Research Area C
Immune responses
Pathogen defence is a critical determinant in host-parasite coevolution and survival of an infected individual. In humans, naturally acquired immunity against Plasmodium infections develops very gradually over the course of the entire childhood and only after several clinical episodes, but remains incomplete, and wanes rapidly after migration out of endemic areas. A better cellular and molecular understanding of both the individual contributions and the interplay of innate and 10 adaptive defence mechanisms in anti-malaria immunity remains a research priority and has important translational implications, ranging from identification of high-risk patients to evidencebased malaria vaccine development. In this research area, three projects will uncover longstanding questions in immunity to malaria parasites.
Projects
Project C1 - 1st Cohort
Dissecting innate immune responses to plasmodia and their impact on disease and vaccination
LEIF ERIK SANDER (Charité) in partnership with Ian Cockburn (ANU)
The project will achieve the first systematic analysis of pattern recognition of viable humaninfecting Plasmodium parasites. Against the background of an abundance of conflicting data of innate sensing in murine models, a careful assessment of human innate responses to Plasmodium infection is particularly desirable. Candidate viability and pathogen-associated molecular patterns will be tested in transgenic sporozoite murine infection models for their potential to enhance live attenuated malaria vaccine strategies.
Kai Pohl
Project C1 - 2nd Cohort
How innate immune recognition shapes plasmodium-specific T-cell responses
LEIF ERIK SANDER (Charité) in partnership with Ian Cockburn (ANU)
There is common consensus that successful eliminating of malaria will require the implementation of an efficacious vaccine against the disease. Thus far, most vaccine candidates provide only modest and rather short-lived protection in the field. Live P. falciparum sporozoites (PfSPZ) have shown promise in healthy volunteers, yet appear to provide short-lived protection in highly endemic areas.
Jason McGowan
Project C2 - 1st Cohort
Identification and analysis of platelet polymorphisms associated with malaria susceptibility
BRENDAN MCMORRAN (ANU) in partnership with Frank Mockenhaupt (Charité)
In the project the seminal finding that platelets are instrumental in killing of Plasmodium-infected erythrocytes permits the functional testing of whether candidate polymorphisms in platelet-associated genes cause malaria susceptibility. This study encompasses genotyping in patient cohorts and cell culture assays as proxy for platelet functions in infected patients. Sporozoite-based immunization strategies are presently one of the most promising roads towards an efficacious malaria vaccine.
Project C2 - 2nd Cohort
BRENDAN MCMORRAN (ANU) in partnership with TBA
The human platelet defense protein, platelet factor 4 (PF4), has intrinsic antiplasmodial activity, but also undesirable chemokine properties. My group has engineered a peptide containing the isolated PF4 antiplasmodial domain, which through cyclization, retains the critical structure of the parent protein. The peptide, cPF4PD, kills cultured blood-stage Plasmodium falciparum with low micromolar potency by specific disruption of the parasite digestive vacuole. We hypothesize the peptide can be used as a scaffold onto which molecules may be conjugated to enable their selective and targeted delivery to parasites residing in host erythrocytes, or the free-living sporozoite. Such a peptide-molecule conjugate approach could be advantageous for various applications, including targeted delivery of antimalarial drugs that have undesirable side effects when administered systemically, improving lead antimalarial compounds that have poor cell uptake activity.
TBA
Project C3 - 1st Cohort
Novel adjuvants for pre-erythrocytic stage vaccines
IAN COCKBURN (ANU) in partnership with Leif Erik Sander (Charité)
The project will combine self-devised immunoglobulin transgenic mice and lentiviral knockdown libraries for the evidence-based development of adjuvants that permit superior B cell responses against inactivated sporozoites, which are notoriously weak in eliciting lasting immunity. Hence, this project could remove a major roadblock in development of whole sporozoite vaccines for use in endemic countries.
Deepyan Chatterjee
Project C4 - 2nd Cohort
Determinants of Semi-Immunity and Disease Tolerance in Malaria
FLORIAN KURTH (HUB, CHARITÉ) in partnership with Ian Cockburn (ANU), Leif Sander (HUB, Charité) and CERMEL
The outcome of malaria in individual patients critically depends on their history of previous infections. Patients who have repeatedly been exposed to Plasmodium tolerate the presence of blood-stage parasites far better than those with first-time infections, e.g. with respect to organ damage. Populations of highly malaria-endemic areas even develop a state of complete absence of symptoms, despite ongoing parasitaemia. Hence, tolerance is a major determinant of what is frequently referred to as “semi-immunity”. Acquired tolerance can also be disadvantageous, particularly with respect to vaccination. For instance, whole sporozoite vaccines (PfSPZ) elicit weaker immune responses and consequently less protection in vaccinees in endemic regions than in malaria-naïve individuals.
Lara Bardtke, Cäcilie Wedel
anu canberra
134 Linnaeus Way
Acton
ACT 2601
Australia
hu berlin
Humboldt-Universität zu Berlin
Unter den Linden 6
10099 Berlin
Germany
