Machine learning of flow cytometry data reveals the delayed innate immune responses correlate with the severity of COVID-19

Front Immunol. 2023 Jan 26:14:974343. doi: 10.3389/fimmu.2023.974343. eCollection 2023.

Abstract

Introduction: The COVID-19 pandemic has posed a major burden on healthcare and economic systems across the globe for over 3 years. Even though vaccines are available, the pathogenesis is still unclear. Multiple studies have indicated heterogeneity of immune responses to SARS-CoV-2, and potentially distinct patient immune types that might be related to disease features. However, those conclusions are mainly inferred by comparing the differences of pathological features between moderate and severe patients, some immunological features may be subjectively overlooked.

Methods: In this study, the relevance scores(RS), reflecting which features play a more critical role in the decision-making process, between immunological features and the COVID-19 severity are objectively calculated through neural network, where the input features include the immune cell counts and the activation marker concentrations of particular cell, and these quantified characteristic data are robustly generated by processing flow cytometry data sets containing the peripheral blood information of COVID-19 patients through PhenoGraph algorithm.

Results: Specifically, the RS between immune cell counts and COVID-19 severity with time indicated that the innate immune responses in severe patients are delayed at the early stage, and the continuous decrease of classical monocytes in peripherial blood is significantly associated with the severity of disease. The RS between activation marker concentrations and COVID-19 severity suggested that the down-regulation of IFN-γ in classical monocytes, Treg, CD8 T cells, and the not down-regulation of IL_17a in classical monocytes, Tregs are highly correlated with the occurrence of severe disease. Finally, a concise dynamic model of immune responses in COVID-19 patients was generalized.

Discussion: These results suggest that the delayed innate immune responses in the early stage, and the abnormal expression of IL-17a and IFN-γ in classical monocytes, Tregs, and CD8 T cells are primarily responsible for the severity of COVID-19.

Keywords: COVID-19; delayed innate immune responses; dynamics model; neural network; relevance scores.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19*
  • Flow Cytometry
  • Humans
  • Immunity, Innate
  • Machine Learning
  • Pandemics
  • SARS-CoV-2

Grants and funding

This work is supported by grants from the National Nature Science Foundation of China (Grant No. 82173388, 32070662, 61832019, 32030063), the Key Research Area Grant 2016YFA0501703 of the Ministry of Science and Technology of China, the Science and Technology Commission of Shanghai Municipality (Grant No.: 19430750600), as well as SJTU JiRLMDS Joint Research Fund and Joint Research Funds for Medical and Engineering and Scientific Research at Shanghai Jiao Tong University (YG2021ZD02).