Investigating The Role For Microparticles In The Pathogenesis Of Cerebral Malaria.
Funder
National Health and Medical Research Council
Funding Amount
$293,931.00
Summary
Fatal malaria is one of the world's most destructive disease burdens. A major complication is Cerebral Malaria (CM). Small vesicles originating from cell membranes, known as microparticles (MP), have recently been shown to play an important role in CM. This project aims to determine the role MP play in CM, the cells they interact with and the consequences of such interactions. It is hoped that project outcomes may provide new approaches in the prevention and treatment of fatal malaria.
I am a clinician-scientist in infectious and tropical diseases, working towards the better understanding of the pathophysiology of malaria and other tropical diseases of public health importance in our region, and new ways of prevention and treatment.
Genetic Dissection Of Biofilm Development By Non-typeable Haemophilus Influenzae
Funder
National Health and Medical Research Council
Funding Amount
$418,516.00
Summary
The bacterial pathogen non-typeable Haemophilus influenzae (NTHi) is a common cause of chronic infections of the middle ear and of the airways of patients suffering cystic fibrosis, or chronic obstructive pulmonary disease (COPD). These infections are associated with bacterial biofilms that are significantly resistant to both antibiotics and immune defences. This project aims to characterise the process of NTHi biofilm development so that novel diagnostic tools and therapeutics can be developed.
We plan to continue our work that to date is consistent with the idea that excessive induction of the enzyme iNOS, and thus production of nitric oxide in key locations, is a central event in how falciparum malaria kills people who become infected with this parasite. This will largely be based on detecting iNOS and nitrotyrosine in tissues from autopsies collected as part of a malaria research programme conducted in Malawi. Laboratory experiments will also be performed. In particular, there is a ....We plan to continue our work that to date is consistent with the idea that excessive induction of the enzyme iNOS, and thus production of nitric oxide in key locations, is a central event in how falciparum malaria kills people who become infected with this parasite. This will largely be based on detecting iNOS and nitrotyrosine in tissues from autopsies collected as part of a malaria research programme conducted in Malawi. Laboratory experiments will also be performed. In particular, there is a body of evidence that suggests the following interactions between inflammatory cytokines and salicylate, with important practical ramifications, in children. 1. Salicylate toxicity, like the acute multi-organ form of childhood malaria it mimics, is probably caused by excess systemic iNOS induction. This plausibly includes the metabolic acidosis, hypoglycaemia, seizures, coma and cerebral oedema seen in both conditions. Both are thus logically susceptible to treatment with specific iNOS inhibitors. 2. The same picture would arise in children when smaller doses of salicylate synergise with IFN-g, IL-1b, and perhaps other cytokines induced by malaria as well as by viruses. This gives the first proposed explanation for Reye's syndrome, defining the circumstances in which it occurs, and predicting a rationale for its treatment. Through the parallels seen in different age groups in malaria and aspirin toxicity, it also rationalises the difference in childhood vs adult malaria syndromes. 3. The overall severity and mortality of childhood malaria in East Africa may be worsened, through this cytokine-salicylate synergy, by home treatment with aspirin when children first become ill. 4. A relative absence of salicylate intake by children in various malarial Pacific Islands may contribute to falciparum malaria being a less severe disease there than in East Africa.Read moreRead less