Age Of Exposure And Immunity To Malaria In Infants
Funder
National Health and Medical Research Council
Funding Amount
$322,000.00
Summary
The development of naturally acquired immunity (NAI) against Plasmodium falciparum (P.falciparum) malaria is poorly understood. Previous studies of continuous and intermittent chemoprophylaxis in infants have provided evidence that the age of first exposure to P.falciparum during infancy may be important in determining the development of NAI, as measured by incidence of clinical malaria during the second year of life. These studies suggest that exposure to P. falciparum prior to 5 months of age ....The development of naturally acquired immunity (NAI) against Plasmodium falciparum (P.falciparum) malaria is poorly understood. Previous studies of continuous and intermittent chemoprophylaxis in infants have provided evidence that the age of first exposure to P.falciparum during infancy may be important in determining the development of NAI, as measured by incidence of clinical malaria during the second year of life. These studies suggest that exposure to P. falciparum prior to 5 months of age does not result in the development of NAI, while exposure to P. falciparum after 5 months of age leads to development of NAI. The overall objective is to evaluate the effect of exposure to P. falciparum erythrocytic stage antigens during different periods of infancy on the development of NAI. In order to explore the effect of age in the build-up of NAI we have designed a 3-arm randomized double-blind placebo-controlled trial in an endemic area of southern Mozambique in which we selectively control exposure to P. falciparum at different periods during infancy (2-5 months, 5-10 months or none) with monthly chemoprophylaxis with Sulphadoxine- Pyrimethamine + Artesunate. Infants will be enrolled at birth from HIV-negative women and allocated to one of three cohorts of 98 children each. Participants will be followed up by active and passive case detection and cross-sectional surveys until 24 months of age. The risk of clinical malaria and anaemia during the second year of life will be compared between cohorts, as well as its correlation with the type and quality of immune responses (antibodies to several P. falciparum antigens, cytokines), oxidative stress markers and host genetic factors. These results should shed light on the determinants of the development of anti-P. falciparum responses early in life and the potential constraints to early life immunisation.Read moreRead less
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