Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4–6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. We apply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C.

Highlights d An ordered sequence of immune changes after birth driven by microbial interactions d Lack of gut bifidobacteria and HMO-utilization genes correlates with systemic inflammation d Feeding B. infantis EVC001 upregulates IFNb and silences intestinal Th2 and Th17 d EVC001-associated indole-3-lactic acid upregulates inhibitory galectin-1 in T cells

Summary Severe disease of SARS-CoV-2 is characterized by vigorous inflammatory responses in the lung, often with a sudden onset after 5–7 days of stable disease. Efforts to modulate this hyperinflammation and the associated acute respiratory distress syndrome rely on the unraveling of the immune cell interactions and cytokines that drive such responses. Given that every patient is captured at different stages of infection, longitudinal monitoring of the immune response is critical and systems-level analyses are required to capture cellular interactions. Here, we report on a systems-level blood immunomonitoring study of 37 adult patients diagnosed with COVID-19 and followed with up to 14 blood samples from acute to recovery phases of the disease. We describe an IFNγ-eosinophil axis activated before lung hyperinflammation and changes in cell-cell co-regulation during different stages of the disease. We also map an immune trajectory during recovery that is shared among patients with severe COVID-19.

Immune-microbe interactions early in life influence an individual's risk of developing allergies, asthma and some autoimmune disorders. Breastfeeding helps guide the development of healthy immune-microbe relationships, in part by providing nutrients to specialized microbes that in turn benefit the host and its developing immune system. Such bacteria having co-evolved with humans are associated with reduced risks of immune mediated diseases but are increasingly rare in modern societies. Here we map an immunological sequence of events, triggered by microbial colonization that distinguish children with different gut bacterial composition. Lack of bifidobacterial species is associated with elevated markers of intestinal inflammation and immune dysregulation and in a randomized trial of breastfed infants, the infant-adapted Bifidobacterium infantis EVC001 silenced intestinal Th2 and Th17 immune responses, while inducing IFN􀁅, and its metabolites skew T-cell polarization in vitro, from Th2 towards Th1, suggesting a healthier immune imprinting during the first critical months of life.

The immune response to SARS-CoV2 is under intense investigation, but not fully understood att this moment. Severe disease is characterized by vigorous inflammatory responses in the lung, often with a sudden onset after 5-7 days of stable disease. Efforts to modulate this hyperinflammation and the associated acute respiratory distress syndrome, rely on the unraveling of the immune cell interactions and cytokines that drive such responses. Systems-level analyses are required to simultaneously capture all immune cell populations and the many protein mediators by which cells communicate. Since every patient analyzed will be captured at different stages of his or her infection, longitudinal monitoring of the immune response is critical. Here we report on a systems-level blood immunomonitoring study of 39 adult patients, hospitalized with severe COVID-19 and followed with up to 14 blood samples from acute to recovery phases of the disease. We describe an IFNg-Eosinophil axis activated prior to lung hyperinflammation and changes in cell-cell coregulation during different stages of the disease. We also map an immune trajectory during recovery that is shared among patients with severe COVID-19.

SARS-CoV2 infection is typically very mild and often asymptomatic in children. A complication is the rare Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever and organ dysfunction and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. We apply systems-level analyses of blood immune cells, cytokines and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV2 and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, is more similar to Kawasaki disease, but also differ from this with respect to T-cell subsets, IL-17A and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests endoglin, an endothelial glycoprotein as one of several candidate targets of autoantibodies in MIS-C.

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