Research Opportunities

Influenza A virus imposes a significant socio-economic burden on humanity.  Vaccination is effective in only 60% of individuals, even under optimal circumstances.  The difficulty stems from the remarkable ability of influenza A virus to evade existing immunity.  IAV’s error prone polymerase enables the rapid antigenic evolution of the two virion surface glycoproteins, neuraminidase (NA) and hemagglutinin (HA).  Since the most potent antibodies (Abs) at neutralizing viral infectivity are directed the HA and NA globular domains, amino acid substitutions in these regions enable IAV to evade Ab-based immunity.  The project focuses on understanding the “immunodominance” of Ab responses to HA and NA in humans.  Immunodominance describes the strong tendency of the immune response to respond to complex antigens in a hierarchical manner, with higher ranking, “immunodominant” antigens potentially suppressing (“immunodominating”) responses to “subdominant” antigens.  By focusing responses on single antigenic sites, it is likely responsible for enabling influenza A virus to evade immunity by allowing the virus to sequentially alter its antigenicity.

Leishmaniasis is an important disease caused by protozoan parasites that are transmitted by infected sand fly bites in tropical and subtropical regions.  Depending on the strain of Leishmania, disease forms in humans range from localized, self-limiting cutaneous lesions to visceralizing infections that are fatal in the absence of treatment.   The specific contribution of parasite genotype to disease outcome remains largely unknown. Taking advantage of a recently revealed sexual cycle that occurs during Leishmania development in the insect vector, our goal is to generate a series of hybrids between cutaneous and visceral strains that will be phenotyped in mouse models of cutaneous and visceral leishmaniasis.  Each hybrid will be subjected to whole genome DNA and RNA-sequencing to follow parental allele, structural variation, including chromosome somy, gene expression, and epigenetic differences that associate with disease outcome.  Experimental approaches will involve genetic manipulation of the parasite, DNA and RNAseq analysis, single cell genomics, and the application of various computational/bioinformatics methods developed to facilitate QTL and GWAS studies that identify linkage between genes and phenotypes. 

In this project you will use state-of-the-art viral sequencing data, combined with epidemiological data and mathematical modeling, to create an integrated understanding of HIV transmission. HIV places an enormous burden on global health. Implementing treatment and interventions can save millions of lives, but to do this effectively requires us to be able to predict the outcome of interventions, and to be able to accurately assess how well they are working once implemented. For HIV, these efforts are hampered by long durations of infections, and rapid within-host viral evolution during infection, meaning the virus an individual is infected with is unlikely to be the same as any viruses they go on to transmit.
 
For this project, you will identify individuals enrolled in the Rakai Community Cohort Project, based in Uganda, who are part of possible transmission chains, and for whom multiple blood samples are available throughout infection and at the time of transmission. These samples will be sequenced using state-of-the-art technology developed at the University of Oxford enabling the sequencing of thousands of whole virus genomes per sample, without the need to break the viral genomes into short fragments (whole-haplotype deep sequencing). Using this data, you will comprehensively characterize viral diversity during infection and at the point of transmission.

Key questions you will tackle are:
 
- Do ‘founder-like’ viruses (similar to those that initiated infection) persist during chronic infection?
- Is there a consistent pattern of evolution towards population consensus virus?
- Are ‘founder-like’ viruses, or ‘consensus-like’ viruses more likely to be transmitted?
- Does the transmission of drug-resistant virus depend on the history of the transmitting partner?

*This project is available for the 2021 Oxford-NIH Pilot Programme*

Understanding HIV incidence at a population level is critical for monitoring the epidemic and understanding the impact of interventions. Using full length sequencing of HIV we are developing models for estimating incidence based on viral diversity which increases with time in the infected host. Using data from longitudinal cohorts we will develop these models and then apply them to large population based interventions to determine their impact.  Experimental approaches include next-generation sequencing, phylogenetic analysis, modelling and statistical methodologies.

Study of the PTM and protein expression dynamics in the Toll-like receptor pathway. Because dynamic PTMs such as phosphorylation, ubiquitination, or glycosylation are essential for the regulation of cell signaling, it is crucial to quantitatively map the PTMs of proteins involved in signaling cascades. We use the data to model the signaling network changes and their impact on innate immunity.

The metabolic repertoire of immune cells – which encompasses metabolic enzymes/pathways, the available nutrient sensors and metabolic checkpoint kinases, and the epigenetic programming of metabolic genes – directly enables and modulates specific immune functions. Capitalizing on a large cohort of patients suffering from rare genetic immunodeficiency that have been whole-genome sequenced, our goal is to delineate the genetic and molecular basis of how cellular metabolism regulates immune-function in human health and disease states. Experimental approaches will involve genomics, molecular biology, cell biology, immunology, and biochemistry with an aim to elucidating mechanisms that lead to new treatment approaches to inborn diseases of immunity.

Malaria remains an important global health problem; with increasing drug resistance and the lack of an effective vaccine, new therapies are needed and should be based on a rigorous understanding of parasite biology. Our NIAID lab has used a multidisciplinary approach to discover and characterize the three known ion channels in bloodstream malaria parasites. Through academic and pharmaceutical collaborations, we have also found potent inhibitors that are being pursued as new antimalarial drugs. Research projects will be tailored to the interests of the trainee and expertise available in possible collaborator labs. These projects may utilize molecular biology including CRISPR and heterologous expression, structural biology including cryoEM, biochemical methods including electrophysiology, epigenetics, and high-throughput screening for drug discovery.  These and other methods are actively used in the lab. Dr. Desai has collaborators at Oxford, Cambridge, and Wellcome Sanger, depending on project.

The last decade has witnessed repeated emergence of RNA viruses with high pathogenic potential in humans including SARS-CoV-2, Zika virus, yellow fever virus and Ebola virus. The inflammatory response to infection is a major driver of pathogenesis, but the molecular mechanisms by which these viruses initiate and dysregulate inflammation are not well defined. Mitochondria are now recognized as critical regulators of the immune system and inflammation, serving as both signaling platforms and as sources of danger-associated molecular patterns (DAMPs) to initiate diverse signaling pathways. SARS-CoV-2, like other positive stranded RNA viruses, uses membranes derived from the ER for their replication factories, but also actively manipulates mitochondria, Golgi apparatus and other membrane bound organelles for replication purposes. However, it is unclear why mitochondria are hijacked during viral replication, and what the consequences of this manipulation are to inter-organelle communication and inflammation. This PhD project will use SARS-CoV-2 infection models in tissue culture and mouse models coupled to cutting-edge microscopy analysis to determine novel ways in which mitochondrial membrane remodelling and organelle contact sites are controlled, and the importance of these events as drivers of inflammation.

Hematopoiesis is a finely tuned process by which mature blood cells of multiple lineages are constantly generated throughout life from hematopoietic stem cells. In humans, definitive hematopoiesis commences in the fetal liver (FL) at around five weeks of gestation, and remains the main site of hematopoiesis throughout fetal life. Hematopoiesis in the bone marrow (BM) starts around 11-12 weeks of gestation, but does not take over as the primary site of hematopoiesis until just after birth. Recent evidence suggests that fetal hematopoiesis is distinct from postnatal hematopoiesis in many ways. Most of these studies have been done on mouse models, but whether these differences exist in, or are a true reflection of hematopoiesis in the human setting, remains to be determined. We, and others have begun to investigate unique features of human fetal hematopoiesis and this project will determine fetal specific programmes that change through ontogeny. This may depend on the physiological processes or demands of that particular developmental stage, and/or in response to specific microenvironmental cues. This research is clinically relevant since the transplantation of hematopoietic stem cells from donors of different ages vary in their regenerative and differentiation potential. Studying hematopoiesis throughout the human lifespan may be important not only to understand normal developmental processes, but also to understand the pathogenesis of postnatal haematological diseases that may have their origins in fetal life. Research by the Roy laboratory particularly focuses on properties of fetal cells that contribute to leukemia initiation in utero and how these might change after birth, and we have recently developed a unique infant acute lymphocytic leukemia (ALL) model. We are particularly interested in ‘oncofetal’ genes that might define the biology of infant and childhood leukemias; and whether they can be manipulated for therapeutic interventions.

*This project is available for the 2021 Oxford-NIH Pilot Programme*

Monoclonal antibodies have emerged in recent years as powerful tools to guide vaccine design and potentially to directly prevent infectious disease. Plasmodium falciparum, which causes malaria, is a relatively unexplored pathogen in this area, with only a few major vaccine candidates dominating the field despite the thousands of proteins expressed by the parasite. This project aims to isolate, characterize and determine the structures of human monoclonal antibodies against known and novel P. falciparum blood-stage antigens using cutting-edge technology. This collaborative project combines the expertise of the Tan lab in isolating human monoclonal antibodies against infectious pathogens and the expertise of the Higgins lab in solving crystal structures of antibody-antigen complexes to identify new sites of vulnerability on parasites at high resolution.

*This project is available for the 2021 Oxford-NIH Pilot Programme*

A previous infection with one of the four dengue viruses increases future risk of severe dengue disease, including hemorrhagic fever, upon infection with a different dengue virus. For this reason, dengue viruses 1-4 are challenging vaccine targets because sub-protective vaccines can increase risk the disease vaccines are designed to prevent. In the Viral Epidemiology and Immunity Unit (Chief, Dr. Katzelnick), we aim to identify correlates of natural and vaccine protection and antibody-dependent enhancement in order to develop better next generation vaccines, extend the longevity of vaccine-induced immunity, and characterize how vaccines may affect viral evolution and transmission.  Our work combines immunology, virology, and epidemiology, including close collaborations with research teams leading longitudinal cohort and vaccine studies in Nicaragua, Sri Lanka, Thailand, Ecuador, the Philippines, and other sites. Specific projects include studying quaternary ‘super-antibodies', which bind epitopes across viral envelope proteins, and testing whether these antibodies provide enduring protection against dengue and other viral diseases. We will also study antigenic evolution away from existing immunity for flaviviruses and coronaviruses. Dr. Katzelnick was part of the NIH OxCam program (2012-2016) and is open to collaborating with research groups at both Oxford and Cambridge to mentor Ph.D. students.