Christopher Sundling

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.

Bakgrund: Tuberkulos (TB) är den bakteriella infektionssjukdom som dödar flest människor i världen varje år. Samtidigt är ca 25% av jordens befolkning infekterad av M. tuberculosis (Mtb), den patogen som leder till TB, och har därför risk att utveckla aktiv sjukdom. Nuvarande diagnostik bygger till stor del på odling eller PCR av bakterien i sputum vid aktiv sjukdom. Det kan dock vara svårt (speciellt för små barn) att producera sputum för diagnostik. Dessutom så begränsas diagnostiken av att metoderna inte lätt kan identifiera TB utanför lungorna. En annan typ av test går istället ut på att stimulera kroppens immunologiska minne mot Mtb för att bestämma om en person är, eller har varit exponerad. Metoden kan dock inte separera individer med aktiv TB mot de som har latent TB. Med en ambitiös målsättning från WHO att minska TB med 90% till 2030 behövs därför förbättrade metoder för identifikation av de med aktiv eller latent TB, samt de som är på väg att utveckla aktiv sjukdom. Målsättning: Genom att undersöka immunsvaret vid aktiv och latent TB vill vi identifiera nya markörer som kan användas till förbättrad TB diagnostik. Vi vill även undersöka vilka faktorer inom immunsvaret som ger upphov till kontroll av Mtb infektionen, vilket skulle kunna vägleda framtida vaccin-forskning. Arbetsplan: Vi använder flera olika metoder för bred karaktärisering av immunsvaret i blod hos individer med aktiv eller latent TB innan och efter stimulering med antigen från Mtb. Vi analyserar sedan datan bioinformatiskt för att identifiera molekyler och mekanismer associerade med patientstratifiering (t ex aktiv mot latent TB, eller nyligen smittad mot kontrollerad eller botad infektion). Vi kommer sedan att utvärdera metoderna i en stor prospektiv EDCTP- och VR-finansierad longitudinell studie där vi följer ca 2000 Mtb-exponerade individer i Afrika. Betydelse: Resistensutvecklingen hos Mtb och en lång behandlingsplan är problematiskt för en generell behandling av infekterade individer. För att nå WHO s mål om minskad TB globalt behövs därför bättre metoder för att identifiera personer med aktiv sjukdom samt de med risk att utveckla aktiv sjukdom.

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.