Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children, 2022, Lee et 100 al

Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children

Spoiler: 101 Authors

Lee D, Le Pen J, Yatim A, Dong B, Aquino Y, Ogishi M, Pescarmona R, Talouarn E, Rinchai D, Zhang P, Perret M, Liu Z, Jordan I, Elmas Bozdemir S, Bayhan GI, Beaufils C, Bizien L, Bisiaux A, Lei W, Hasan M, Chen J, Gaughan C, Asthana A, Libri V, Luna JM, Jaffré F, Hoffmann HH, Michailidis E, Moreews M, Seeleuthner Y, Bilguvar K, Mane S, Flores C, Zhang Y, Arias AA, Bailey R, Schlüter A, Milisavljevic B, Bigio B, Le Voyer T, Materna M, Gervais A, Moncada-Velez M, Pala F, Lazarov T, Levy R, Neehus AL, Rosain J, Peel J, Chan YH, Morin MP, Pino-Ramirez RM, Belkaya S, Lorenzo L, Anton J, Delafontaine S, Toubiana J, Bajolle F, Fumadó V, DeDiego ML, Fidouh N, Rozenberg F, Pérez-Tur J, Chen S, Evans T, Geissmann F, Lebon P, Weiss SR, Bonnet D, Duval X; CoV-Contact Cohort§, Covid HGE, Pan-Hammarström Q, Planas AM, Meyts I, Haerynck F, Pujol A, Sancho-Shimizu V, Dalgard C, Bustamante J, Puel A, Boisson-Dupuis S, Boisson B, Maniatis T, Zhang Q, Bastard P, Notarangelo L, Béziat V, Perez de Diego R, Rodriguez-Gallego C, Su HC, Lifton RP, Jouanguy E, Cobat A, Alsina L, Keles S, Haddad E, Abel L, Belot A, Quintana-Murci L, Rice CM, Silverman RH, Zhang SY, Casanova JL.

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic dsRNA-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the ssRNA-degrading RNase L. Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNASEL deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or SARS-CoV-2 stimulation. Exogenous 2-5A suppresses cytokine production in OAS1- but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by MAVS deficiency.

Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.

Link | PubMed | PDF (Science)

 

Fascinating. My impression from studying genetics as amateur is that what looks like a hyperinflammatory disease on the outside often has at its basis an immune deficiency and this appears to be the case here as well.

It sounds like this is big news for many patients, not just the ones with MIS-C but also those with Kawasaki disease.

 

Selected abridged quotes, with added links, from the introduction —

 

• OAS1 - 2'-5'-oligoadenylate synthetase 1
• OAS2 - 2'-5'-oligoadenylate synthetase 2
• RNase L - Ribonuclease L (latent) or 2'-5' oligoadenylate synthetase-dependent ribonuclease: interferon-induced destructor of RNA
• MAVS - Mitochondrial antiviral-signaling protein

 

Selected abridged quotes, from the discussion —

 

See also

• Polyclonal expansion of TCR Vb 21.3+ CD4+ and CD8+ T cells is a hallmark of multisystem inflammatory syndrome in children (May 2021).

 

Yes I agree this could be very important in our understanding of KD. Not out of the question that LC (±ME) have a similar explanation. I'm thinking of my own (retrospectively likely) asymptomatic COVID infection, together with all the stories of apparently spontaneous development of ME that are then breathlessly misattributed to various psychosocial explanations*.

An inborn error of immunity that may not negatively affect the acute handling of viral infection but then may leave the system in some form of immune dysregulation would also be unlikely to significantly affect reproductive fitness. Potentially these or similar mutations might not be uncommon. GWAS studies important to help answer these sorts of questions. [ETA: to be clear of course MIS-C is rare enough for this IEI explanation, while LC is certainly not rare so much more likely to be a different mechanism.]

* "A little more psychology and a little less T cells would be welcome."