aim to define the impact of specific components of the immune system n the generation, maintenance and effectiveness of anti-viral immunity. The well characterized MCMV model will be used to address these issues.Read moreRead less
Modulation Of Leishmaniasis By The Proinflammatory Cytokines TNF
Funder
National Health and Medical Research Council
Funding Amount
$288,911.00
Summary
We have established a mouse model that has been genetically modified and cannot produce the cytokine tumour necrosis factor. This cytokine is secreted in the beginning of the inflammatory response. If these mice are infected with a parasite they are not able to heal the infection and die quickly. We can demonstrate that these mice cannot regulate the beginning inflammatory response and do not form a cellular infiltrate at the site of infection.
Improving Adaptive Anti-viral Responses: A Key To Eliminating Persistent Viral Infection
Funder
National Health and Medical Research Council
Funding Amount
$402,391.00
Summary
Cytomegalovirus (CMV) can cause a persistent infection that can result in adverse clinical outcomes. Our previous work established that suboptimal adaptive immunity is responsible for viral persistence. This proposal will define the defect in adaptive immunity, its causes and how to improve it. The understanding gained from the proposed studies will provide crucial information for the development of improved anti-viral therapies and vaccines.
Human cytomegalovirus (HCMV) is a classic example of a group of herpes viruses, which is found universally throughout all geographic locations and socioeconomic groups, and infects 50% of adults in developed countries. HCMV infection is important to certain high-risk groups. Major areas of concern are: (1) the risk of infection to unborn baby during pregnancy, (2) the risk of infection to people who work with children, and (3) the risk of infection to immunocompromised persons (e.g. organ transp ....Human cytomegalovirus (HCMV) is a classic example of a group of herpes viruses, which is found universally throughout all geographic locations and socioeconomic groups, and infects 50% of adults in developed countries. HCMV infection is important to certain high-risk groups. Major areas of concern are: (1) the risk of infection to unborn baby during pregnancy, (2) the risk of infection to people who work with children, and (3) the risk of infection to immunocompromised persons (e.g. organ transplant patients and HIV-infected individuals). Epidemiological studies have shown that 80%-90% of developing unborn babies who acquire congenital HCMV infection displays a variable pattern of pathological sequelae within the first few years of life that may include hearing loss, vision impairment and mental retardation. There is an increasing argument that a reduction in HCMV load will have a significant effect on the sequelae associated with congenital HCMV infection. Indeed, vaccination provides the most practical modality of achieving such a reduction in HCMV load. To develop such a vaccine, formulation based on viral antigens that activate both protective cellular and humoral responses needs to be tested to assess its immunogenicity. No such vaccine is presently available for HCMV. In this application we have sought to develop a prophylactic vaccine and to test its efficacy in a immunocompetent transgenic mouse model and as well under conditions of immunosuppression (CD4 T cell deficient). The overall strategy is to use this prophylactic vaccine to stimulate the cellular (CD8+ and CD4+ T cells) and humoral responses against multiple HCMV antigens. This vaccine will be based on the novel chimeric polyepitope technology and exploits a novel replication deficient adenovirus expression system which has recently been approved for human use.Read moreRead less
Effects Of Natural Sequence Variation On Evasion Of Cytotoxic T Lymphocytes By Murine Cytomegalovirus.
Funder
National Health and Medical Research Council
Funding Amount
$553,167.00
Summary
Human cytomegalovirus persists for the life time of an infected person. It has many ways of achieving this, including interfering with the host immune response. This project seeks to explore this using a mouse model and murine CMV. Specifically we will focus on a set of viral genes that inhibit host recognition of virally infected cells. Sequence variation in these genes suggests that they function differently in different strains of virus: we will examine the consequences of this variation.