Main Questions

Pathogenesis 

What are the molecular mechanisms of breakdown of the blood brain barrier in cerebral malaria? 

Cerebral malaria is correlated with vascular activation that leads to a breakdown of the blood brain barrier where brain microvascular endothelial cells down regulate junction proteins leading to vascular leak and edema. Current work is investigating the cross-talk between brain microvascular endothelial cells and other cells of the neurovascular unit (astrocytes, pericytes and microglia) in cerebral malaria.   

How do Eph receptors mediate organ-specific pathologies in malaria? 

Eph receptors are the largest family of tyrosine receptor kinases. We have discovered that these molecules play a central role in mediating a number of pathogenic symptoms in malaria including malaria-associated liver fibrosis and opening of the blood brain barrier during neurological manifestations of Plasmodium infection. Current work is determining the molecular mechanisms by which this family of receptor tyrosine kinases mediate pathogenesis of malaria with a view to designing novel Eph-based therapies for use in malaria. 

What are the underlying causes for malaria-induced thrombocytopenia? 

We have previously shown that platelets mediate organ-specific pathologies in malaria. Thrombocytopenia, a drop in the number of circulating platelets in the bloodstream, can be an indicator of the severity of malaria. Although this can occur due to consumption of platelets that become activated in blood stage Plasmodium infection and adhere onto Plasmodium-infected red blood cells, we are investigating a defect in platelet production in the bone marrow via bone marrow inflammation which occurs during Plasmodium infection. 

What are the immunological mechanisms underpinning the asymptomatic carriage of Plasmodium parasites? 

Asymptomatic carriage of Plasmodium parasites, although without overt symptoms, is thought to have long-term effects on individual health, and to be responsible for the persistence of malaria in many endemic zones. Asymptomatic carriers often do not seek medical attention - they serve as human reservoirs of Plasmodium infection and can represent >80% of infections in some endemic settings.  The host-parasite interactions shaping the asymptomatic outcome of malaria infections are not fully understood. In collaboration with Dr Lawrence Ayong’s lab at the Centre Pasteur Cameroon we are investigating the immunological mechanisms underpinning the asymptomatic carriage of Plasmodium parasites. We were also recently funded by the National Institute for Allergy and Infectious Diseases to develop a genetic mouse model of asymptomatic malaria using the Collaborative Cross mouse colonies at UNC. 

How does co-infection with other pathogens modulate the pathogenesis of malaria? 

Most individuals with Plasmodium infection are co-infected with other pathogens. We are investigating the mechanistic basis by which co-infection with acute gammaherpesviruses such as Epstein Barr Virus, suppresses anti-malarial humoral responses leading to the development of severe malaria. We are also investigating how pre-existing malaria can predispose individuals to more severe bacterial infections such as with Streptococcus pneumonia 

Adaptive immune responses in malaria 

How do ephrin ligands modulate T cell function in response to Plasmodium infection? 

Ephrin ligands are expressed on germinal center B cells, as well as on T follicular helper cells during malaria. Current projects in the Lamb lab are defining the role that these molecules play in modulating adaptive immune responses that control Plasmodium parasitemia. 

What are the functions of T cells with lower affinity TCRs? T cells express T cell receptors (TCR) on their surface that recognize peptide epitopes derived from malaria parasite proteins presented in the context of MHC-I or MHC-II molecules on the surface of antigen presenting cells (APCs). Antigen-specific T cells display a wide range in affinity for antigen. Current clonal selection theories postulate that T cells bearing TCRs with the highest affinity for antigen will predominate the immune response. In collaboration with Dr Brian Evavold’s lab, also in the Department of Pathology at the University of Utah, we have made the paradigm-shifting discovery that the majority of pathogenic CD8 T cells responsible for breakdown of the blood brain barrier in the well-established Plasmodium berghei ANKA model of experimental cerebral malaria (ECM) harbor T cell receptors that display low affinity for immunodominant Plasmodium peptides. Current work on this project investigates the basis for the expansion of lower affinity T cells during Plasmodium infection and the pathogenic function of lower affinity T cells.  

How can the transcriptomic profiles of related adaptive immune cells be analyzed single cell RNA sequencing? 

Current methods of single cell RNA sequencing analysis are susceptible to spurious results, in particular when the cells of interest are highly similar. We are developing novel algorithms incorporating known biological features of T and B cells to better analyze single cell transcriptomic profiles.  

Vaccination 

What is the optimal way to deliver subunit vaccines to generate efficacious anti-malarial responses? 

Vaccination to protect against infection is a life-saving concept, made famous by Edward Jenner who used cowpox to protect individuals against smallpox. Recent release of the RTS,S vaccine against malaria showed limited and transient protection against malarial disease in the field, but demonstrated that vaccination against malaria might be possible. One of the challenges to mass vaccination in disease endemic countries is the costly administration by injection. In collaboration with Anita Corbett Emory University, we are developing an oral vaccine delivery system to express and deliver malaria antigens via probiotic yeast.