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The Dysregulation of the Monocyte-Dendritic Cell Interplay Is Associated with In-Hospital Mortality in COVID-19
Domenico Galati1, Domenico Mallardo2, Carmine Nicastro3
1Hematology-Oncology and Stem Cell Transplantation Unit, Department of Hematology and Innovative Diagnostics, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy.
Abstract:
Background: The monocyte-phagocyte system (MPS), including monocytes/macrophages and dendritic cells (DCs), plays a key role in anti-viral immunity. We aimed to analyze the prognostic value of the MPS components on in-hospital mortality in a cohort of 58 patients (M/F; mean age ± SD years) with COVID-19 pneumonia and 22 age- and sex-matched healthy controls. Methods: We measured frequencies and absolute numbers of peripheral blood CD169+ monocytes, conventional CD1c+ and CD141+ (namely cDC2 and cDC1), and plasmacytoid CD303+ DCs by means of multi-parametric flow cytometry. A gene profile analysis of 770 immune-inflammatory-related human genes and 20 SARS-CoV-2 genes was also performed. Results: Median frequencies and absolute counts of CD169-expressing monocytes were significantly higher in COVID-19 patients than in controls (p 0.04 and p 0.01, respectively). Conversely, percentages and absolute numbers of all DC subsets were markedly depleted in patients (p < 0.0001). COVID-19 cases with absolute counts of CD169+ monocytes above the median value of 114.68/μL had significantly higher in-hospital mortality (HR 4.96; 95% CI: 1.42-17.27; p = 0.02). Interleukin (IL)-6 concentrations were significantly increased in COVID-19 patients (p < 0.0001 vs. controls), and negatively correlated with the absolute counts of circulating CD1c+ cDC2 (r = -0.29, p = 0.034) and CD303+ pDC (r = -0.29, p = 0.036) subsets. Viral genes were upregulated in patients with worse outcomes along with inflammatory mediators such as interleukin (IL)-1 beta, tumor necrosis-α (TNF-α) and the anticoagulant protein (PROS1). Conversely, surviving patients had upregulated genes related to inflammatory and anti-viral-related pathways along with the T cell membrane molecule CD4. Conclusions: Our results suggest that the dysregulated interplay between the different components of the MPS along with the imbalance between viral gene expression and host anti-viral immunity negatively impacts COVID-19 outcomes. Although the clinical scenario of COVID-19 has changed over time, a deepening of its pathogenesis remains a priority in clinical and experimental research.
Insights
Elevated CD169-expressing monocytes in COVID-19 patients correlate with higher mortality. Dendritic cell depletion and immune dysregulation impact COVID-19 outcomes, highlighting the need for further pathogenesis research.
Area of Science:
- Immunology
- Virology
- Critical Care Medicine
Background:
- The monocyte-phagocyte system (MPS), comprising monocytes/macrophages and dendritic cells (DCs), is crucial for anti-viral immunity.
- COVID-19 pneumonia presents a significant challenge, necessitating an understanding of immune system involvement in disease severity and mortality.
Purpose of the Study:
- To investigate the prognostic significance of monocyte-phagocyte system components in predicting in-hospital mortality among COVID-19 pneumonia patients.
- To analyze the relationship between specific immune cell subsets, viral gene expression, and clinical outcomes in COVID-19.
Main Methods:
- Multi-parametric flow cytometry was used to quantify peripheral blood CD169+ monocytes, CD1c+ (cDC2), CD141+ (cDC1), and CD303+ (pDC) dendritic cells.
- Gene expression profiling was conducted for immune-inflammatory and SARS-CoV-2 related genes.
- Statistical analysis compared immune cell counts and gene profiles between COVID-19 patients and healthy controls, and correlated findings with mortality.
Main Results:
- COVID-19 patients exhibited significantly higher frequencies and counts of CD169+ monocytes compared to controls.
- All dendritic cell subsets (cDC1, cDC2, pDC) were markedly depleted in COVID-19 patients.
- Higher CD169+ monocyte counts were associated with significantly increased in-hospital mortality (HR 4.96). Elevated IL-6 levels correlated with reduced cDC2 and pDC counts. Worse outcomes were linked to upregulated viral genes and inflammatory mediators, while survivors showed enhanced anti-viral and inflammatory gene expression.
Conclusions:
- The study suggests that a dysregulated monocyte-phagocyte system and an imbalance between viral gene expression and host anti-viral responses negatively influence COVID-19 outcomes.
- Understanding the complex pathogenesis of COVID-19, despite evolving clinical scenarios, remains critical for both clinical and experimental research.
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