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A unique dysregulation pattern of lipid metabolism and immune responses in patients with omicron SARS-CoV-2 recurrence

The occurrence of re-positive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in discharged patients infected with Omicron is common. But, the potential nature of host response in these patients remains unknown. Here,

The occurrence of re-positive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in discharged patients infected with Omicron is common. But, the potential nature of host response in these patients remains unknown. Here, we report a unique host response pattern through mass spectrometry-based proteomics from patients with Omicron SARS-CoV-2 recurred positive (Omi-Rec) after discharge.
In this study, proteomic experiments were conducted at the Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University (Zhejiang, Southeast China). The experimental details are described in the Supplementary materials. This study was approved by the Institutional Review Board of Xixi Hospital. Informed consent was waived because of the retrospective nature of this study.
A total of 12 patients who recovered from Omicron infection were enrolled for subsequent analysis, 8 patients maintained negative SARS-CoV-2 RNA after discharge (Omi-Neg group) and 4 were SARS-CoV-2 RNA re-positive patients after discharge from the hospital (Omi-Rec group). As shown in Supplementary Table S1, there were no significant differences in all baseline characteristics between Omi-Rec cases and Omi-Neg controls on admission. But, significant differences were observed in 40 circulating proteins between the two groups (fold-change >1.2 and P-values <0.05; Figure 1a and b). Principal component analysis (PCA) showed that dysregulated proteomes of each group clustered tightly apart from each other (Figure 1c), consolidating that these 40 proteins well resolved Omi-Rec and Omi-Neg types.
Submitted: 10 July 2022 V C The Author(s) 2022. Published by Oxford University Press on behalf of the Association of Physicians. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Of note, the Omi-Rec showed enriched lipid metabolism and immune-related pathways, including Cholesterol metabolism, Peroxisome proliferators-activatedreceptor (PPAR) signaling pathway, Vitamin digestion and absorption, Fat digestion and absorption, Intestinal immune network for IgA production, Tuberculosis, Inflammatory bowel disease, Leishmaniasis, Antigen processing and presentation, Th1 and Th2 cell differentiation, Rheumatoid arthritis, Th17 cell differentiation, HIF-1 signaling pathway, Toxoplasmosis, Lysosome and Phagosome (Figure 1d). This indicates lipid metabolism disturbance and immune dysregulation in Omi-Rec patients.
The Omi-Rec patients showed four significantly downregulated proteins related to metabolism pathways, including Apolipoprotein A-I (APOA1), Apolipoprotein A-II (APOA2), Phospholipid transfer protein (PLTP) and Apolipoprotein A-IV (APOA4) compared to Omi-Neg patients (Figure 1e). Some recent studies have reported that patients with diverse infections, such as Epstein-Barr virus, cytomegalovirus and tuberculosis, had lower levels of lipoproteins in comparison with noninfected individuals. [1][2][3] In the research by Vignesh et al., 4 lower lipid was also observed in COVID-19 patients compared to uninfected controls. Consistent with these reports, our research revealed the reduced lipoprotein pattern in Omi-Rec patients and highlights the important role of lipid metabolism in SARS-CoV-2 shedding.
In addition to the downregulation pattern of lipid metabolism, our proteomic analysis also exhibited significant dysregulation of immune-related proteins, including HLA class II histocompatibility antigen, DR alpha chain (HLA-DRA), Cathepsin S (CTSS), Hexokinase-3 (HK3), Arylsulfatase G (ARSG) and Transferrin (TF) in Omi-Rec cases. The proteins of HLA-DRA, 5 ARSG 6 and CTSS 7 guide antibody-mediated immune response, lysosome and macrophage activation, to ultimately eliminate the infectious agents. Interestingly, our data showed the reduction of the three proteins in the pathway of Antigen processing and presentation, Lysosome and Phagosome, suggesting that the primary immune responses were suppressed in Omi-Rec patients. Apart from these proteins, we also observed marked alterations of TF and HK3 in the HIF-1 signaling pathway. These observations are consistent with a recent proteotranscriptomics study reporting a dysregulation of the HIF-1 signaling pathway in SARS-CoV-2 infected cells. 8 Our study has limitations. The inherent shortcomings due to the small sample size make it difficult to reach a firm conclusion. Future analyses of larger cohorts are needed to systematically investigate the entire landscape of Omi-Rec host responses.
Currently, the re-positivity of Omicron SARS-CoV-2 tests is widely reported. However, the mechanism leading to these repositive cases is still unclear. 9 From this current study, our proteomic analysis demonstrated a unique pattern of lipid metabolism and immune response in Omi-Rec patients, which might spur further interest in exploring the association of lipid levels with inflammation in Omi-Rec patients and identifying a possible molecular link between lipoprotein metabolism, immune regulation and SARS-CoV-2 re-positive. The significant dysregulation proteins presented in our study may be valuable potential targets for identifying or treating Omicron-infected patients' re-positive episodes.

Supplementary material
Supplementary material is available at QJMED online.