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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.

Research problem and overall purpose

COVID-19 has affected more than 2.4 million persons in Sweden. Some have a prolonged course after initial disease with debilitating symptoms

Post-Acute COVID-19 Syndrome (PACS). The overall purpose of the research project is to characterise PACS patients regarding severity of residual symptoms, objectively analyse functional and patophysiological impairment in affected organs and explore underlying immunomechanistic causes.Relevance Investigating longterm PACS effects and increase the understanding of the various phenotypes and underlying mechanisms will generate effective ways to inform on novel treatment strategies and better protocols for clinical follow-up and design interventions for prevention. Data and methods In-depth phenotyping is generated from our post-COVID outpatient clinic with regular monitoring of previously hospitalized patients with initial severe Covid-19 and non-hospitalized PACS patients. A cohort of age and sex matched  COVID-19 patients without PACS  constitute a control group. We will perform systems-level analyses of blood immune cells, plasma proteins and bio-energetic measurements of blood cells in combination with whole genome sequencing from patients with severe PACS.Plan for project realization Abundant phenotypic patient data is now available for analysis as well as blood samples for immuno-mechanistic analysis. In depth studies of pulmonary, cardiovascular and other long term complications are ongoing.

Post covid condition (PCC) affects approximately 10% of people infected with SARS-CoV-2. With half a billion confirmed COVID-19 cases globally, the magnitude of the expected Post COVID healthcare problem is enormous. No treatment options to date have shown efficacy.We hypothesize that part of PCC is a chronic inflammation involving the endothelium started by COVID-19 and treatable by the anti-inflammatory effects of hyperbaric oxygen (HBO2). HBO2 delivered by inhalation of 100% oxygen in a hyperbaric chamber in daily treatments over several weeks, has several anti-inflammatory effects. It is used for chronic inflammatory conditions such as osteomyelitis, radiation cystitis and acute flares of ulcerative colitis. The purpose of this proposal is to investigate biomarkers, epigenetic signatures and response to HBO2 in a clinical trial that may explain mechanisms of the post COVID condition and enable future precision medicine.Aims: To investigate biomarkers, redox-balance and epigenetic profile of patients with PCCTo determine the efficacy of HBOT on endothelial dysfunction, objective physical performance, autonomic dysfunction, restorative sleep.To investigate if the effect of HBOT in PCC in a clinical trial correlates with age, gender and epigenetic signatures. Preliminary results from our clinical trial on 31 acute covid-19 indicates effect from HBO but treatment may need individual tailoring. To date we have treated 20 PCC patients, aiming for a total of 80 participants.

We have recently discovered three cardiovascular phenotypes in post covid: Postural orthostatic tachycardia syndrome (POTS), unspecific sinus tachycardia and cardiac microvascular dysfunction. The pathophysiology and optimal treatment strategies for these remain unknown. The overall aim is to characterize several biological aspects of the cardiovascular phenotypes to identify pathophysiological mechanisms (identifying novel therapeutic targets) and to conduct a series proof-of-concept randomized, placebo-controlled, double-blind, clinical trials (RCTs) using available interventions targeting putative mechanisms.Patients will be included from the post covid clinic at Karolinska University Hospital and the study will run 2022-2025. In collaboration with several experts at Karolinska University Hospital and nationally, stress-perfusion cardiac magnetic resonance imaging (microvascular dysfunction), endothelial function studies and advanced assessment of dysautonomias (e.g. POTS) will be performed. Protein- and lipid biomarkers (proteomics and lipidomics

mass spectrometry) will be analyzed. In parallel, proof-of-concept RCT using drugs with documented effect in similar diseases will be conducted. These RCTs will then serve as a foundation for future clinical studies targeting discovered mechanisms. The result from this study may lead to rapid implementation of evidence-based treatment and discoveries of novel therapeutic targets in a large and underserved patient population.

Since the inception of the SARS-CoV-2 pandemic, the focus of authorities and healthcare providers has been on reducing the mortality acute, severe form of COVID-19. While the mortality rate of individuals affected by severe COVID-19 has been relatively high, they have made up a small proportion of those infected. A much larger group of severely affected individuals has instead emerged: those with persistent disease. It is important to highlight that the majority of long-COVID patients do not consist of individuals with prolonged recovery after hospitalization, but instead constitute a completely different phenotype of the disease, in a different demographic group. While those requiring hospital care are largely elderly or multi-morbid individuals, the majority of long-COVID patients are formerly young, mentally and physically strong individuals who due to mild initial symptoms generally did not seek hospital care. Here we will develop a home monitoring system to facilitate continuous follow-up of long-COVID patients. Identification of daily fluctuations, activity and physiological parameters will help identify sub-groups of the disease, with specific emphasis on those with lung involvement. Associated molecular biomarkers will be evaluated using our systems medicine workflow both in lung samples collected with bronchoscopy, and in a non-invasive fashion using PExA. The fully developed system will also be used to evaluate the effectiveness of various forms of treatment.