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

[SNT Gatchaman]

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)

 

[Hoopoe]

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.

 

[SNT Gatchaman]

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

We have shown that inborn errors of type I interferon (IFN) immunity and their phenocopies — autoantibodies against type I IFNs — collectively underlie at least 15% of cases of critical COVID-19 pneumonia in unvaccinated patients.

multisystem inflammatory syndrome in children (MIS-C), occurs predominantly in children, typically 4 weeks after infection. Its prevalence is estimated at about 1 per 10,000 infected children

Children with MIS-C do not suffer from hypoxemic pneumonia and typically display no detectable viral infection of the upper respiratory tract at disease onset.

Initial reports of MIS-C described it as an atypical form of Kawasaki disease (KD), as its clinical features included fever, rash, abdominal pain, myocarditis, lymphadenopathy, coronary aneurysm, and elevated biological markers of acute inflammation.

The elevated markers frequently detected in MIS-C patients suggest that inflammation occurs in various organs. These include surrogates of cardiovascular endothelial injury [e.g., troponin and B-type natriuretic peptide (BNP)] and gastrointestinal epithelial injury [e.g., LPS-binding protein (LBP) and soluble CD14]. Various leukocyte subsets are also affected.

Sustained monocyte activation has been consistently reported as a key immunological feature of MIS-C, with high levels of pro-inflammatory markers, including ferritin, IL-1RA, IL-6, IL-10, IL-18, MCP1 (CCL2), and TNF.

An immunological phenotype unique to MIS-C, observed in ~75% of patients, is the polyclonal expansion of CD4+ and CD8+ T cells bearing the Vβ21.3 segment.

We hypothesized that monogenic inborn errors of immunity (IEI) to SARS-CoV-2 may underlie MIS-C in some children and that the identification of these inborn errors may clarify the molecular, cellular, and immunological basis of disease.

 

[SNT Gatchaman]

• 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

 

[SNT Gatchaman]

Selected abridged quotes, from the discussion —

OAS–RNase L–deficient monocytic cell lines, monocyte-derived dendritic cells [...], and primary monocytes from patients displayed excessive inflammatory responses to intracellular dsRNA, SARS-CoV-2, SARS-CoV-2–infected cells, and their RNA, providing a plausible mechanism for MIS-C.

In these patients, MIS-C may result primarily from an excessive response of monocytes [...] to SARS-CoV-2 dsRNA intermediates or by-products, followed by the presentation of a viral superantigen to T cells, resulting in the activation and expansion of Vβ21.3+ CD4+ and CD8+ T cells.

The SARS-CoV-2–related RNA products that trigger phagocyte activation, the viral superantigen(s) that activate T cells, and the HLA restriction elements all remain to be discovered.

MIS-C in other patients may result from [Inborn Errors of Immunity] that may or may not be related to the OAS–RNase L pathway. Our findings also suggest that other forms of [Kawasaki disease] may be caused by other virus-specific IEI in other patients.

The notion that the OAS–RNase L pathway is essential for antiviral immunity in mononuclear phagocytic cells was first proposed nearly 40 years ago.

Intriguingly, the OAS–RNase L pathway is apparently dispensable for protective immunity to SARS-CoV-2 in the respiratory tract. Indeed, none of the five MIS-C patients had a pulmonary phenotype, and no viral replication was detectable in the upper respiratory tract of any of the five children at the onset of MIS-C.

Our finding that the human OAS–RNase L pathway is crucial for regulation of the mononuclear phagocyte response to SARS-CoV-2, but not for SARS-CoV-2 restriction in the respiratory tract, suggests that the main protective action of this pathway is mediated by the control of phagocyte-driven systemic inflammation at a later stage of disease rather than viral restriction in the respiratory tract early on.

Our data suggest that human OAS1, OAS2, and RNase L are each essential for the correct regulation of immunity to SARS-CoV-2, but otherwise largely redundant in natural conditions of infection. It is also clear that the RNase L-dependent functions of OAS1 and OAS2 are crucial for the regulation of immunity to SARS-CoV-2 within the same cells, as the genetic deficiency of any of these three components results in the same immunological and clinical phenotype, namely MIS-C.

 

[SNT Gatchaman]

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).

 

[SNT Gatchaman]

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

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."