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Tuberculosis (TB) is the infectious disease that annually claims most lives worldwide. A contributing factor is its global spread, with approximately 25% of the world's population estimated to have been infected by M. tuberculosis (Mtb), causing TB. As carriers of Mtb, individuals are at risk of developing active disease throughout their lives, although it typically occurs within two years after infection. However, the majority of those infected never develop TB, indicating that most individuals exposed develop an immune response capable of controlling the infection. Currently, little is known about how this protection operates. By investigating the immune response in individuals at various stages of Mtb infection and TB disease and in different tissues, we aim to identify biological markers and mechanisms associated with infection control and disease progression. We employ several omics-based methods for broad and in-depth characterization of the immune response. We then integrate and analyze the data bioinformatically to identify overarching biological patterns associated with patient stratification. These findings are further mechanistically investigated using frozen cells from our patient cohorts as well as through cell models. These findings can be utilized to develop novel TB diagnostics that detect the disease at an earlier stage, as well as to understand the mechanisms underlying protection, which can guide future vaccine and treatment research.

Upon repeated or chronic infection, the immune system can be trained to decrease its inflammatory response. These changes enable some pathogens, such as malaria and tuberculosis to co-exist with the host with minimal impact on the host’s health. In this project, our overall aim is to study how the immune system adapts to and controls infection without leading to symptomatic disease. We have established unique cohorts of individuals with either clinical or asymptomatic malaria and clinical or asymptomatic tuberculosis. We will investigate these cohorts at an integrated systems level, cellular level, and molecular level. Our systems immunology approach includes integrating proteomic data from plasma with transcriptomic, phenotypic, and functional peripheral blood cell data and identifying differences associated with symptomatic or asymptomatic infection. We will then assess the effect of the inflammatory response on the B cell compartment, including CD11c+ B cell differentiation and antibody production. Antibody-NK cell interplay will then be evaluated functionally at bulk and single-cell resolution. Finally, we will investigate the role of individual transcription factors and cellular proteins in B cells and monocytes responding to infection or in vitro stimulation. Collectively, these experiments will improve our understanding of tolerance at the whole immune system level, the cellular level, and the molecular level.

Malaria is a potentially severe and fatal infection in non-immune individuals. An efficacious vaccine is urgently needed. Vaccine design is challenged by strain-specific immunity and extensive diversity of many of the potential vaccine targets, as well as how protection can be maintained. The aim of this project is to improve the understanding the naturally acquired immunity to malaria to guide vaccine development, focusing on antigen diversity and maintenance of immunity. The project will explore the antigen diversity of highly polymorphic merozoite surface proteins, in relation to immune responses and their role in protection. A newly developed sequencing method will allow characterization of antigen diversity across geographical areas, and the design of a peptide microarray that will be used to investigate the breadth, magnitude and cross-reactivity of antibody responses. In addition, monoclonal antibodies will be isolated to investigate whether increasing breadth of antibody responses is a result of increased breadth of individual antibody lineages or acquisition of new antibody specificities. Maintenance of immunity and memory B cell responses will be studied using a newly developed multiplex B cell FluoroSpot method. Studies are performed in on longitudinal cohort in malaria endemic areas , as well as travellers and migrants in a non-endemic setting. The overall aim is to contribute to the development of an efficacious multicomponent vaccine against malaria.