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Gerondakis S.,Burnet Institute
Cold Spring Harbor perspectives in biology | Year: 2010

This article focuses on the functions of NF-kappaB that vitally impact lymphocytes and thus adaptive immunity. NF-kappaB has long been known to be essential for many of the responses of mature lymphocytes to invading pathogens. In addition, NF-kappaB has important functions in shaping the immune system so it is able to generate adaptive responses to pathogens. In both contexts, NF-kappaB executes critical cell-autonomous functions within lymphocytes as well as within supportive cells, such as antigen-presenting cells or epithelial cells. It is these aspects of NF-kappaB's physiologic impact that we address in this article. Source


Chan J.A.,Burnet Institute
Cellular and molecular life sciences : CMLS | Year: 2014

Understanding the targets and mechanisms of human immunity to malaria caused by Plasmodium falciparum is crucial for advancing effective vaccines and developing tools for measuring immunity and exposure in populations. Acquired immunity to malaria predominantly targets the blood stage of infection when merozoites of Plasmodium spp. infect erythrocytes and replicate within them. During the intra-erythrocytic development of P. falciparum, numerous parasite-derived antigens are expressed on the surface of infected erythrocytes (IEs). These antigens enable P. falciparum-IEs to adhere in the vasculature and accumulate in multiple organs, which is a key process in the pathogenesis of disease. IE surface antigens, often referred to as variant surface antigens, are important targets of acquired protective immunity and include PfEMP1, RIFIN, STEVOR and SURFIN. These antigens are highly polymorphic and encoded by multigene families, which generate substantial antigenic diversity to mediate immune evasion. The most important immune target appears to be PfEMP1, which is a major ligand for vascular adhesion and sequestration of IEs. Studies are beginning to identify specific variants of PfEMP1 linked to disease pathogenesis that may be suitable for vaccine development, but overcoming antigenic diversity in PfEMP1 remains a major challenge. Much less is known about other surface antigens, or antigens on the surface of gametocyte-IEs, the effector mechanisms that mediate immunity, and how immunity is acquired and maintained over time; these are important topics for future research. Source


Maartens G.,University of Cape Town | Celum C.,University of Washington | Lewin S.R.,Monash University | Lewin S.R.,Infectious Diseases Unit | Lewin S.R.,Burnet Institute
The Lancet | Year: 2014

HIV prevalence is increasing worldwide because people on antiretroviral therapy are living longer, although new infections decreased from 3.3 million in 2002, to 2.3 million in 2012. Global AIDS-related deaths peaked at 2.3 million in 2005, and decreased to 1.6 million by 2012. An estimated 9.7 million people in low-income and middle-income countries had started antiretroviral therapy by 2012. New insights into the mechanisms of latent infection and the importance of reservoirs of infection might eventually lead to a cure. The role of immune activation in the pathogenesis of non-AIDS clinical events (major causes of morbidity and mortality in people on antiretroviral therapy) is receiving increased recognition. Breakthroughs in the prevention of HIV important to public health include male medical circumcision, antiretrovirals to prevent mother-to-child transmission, antiretroviral therapy in people with HIV to prevent transmission, and antiretrovirals for pre-exposure prophylaxis. Research into other prevention interventions, notably vaccines and vaginal microbicides, is in progress. Source


Individuals that are exposed to malaria eventually develop immunity to the disease with one possible mechanism being the gradual acquisition of antibodies to the range of parasite variant surface antigens in their local area. Major antibody targets include the large and highly polymorphic Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family of proteins. Here, we use a protein microarray containing 123 recombinant PfEMP1-DBLα domains (VAR) from Papua New Guinea to seroprofile 38 nonimmune children (<4 years) and 29 hyperimmune adults (≥15 years) from the same local area. The overall magnitude, prevalence and breadth of antibody response to VAR was limited at <2 years and 2-2.9 years, peaked at 3-4 years and decreased for adults compared with the oldest children. An increasing proportion of individuals recognized large numbers of VAR proteins (>20) with age, consistent with the breadth of response stabilizing with age. In addition, the antibody response was limited in uninfected children compared with infected children but was similar in adults irrespective of infection status. Analysis of the variant-specific response confirmed that the antibody signature expands with age and infection. This also revealed that the antibody signatures of the youngest children overlapped substantially, suggesting that they are exposed to the same subset of PfEMP1 variants. VAR proteins were either seroprevalent from early in life, (<3 years), from later in childhood (≥3 years) or rarely recognized. Group 2 VAR proteins (Cys2/MFK-REY+) were serodominant in infants (<1-year-old) and all other sequence subgroups became more seroprevalent with age. The results confirm that the anti-PfEMP1-DBLα antibody responses increase in magnitude and prevalence with age and further demonstrate that they increase in stability and complexity. The protein microarray approach provides a unique platform to rapidly profile variant-specific antibodies to malaria and suggests novel insights into the acquisition of immunity to malaria. Source


Towbin J.A.,Burnet Institute
Heart Failure Clinics | Year: 2010

In this article the newly classified cardiomyopathy known as left ventricular noncompaction is discussed. This genetic inherited form of heart disease has substantial risk of heart failure, stroke, metabolic derangement, arrhythmias, and sudden cardiac death. The disorder seems to occur because of an arrest of the normal process of development, and the genes identified to date seem to encode for cytoskeletal or sarcomeric proteins. These features are outlined. © 2010. Source

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