Preprint Antibody repertoire associated with clinically diverse presentations of pediatric SARS-CoV-2 infection, 2025, Bruiners et al.

[SNT Gatchaman]

Antibody repertoire associated with clinically diverse presentations of pediatric SARS-CoV-2 infection

Spoiler: Authors

Natalie Bruiners; Rahul Ukey; Katherine C Konvinse; Marlayna Harris; Muge Kalaycioglu; Jason H Yang; Emily Yang; Usha Ganapathi; William Honnen; Tracy Andrews; Benjamin Richlin; Christian Suarez; Sunanda Gaur; Elizabeth Ricciardi; Uzma N Hasan; William Cuddy; Aalok R Singh; Hulya Bukulmez; David C Kaelber; Yukiko Kimura; Abraham Pinter; Stacey Napoli; Sandra Moroso-Fela; Lawrence C Kleinman; Daniel B Horton; Paul J Utz; Maria Laura Gennaro

Pediatric SARS-CoV-2 infection results in clinical presentations ranging from asymptomatic/mild infection to severe pulmonary COVID-19, to Multisystem Inflammatory Syndrome in Children (MIS-C), characterized by hyperinflammation and multi-organ involvement. While various aspects of antibody responses to pediatric SARS-CoV-2 infection manifestations have been reported, parallel studies of antibody responses to viral and self-antigens are understudied.

We tested whether clinical presentations of increasing severity corresponded to different antiviral antibody and autoantibody signatures. Using custom arrays, we found that, relative to uninfected subjects, all SARS-CoV-2 infection manifestations were associated with increased autoantibody production, suggesting pediatric SARS-CoV-2 infection as a risk factor for autoimmune complications. Subtle differences were seen in autoantibody patterns among infection groups, with some autoantibodies more associated with mild manifestations and others with severe ones.

When we compared MIS-C and severe COVID-19 subjects, we found differences in IgG (mostly IgG1) abundance but not in Fc-mediated effector functions. Thus, MIS-C may be associated with abnormal antibody function, suggesting that this syndrome, and perhaps other post-acute sequelae of SARS-CoV-2 infection, may be associated with antibody dysfunction.

Our study shows that the antibody repertoire varies with clinical presentation of SARS-CoV-2 in children and its analysis may help understand long COVID pathogenesis.

Web | PDF | Preprint: MedRxiv | Open Access

 

[SNT Gatchaman]

Interestingly, we also observed that IgG antibodies against Bcl-2 interacting protein 3 (BNIP3), a protein involved in cell death […] were higher in HCs relative to all infected groups

Noting in reference to the DecodeME thread —

FBXL4 regulates mitophagy, which is a process where surplus, aged or damaged mitochondria are degraded.

When FBXL4 is absent, the levels of BNIP3 and NIX raise and hyperactive mitophagy results. Loss-of-function mutations in FBXL4 are known to cause mitochondrial DNA depletion syndrome 13.

In DecodeME, the FBXL4 variant that was associated with ME/CFS was rs97984426. I couldn't find information on whether it would lead to icreased or decreased mitophagy.

It appears that FBXL4 loss is deleterious to mitochondrial function

A 'surplus' in mitophagy taking out mildly damaged mitochondria can over time lead to decreased numbers of mitochondria. Moreover, mildly damaged mitochondria are still producing energy which is why in classical mitochondrial disease treament isn't as 'straightforward' as improving mitophagy.

My question would be could Covid infections impair/reduce regulatory autoantibodies against BNIP3 that are present in HCs, so that loss-of-function of FBXL4 and now loss of anti-BNIP3 AAbs leads to a rise in BNIP3 above threshold. More mitophagy -> decreased mitochondrial biomass.

Systrom (IIMEC17)—

"It may, potentially, if it holds up be somewhat unique to ME and long Covid. And that what we find is an index of mitochondrial biomass, which is the citrate synthase function. It's a marker of the number of mitochondria or biomass of mitochondria in the muscle. And it's decreased overall."