Unvaccinated individuals exhibit significant clinical variability during primary infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic . In particular, common genetic factors serve as modest risk factors for disease progression. For example, about 15% of critical cases of COVID-19 among unvaccinated patients have been associated with innate errors of immunity involving type I interferon (IFN) and its phenocopies (type I IFN autoantibodies).
Study: In simple terms, MIS-C is the manifestation of a strong response of monocytes or other mononuclear phagocytes to SARS-CoV-2 dsRNA intermediates. Image credit: NIAID
background
It has been documented that children are rarely affected by COVID-19. However, a small percentage, i.e. 1 in 10,000 infected children, develop multisystem inflammatory syndrome in children (MIS-C), a serious disease. MIS-C usually develops four weeks after infection.
During the initial phase of the disease, children with MIS-C usually do not have viral upper respiratory tract infection or symptoms related to hypoxemic pneumonia. Most patients with MIS-C test positive for anti-SARS-CoV-2 antibodies. Clinical features of MIS-C in children include rash, coronary aneurysm, elevated biomarkers of acute inflammation, abdominal pain, fever, myocarditis, and lymphadenopathy. These patients also develop inflammation in various organs.
Elevated levels of biological markers such as LPS-binding protein (LBP) and soluble CD14 indicate gastrointestinal epithelial injury, and troponin and B-type natriuretic peptide (BNP) determine cardiovascular endothelial injury. Persistent monocyte activation is a crucial immunological feature of MIS-C.
Children with MIS-C showed increased proinflammatory markers (eg, IL-18, IL-6, MCP1 (CCL2), ferritin, TNF, and IL-1RA). In addition, IFN-type II (IFN-γ) signaling biomarkers were observed to increase during the early phase of infection. About 75% of patients had an immunological phenotype unique to MIS-C, that is, polyclonal expansion of CD4+ and CD8+ T cells carrying the Vβ21.3 segment. Although several cellular, molecular, and clinical aspects of MIS-C have been discovered, the underlying cause of this disease remains unclear.
A recent study in the journal Science determined the underlying cause of SARS-CoV-2-related MIS-C in some children. He hypothesized that monogenic innate errors of immunity (IEIs) are the main reason for this condition. It is hoped that the identification of these inborn errors will help elucidate the cellular, molecular and immunological basis of the disease.
About the study
A total of 558 patients with MIS-C (60.4% boys and 39.6% girls) were enrolled in this study. Participants come from Europe, Asia, Africa and America. Five MIS-C patients were selected from the study cohort and designated as P1 (Philippines), P2 (Spain), P3 (Turkey), P4 (Turkey), and P5 (Canada). Among these five patients, two were boys and three were girls aged between 3 months and 14 years at the time of diagnosis.
The biomarkers present in these patients indicated the severity of the disease. P1, P3 and P4 were associated with severe MIS-C infection, where P1 contained an OAS1 mutation, leading to a coronary aneurysm. P3 (OAS2) and P4 (OAS2) were associated with myocarditis and polyneuropathy, respectively. In particular, P2 containing the OAS2 mutation and P5 with RNASEL showed milder symptoms of MIS-C.
Results of the study
Elevated levels of soluble CD25, IFN-γ, MCP1 (CCL2), IL-1RA, and IL-18 were observed at P1, P2, and P5 during cytokine profiling. This finding was in line with previous reports on the immune profiles of children with MIS-C.
mRNA sequencing (RNAseq) of blood samples collected from P1 and P2 indicated unique transcriptomic signatures that differed from the healthy control group and children with acute COVID-19 pneumonia. However, these transcriptomic signatures were found to be similar to previously reported MIS-C patients.
In particular, autosomal recessive (AR) deficiencies of OAS1, OAS2, and RNASEL were determined as genetic etiologies of MIS-C at P1–P5. OAS-RNase L-deficient monocytic cell lines and primary monocytes identified from patients with increased inflammatory responses to intracellular dsRNA, SARS-CoV-2-infected cells, SARS-CoV-2 and the their RNA, could be the possible underlying mechanisms for MIS -C.
Simply put, MIS-C is the manifestation of a strong response of monocytes or other mononuclear phagocytes to SARS-CoV-2 dsRNA intermediates. Subsequently, the presence of a viral superantigen against T cells induces the activation and expansion of Vβ21.3+ CD4+ and CD8+ T cells.
The current study revealed that IEIs, which may or may not be related to the OAS-RNase L pathway, may drive MIS-C in children. However, the human OAS-RNase L pathway was found to be extremely important for regulating the mononuclear phagocyte response to SARS-CoV-2, but not for the restriction of SARS-CoV-2 to the respiratory tract. This finding indicates that phagocyte-driven systemic inflammation regulates the key protective function of this pathway at a later stage of disease rather than viral airway restriction.
In summary, human OAS1, OAS2, and RNase L play important roles in the proper regulation of the immune response to SARS-CoV-2 infection. Genetic deficiency of any of these three components drives MIS-C in children.
Future perspectives
SARS-CoV-2-related RNA products that induce phagocyte activation, HLA restriction elements, and viral superantigens that activate T cells need to be determined in the future. should study the effect of AR OAS-RNase L deficiency on antiviral responses in cells of other tissues injured during MIS-C (eg, endothelial cells, enterocytes, and cardiomyocytes).