Host Genetics and Antiviral Immune Responses in Adult Patients With Multisystem Inflammatory Syndrome

Abstract

COVID-19 associated multisystem inflammatory syndrome (MIS) is a rare condition mostly affecting children but also adults (MIS-A). Although severe systemic inflammation and multiorgan dysfunction are hallmarks of the syndrome, the underlying pathogenesis is unclear. We aimed to provide novel immunological and genetic descriptions of MIS-A patients. Cytokine responses (IL-6, IL-1β, TNFα, CXCL10, type I, II and III interferons) following SARS-CoV-2 infection of peripheral blood mononuclear cells in vitro were analyzed as well as antibodies against IFNα and IFNω (by ELISA) in patients and healthy controls. We also performed whole exome sequencing (WES) of patient DNA. A total of five patients (ages 19, 23, 33, 38, 50 years) were included. The patients shared characteristic features, although organ involvement and the time course of disease varied slightly. SARS-CoV-2 in vitro infection of patient PBMCs revealed impaired type I and III interferon responses and reduced CXCL10 expression, whereas production of proinflammatory cytokines were less affected, compared to healthy controls. Presence of interferon autoantibodies was not detected. Whole exome sequencing analysis of patient DNA revealed 12 rare potentially disease-causing variants in genes related to autophagy, classical Kawasaki disease, restriction factors and immune responses. In conclusion, we observed an impaired production of type I and III interferons in response to SARS-CoV-2 infection and detected several rare potentially disease-causing gene variants potentially contributing to MIS-A.

Keywords: SARS-CoV-2; coronavirus disease 2019; interferon; multisystem inflammatory syndrome; whole exome sequencing.

Figure 1

Disease course and organ manifestations. ICU, intensive care unit; IVIG, intravenous immunoglobulin; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 2

Antiviral and inflammatory responses of patient PBMCs in response to SARS-CoV-2 infection. (A–H) Patient (P1-P5), healthy controls (HC) (n=5) and COVID-19 intensive care unit (ICU) patient (COVID-19) (n=9) peripheral blood mononuclear cells were left untreated (UT) or infected with SARS-CoV-2 at a multiplicity of infection of 0.5 for 24 h. Induction of IFNs and proinflammatory cytokines was measured in supernatants by U-plex mesoscale technology. Data are pooled from two independent experiments, but the experiment was performed only once for each patient due to limited patient material. All stimulations were done in triplicate in the individual experiments. (I) Autoantibodies against IFNα and IFNω measured in serum from patients, healthy controls (n=15) and COVID-19 ICU patients (n=13) by ELISA, y-axis depicts blank-corrected OD450-630. Values above 0.5 (dashed line) are considered positive. Statistical differences were calculated using Kruskal-Wallis with correction for multiple comparisons by Dunn’s test. *p < 0.05, **p < 0.01, ***p < 0.001. Each line, showing the result of a statistical test, compares one patient with the HC or the COVID-19 ICU group. Only comparisons between patient and controls, which are statistically different, are indicated on the graph.