key: cord-1012201-nrrl4kjc
authors: Rivas, Magali Noval; Porritt, Rebecca A.; Cheng, Mary Hongying; Bahar, Ivet; Arditi, Moshe
title: COVID-19 Associated Multisystem Inflammatory Syndrome in Children (MIS-C): a novel disease that mimics Toxic Shock Syndrome. The superantigen hypothesis
date: 2020-10-16
journal: J Allergy Clin Immunol
DOI: 10.1016/j.jaci.2020.10.008
sha: 7a11eb64020481c37525cc86cf9f3bd0d79e7516
doc_id: 1012201
cord_uid: nrrl4kjc

nan

As of mid-September, the novel severe acute respiratory syndrome coronavirus 2 26 (SARS-CoV-2) has infected more than 30 million people, resulting in approximately one 27 million deaths worldwide, including over 200,000 deaths in the USA alone. Fever, dry 28 cough, breathing difficulties and gastrointestinal (GI) symptoms are typical features of 29 coronavirus disease-2019 . Although 80% of infected people develop a mild 30 disease, approximately 20% progress to severe COVID-19, which is associated with 31 lung damage and breathing difficulties, and may lead to respiratory failure and death. 32

Exacerbation of the COVID-19 immune response manifested by extensive cytokines 33 release, called cytokine storm, may lead to multisystem inflammatory syndrome that is 34 fatal in 28% of cases 1 . Children can also be infected with SARS-CoV-2 (<2%), however 35 the majority of confirmed pediatric cases have a less severe outcome and milder 36

In late April, 2020, reports from Europe described the emergence of a new febrile 38 pediatric entity that involved persistent fever, systemic hyperinflammation, multiorgan 39 involvement with prominent and severe GI symptoms, and cardiogenic shock and 40 hypotension, requiring pediatric ICU care in the majority of cases. Some who developed 41 this syndrome, referred to as COVID-19-associated Multisystem Inflammatory which are all very rare in KD 2 . In addition, the overall clinical picture of MIS-C is similar 55 in many respects to the late, severe COVID-19 phase in adults, which is characterized 56 by a cytokine storm, hyperinflammation, and multiorgan damage, and often includes 57 severe myocarditis and acute kidney injury, and laboratory and clinical features of TSS 4 . 58

A causal link between SARS-CoV-2 infection and MIS-C has not yet been clearly 59 established, however, many MIS-C patients were reportedly exposed to someone 60 known or suspected to have COVID-19. Although only around a third of MIS-C patients 61 are positive for SARS-CoV-2 by PCR, a large majority are PCR-negative but positive 62 serologically for SARS-CoV-2 antibodies and/or have a history of mild COVID-19 63 infection or exposure several weeks before presentation. Such timing suggests that 64 MIS-C is a post-infectious disease or immune or autoimmune disease. Moreover, the 65 virus may still be present in the GI tract of these patients, as they demonstrate very 66 severe GI symptoms. 67

Through structure-based computational modeling, we discovered that the SARS-68

CoV-2 S gene encodes a high-affinity SAg-like sequence motif near the S1/S2 cleavage adult COVID-19 patients 9 . The pathologic mechanisms leading to these symptoms 93 remain unknown. Interestingly, SAg-induced TSS has been associated with long-term 94 neuropsychologic deficits in adults, including cognitive decline 10 , and we identified a 95 homology between the SAg motif of SARS-CoV-2 and neurotoxin-like sequences which 96 are able to bind the TCR 5 . Notably, SARS-CoV-2 spike contain other neurotoxin-like 97 motifs as well, including in particular the segment T299-Y351 which has been recently 98 observed to be a highly cross-reactive epitope that triggers CD4 + T cell response 5 . It 99 will be interesting to determine whether these neurotoxin-like sequences in the SARS-100

CoV-2 S protein contribute to the neurological manifestations observed in children with 101

Why only a small fraction of SARS-CoV-2 infected children develop MIS-C 103 remains unclear. It is possible that a poor initial antibody response to the virus in a 104 subset of children fails to produce neutralizing antibodies, leading to immune 105 enhancement following SARS-CoV-2 re-exposure. Alternatively, some human leukocyte 106 antigen (HLA) types may be more permissive, and respond more robustly to certain viral 107 antigenic structures 5 . Indeed, among the reported cases from London 2 , 50% of MIS-C 108 patients were of Afro-Caribbean descent, which suggests a possible genetic component 109

for MIS-C susceptibility. 110

Finally, our findings suggest that immunomodulatory therapeutic approaches 111 used for TSS, such as IVIG and steroids, may also be effective for MIS-C. Indeed, most 112 MIS-C patients respond well to intravenous immunoglobulin (IVIG; 2 gm/kg) and aspirin, 113 with or without steroids 3 . Given the structural similarities between SEB and the SARS-114 J o u r n a l P r e -p r o o f CoV-2 S protein SAg motif 5 , it is possible that antibodies within IVIG that neutralize 115 SEB cross-react with SARS-CoV-2 S, which may in part explain the beneficial response 116

of MIS-C cases to IVIG. In addition, in the mouse model of TSS, lethal SEB 117 superantigen challenge can be prevented by short peptide mimetics of the SAg motif 6 . 118

Therefore, it would be important to investigate the therapeutic potential of peptide 119 mimetics of SARS-CoV-2 spike SAg-like region in COVID-19-induced 120 hyperinflammatory syndromes in future studies. Further elucidation of the parameters 121 affecting the interaction between SARS-CoV-2 S glycoprotein and immune cells will be 122 necessary to design effective preventive and therapeutic interventions. 123 124

We gratefully acknowledge support from NIH awards P41 GM103712 (to IB) and R01 126 AI072726 (to MA). 127  TABLE 1 

The trinity of COVID-19: immunity, 129 inflammation and intervention

Clinical 131 Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome 132 Temporally Associated With SARS-CoV-2

Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy 135 Children and Adolescents in New York City

Novel paediatric 137 presentation of COVID-19 with ARDS and cytokine storm syndrome without respiratory 138 symptoms

Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed 141 TCR repertoire in patients with hyperinflammation

Binding of superantigen 143 toxins into the CD28 homodimer interface is essential for induction of cytokine genes 144 that mediate lethal shock

The Immunology 146 of Multisystem Inflammatory Syndrome in Children with COVID-19

Engagement of MHC class II molecules by staphylococcal 148 superantigens activates src-type protein tyrosine kinases

Neurological 150 associations of COVID-19

Persistent 152 neuropsychological sequelae of toxic shock syndrome