Role Of The Natural Killer Complex In The Control Of Murine Malarial Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
Natural Killer (NK )cells are an essential arm of the innate immune system. NK cell function is controlled by a series of cell surface receptors encoded within a defined genetic region named the Natural Killer Complex (NKC). This region appears to be highly polymorphic both in mice and humans. It is known that different mouse strains, which differ in the expression of NKC molecules have distinct ability to mount inflammatory responses during infection. In fact, we have previously shown that the ....Natural Killer (NK )cells are an essential arm of the innate immune system. NK cell function is controlled by a series of cell surface receptors encoded within a defined genetic region named the Natural Killer Complex (NKC). This region appears to be highly polymorphic both in mice and humans. It is known that different mouse strains, which differ in the expression of NKC molecules have distinct ability to mount inflammatory responses during infection. In fact, we have previously shown that the differential expression of NKC molecules in mice accounts for the degree of susceptibility to Plasmodium berghei-mediated cerebral malaria, a syndrome that accurately reproduces malarial disease induced by Plasmodium falciparum in humans and that results from an exacerbated pro-inflammatory response to infection. Since the NKC comprises several genes and multi-gene families, the main objective of this proposal is to identify which molecule-s within this genetic region are responsible for the induction of cerebral malaria pathogenesis. Our preliminary results indicate that an activation receptor named Ly49D, which is only expressed on the surface of NK cells from cerebral malaria-susceptible mice, plays a key role in disease-induction. Activation of Ly49D induces NK cells to secrete large amounts of IFN-gamma, a pro-inflammatory cytokine known to mediate cerebral-malaria pathogenesis. We will characterize the immunological function of Ly49D+ NK cells during P. berghei infection and determine whether these cells are the main source of IFN-gamma production. We will also identify the ligand (from parasite or host origin) responsible for the stimulation of this NKC activation receptor during malaria infection. The identification and characterization of these NKC receptors will provide new insights to explain the immunological basis of malarial pathogenesis and could lead to the development of therapeutical approaches designed to prevent severe malarial disease.Read moreRead less
I am an Immunologist interested in the role of B-lymphocytes, their survival and expression of a novel chemoreceptor in Autoimmunity. I also study the important role of Neuropeptide Y in modulating key immune functions.
Viral Immune Evasion From The NK Cell Ly49H Activation Receptor
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
Infection with human cytomegalovirus (HCMV) remains a significant health problem for individuals whose immune systems are immunocompromised (transplant patients and AIDS patients) or poorly developed (such as the foetus and newborn children). While drugs are available to treat HCMV infection the emergence of viral drug escape mutants means there is a medical necessity to develop new therapies and vaccines against this agent. As a basis for this it is important to develop a better understand the ....Infection with human cytomegalovirus (HCMV) remains a significant health problem for individuals whose immune systems are immunocompromised (transplant patients and AIDS patients) or poorly developed (such as the foetus and newborn children). While drugs are available to treat HCMV infection the emergence of viral drug escape mutants means there is a medical necessity to develop new therapies and vaccines against this agent. As a basis for this it is important to develop a better understand the host-virus relationship to rationally design appropriate treatments. As HCMV is species specific and does not infect experimental animals, the murine cytomegalovirus (MCMV) in mice is widely used as a model for HCMV disease. MCMV infection is controlled by both innate and adaptive arms of the host's immune response. Natural killer (NK) cells constitute an important frontline defence against MCMV and understanding how they are activated is of importance to harnessing them for anti-viral control measures. Recently we have shown that NK cells are activated via the interaction of an NK cell activation receptor (Ly49H) with a MCMV-encoded ligand (m157). However, we have also found that MCMV can rapidly mutate its m157 gene to evade effective NK cell control and that wild populations of MCMV have foms of m157 that don't bind to Ly49H. Other studies suggest that m157 can bind to inhibitory NK cell receptors, such as Ly49I, and inactivate the NK cell response. This study seeks to understand the dynamics of the m157-Ly49H and m157-Ly49I interactions. As HCMV infection is also regulated at early stages by NK cells, an understanding of how CMV can rapidly mutate its m157 gene to avoid interaction with Ly49H-expressing NK cells has important implications for understanding human disease caused by HCMV, in terms of potential viral escape from NK cell surveillance.Read moreRead less
Regulation Of TNF And SFK Signalling In Immune Cells By TCPTP
Funder
National Health and Medical Research Council
Funding Amount
$454,023.00
Summary
Tumour necrosis factor (TNF) is a potent proinflammatory cytokine that plays an important role in immunity and inflammation. TNF acts on the cell surface to activate two key cellular communication or signalling pathways: the mitogen-activated protein kinase (MAPK) pathway and the nuclear factor kappaB (NFkappaB) pathway. The relative activation of the two pathways can dictate whether cells live and proliferate or differentiate or otherwise die in response to TNF, and therefore determine the natu ....Tumour necrosis factor (TNF) is a potent proinflammatory cytokine that plays an important role in immunity and inflammation. TNF acts on the cell surface to activate two key cellular communication or signalling pathways: the mitogen-activated protein kinase (MAPK) pathway and the nuclear factor kappaB (NFkappaB) pathway. The relative activation of the two pathways can dictate whether cells live and proliferate or differentiate or otherwise die in response to TNF, and therefore determine the nature of the immune or inflammatory response. The T-cell protein tyrosine phosphatase (TCPTP) is known to be important in the immune system and serves as a negative regulator of inflammation. Our preliminary studies have identified TCPTP as a selective regulator of TNF-induced MAPK but not NFkappaB signaling. TCPTP exerts its effects by inactivating Src family kinases (SFK) which are themselves integral to immune and inflammatory responses. In this proposal we will elucidate the molecular basis for TCPTP function in TNF- signalling and characterise the role of TCPTP in TNF and SFK functions in immune cells, in particular T-cells.Read moreRead less