Long-term dysregulation of plasma peptidome in mild and multiple COVID-19 recovered patients revealed by a novel peptidomics workflow, 2024, Song+

[SNT Gatchaman]

Long-term dysregulation of plasma peptidome in mild and multiple COVID-19 recovered patients revealed by a novel efficient peptidomics workflow
Song, Zhijing; Liu, Chaoran; Liu, Yaozhou; Bian, Zheng; Sun, Qing; He, Ting; Su, Rong; Huang, Shengchun; Dai, Ningbin; Zhao, Ke li; Li, Yan; Liang, Kai

After recovering from COVID-19, many patients experience “long COVID” symptoms. Existing research has predominantly focused on moderate to severe cases, with limited studies examining mild cases and recurrent infections. The circulating low-molecular-weight (LMW) peptidome, involving lipid metabolism, coagulation, and immune pathways, is crucial for understanding COVID-19’s long-term effects.

We developed a peptidomics workflow utilizing solid-phase extraction with highly wrinkled GO-Fe3O4 composite materials (HWGO-F) and nanoLC-MS/MS detection. By altering the pH, HWGO-F enhances plasma peptide adsorption and purification. Compared to traditional methods, our workflow offers improved detection depth and reproducibility for over 70% of peptide signals with CV < 20%. We investigated plasma peptide profiles in mild COVID-19 patients post-recovery from single or second infections. The findings indicate persistent abnormalities in initial COVID-19 infections’ plasma peptide profiles, gradually diminishing over time. Secondary infections prolong recovery. Disrupted functions include lipid metabolism, coagulation and complement cascades, and infection-related pathways.

Lipid metabolism may normalize within 3 months, while coagulation and immune abnormalities can last 3–6 months. After secondary infections, lipid metabolism irregularities may last at least 1 month, with extended coagulation and immune imbalances. These results provide a theoretical foundation for understanding the widespread occurrence of long COVID and guide recovery care for mild cases.

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[SNT Gatchaman]

In this study, we collected plasma samples from patients who had recovered from their first and second mild COVID-19 infections at 1, 3, and 6 months post-recovery, with samples from uninfected individuals as healthy controls (HCs).

A total of 60 samples from participants without underlying diseases were prospectively enrolled, including 50 samples from RPs and 10 from HCs. All these patients diagnosed with COVID-19 were confirmed to be SARSCoV-2-positive infections through nucleic acid throat swabs or antigen tests during their illness and exhibited typical symptoms associated with mild COVID-19, such as fever, cough, sore throat, and fatigue. All participants recovered within a period of 7 to 14 days and subsequently tested negative for the virus using the same test.

Even post-recovery, a subset of patients continued to exhibit enduring symptoms such as cough and fatigue

Lipoproteins APOA-I, APOE, APOC-I, and APOC-III are related to cholesterol and lipid metabolism and transport, and their derived peptides showed a clear downward trend as the recovery period extends.[…] A possible explanation is the infection-induced elevation in the levels of matrix metalloproteinases (MMPs), which leads to extensive degradation of lipoproteins (MEROPS database), thereby causing an increase in lipoprotein-derived peptide levels. This condition gradually alleviates over 3 to 6 months post-recovery.

The peptide segments related to thrombin cleavage were significantly lower than the HCs in both the first and second infections during the 1–3 months after infection, and the recovery of these peptides was limited even at 6 months post-infection. This result suggests that thrombin activity likely decreases after infection, and its recovery is relatively slow. Another enzyme related to fibrinogen is plasmin. […] Contrary to thrombin cleavage, we found that the peptide sequences produced by plasmin cleavage were significantly higher than the HCs during the 1–6 months post-infection. This suggests that plasmin activity likely increases during the recovery period after infection.

Complement 3 (C3) is an important protein in the complement activation cascade. […] The decline of C3f is even more significant during the recovery period after a second infection. However, the signal of C3f in HCs is relatively high, almost close to the levels just after recovery from infection. This result suggests that the cleavage of C3 may be regulated by different mechanisms under infected and non-infected conditions.

We found that not only cholesterol metabolism, but also abnormalities in lipid and vitamin digestion and absorption also continue after recovery.

Changes in complement and coagulation functions are significant characteristic and risk factor of COVID-19 infection. Neutrophil extracellular traps enriched with complement factors are key influencers of immune thrombosis formation in COVID-19. Our results show that even in mild infections, abnormal regulation of complement and coagulation functions persists post-recovery, which may last for several months. During the entire recovery period we monitored, the products of fibrinogen cleaved by thrombin and plasmin showed significant changes, indicating that the balance of hemolysis and coagulation might still be disturbed to a certain extent after recovery.