Key Points
- Profiling patient serum using HuProt™, a human proteome microarray containing over 21,000+ full-length human proteins, facilitated the detection of autoantibodies linked to neurological symptoms in a subset of patients with long COVID.
- Passive transfer of purified IgG from patients to healthy mice revealed that patient autoantibodies were sufficient to recreate neurological symptoms, suggesting that they may play a role in driving these symptoms in long COVID and could be useful in the diagnosis and treatment of autoantibody-mediated long COVID endotypes.
What is Driving the Development of Long COVID?
Despite its prevalence, the precise mechanisms driving the development of long COVID after infection with SARS-CoV-2 are not well understood. Recently, researchers at Yale and the Icahn School of Medicine investigated the role of autoantibodies in the development of neurological symptoms associated with long COVID. Through immunofluorescence staining, they first examined the reactivity of patient IgG against various tissues and discovered selective reactivity with neural tissues. Reactivity across different neural tissues was consistent with the neurological symptoms observed.
HuProt™ Used to Screen Patient Plasma
To identify autoantibody targets in long COVID, researchers employed HuProt human proteome microarrays, which contain over 21,000+ unique full-length human proteins, to screen patient plasma. This experiment identified diverse autoantibody profiles with increased autoreactivity to common autoantigens and neurological targets compared to healthy controls. Following validation through mass spectrometry and ELISA, the proteins USP5 and MED20 emerged as top hits from the screen. These proteins have previously been implicated in chronic pain and neurological disorders, respectively, which is highly concordant with symptoms reported in long COVID.
HuProt™ Identifies Autoimmune Targets
The identification of USP5 and MED20 as hits through screening with HuProt highlights the power of unbiased, high-throughput screening across the human proteome to enable the detection of previously unrecognized autoimmune targets with potential clinical relevance. Notably, these hits were only observed in a subset of patients, reflecting the diversity of patient autoantibody profiles and the range of symptoms associated with the condition.
GRAPHS: ELISA and Area Under Curve (AUC) analysis for MED20 and USP5, the top targets identified through HuProt. MED20 and USP5 positive participants showed IgG reactivity in ELISA across a serial dilution of the autoantigens.
Further experiments involving passive transfer of purified IgG from long COVID patients to healthy mice were able to recapitulate neurological symptoms of long COVID, including increased sensitivity to pain and loss of coordination, underscoring their potential role in the neurological manifestations of the disease. Additional research is essential to explore the full impact of autoantibodies in long COVID, as these findings suggest they could be important in symptom development and progression. To this end, HuProt™ can serve as an invaluable tool in identifying autoimmune targets, offering a pathway for more precise diagnostic and therapeutic strategies for diseases like long COVID.
FIGURE AND GRAPHS CREDIT: "A causal link between autoantibodies and neurological symptoms in long COVID" - Keyla Santos Guedes de Sa1, et. al. medRxiv 2024.
REFERENCE
De Sa KS, Silva J, Bayarri-Olmos R, et al. A causal link between autoantibodies and neurological symptoms in long COVID. medRxiv. 2024; https://doi.org/10.1101/2024.06.18.24309100