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 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 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 C1 - 2nd Cohort

Title - t.b.a. 

 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 - 2nd Cohort 

Utilization of platelet-derived peptides to explore Plasmodium biology and develop antimalarial drug leads.

BRENDAN MCMORRAN (ANU) in partnership with TBA

The human platelet defense protein, platelet factor 4 (PF4), has intrinsic antiplasmodial activity (McMorran, Wieczorski et al. 2012) 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. Its mechanism of action involves selective penetration and accumulation inside the intraerythrocytic parasite without damaging the host cell or parasite membranes; it does not accumulate in uninfected cells. This selective activity is accounted by the peptide’s specific binding and penetration of membranes with exposed negatively charged phospholipid headgroups (Lawrence, Dennis et al. 2018). Unpublished data indicate the peptide also selectively accumulates in the digestive vacuole of gametocytes (in collaboration with Daniela Cihalova and Alex Maier, IRTG, ANU), and the cytosol of sporozoites (in collaboration with Kai Pohl and Ian Cockburn, IRTG, ANU). We hypothesize the peptide can be used as a scaffold onto which molecules (peptides or small 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 (eg. primaquine in G6PD-deficient individuals), improving lead antimalarial compounds that have poor cell uptake activity, and enable intraparasite delivery of probes or enzymes to explore different aspects of parasite biology (eg. proximity labelling for mass spectrometry). I would be interested in exploring any of these applications in collaboration with other IRTG members.

TBA


Project C3 - 2nd Cohort 

Understanding the basis of strain specific protection against malaria. 

IAN COCKBURN (ANU) in partnership with Leif Erik Sander (Charité)

Controlled human malaria infection via sporozoite challenge with defined strains on parasites fails in around 1/3 individuals in endemic areas. It has been hypothesized that this is due to liver stage immunity, however no evidence has been found of naturally occurring liver stage immunity numerous previous studies. We hypothesise instead, that protection is mediated by antibodies that target the variant surface antigens expressed by first blood stage parasites emerging from the liver. This is based on previous work that suggests that the var genes that encode variant surface antigens epigentically reset after passage through the mosquito. To test this hypothesis we will isolate sera and generate monoclonal antibodies specific for PfEMP1 from individuals in Kilifi, Kenya who did not develop malaria infection and screen them for reactivity with those var genes known to emerge first after infection. We will examine how strain specific these antibodies are and determine their ability to prevent adhesion and induce parasite clearance. The ultimate aim of this project is to identify a panel of highly cross reactive var genes capable of neutralizing multiple strains of parasites rapidly by targeting the first parasites to emerge from the liver.

TBA


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