Immune and metabolic perturbations in COVID-19-associated pulmonary mucormycosis: A transcriptome analysis of innate immune cells
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Published on: February 28, 2021
Manpreet Dhaliwal1, Valliappan Muthu2, Arunima Sharma3
1Department of Paediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Background And Objectives:
The mechanisms underlying COVID-19-associated pulmonary mucormycosis (CAPM) remain unclear. We use a transcriptomic analysis of the innate immune cells to investigate the host immune and metabolic response pathways in patients with CAPM.
Patients And Methods:
We enrolled subjects with CAPM (n = 5), pulmonary mucormycosis (PM) without COVID-19 (n = 5), COVID-19 (without mucormycosis, n = 5), healthy controls (n = 5) without comorbid illness and negative for SARS-CoV-2. Peripheral blood samples from cases were collected before initiating antifungal therapy, and neutrophils and monocytes were isolated. RNA sequencing was performed using Illumina HiSeqX from monocytes and neutrophils. Raw reads were aligned with HISAT-2 pipeline and DESeq2 was used for differential gene expression. Gene ontology (GO) and metabolic pathway analysis were performed using Shiny GO application and R packages (ggplot2, Pathview).
Results:
The derangement of core immune and metabolic responses in CAPM patients was noted. Pattern recognition receptors, dectin-2, MCL, FcRγ receptors and CLEC-2, were upregulated, but signalling pathways such as JAK-STAT, IL-17 and CARD-9 were downregulated; mTOR and MAP-kinase signalling were elevated in monocytes from CAPM patients. The complement receptors, NETosis, and pro-inflammatory responses, such as S100A8/A9, lipocalin and MMP9, were elevated. The major metabolic pathways of glucose metabolism-glycolysis/gluconeogenesis, pentose phosphate pathway, HIF signalling and iron metabolism-ferroptosis were also upregulated in CAPM.
Conclusions:
We identified significant alterations in the metabolic pathways possibly leading to cellular iron overload and a hyperglycaemic state. Immune responses revealed altered recognition, signalling, effector functions and a pro-inflammatory state in monocytes and neutrophils from CAPM patients.
Insights
COVID-19-associated pulmonary mucormycosis (CAPM) involves altered immune and metabolic pathways. Transcriptomic analysis reveals dysregulated immune cell responses and upregulated metabolic pathways, potentially causing iron overload and hyperglycemia in CAPM patients.
Area of Science:
- Immunology
- Infectious Diseases
- Metabolomics
Background:
- Mechanisms of COVID-19-associated pulmonary mucormycosis (CAPM) are not fully understood.
- Investigating host immune and metabolic responses in CAPM is crucial.
Purpose of the Study:
- To elucidate the host immune and metabolic pathways in CAPM using transcriptomic analysis of innate immune cells.
- To compare immune and metabolic profiles of CAPM patients with COVID-19 patients and healthy controls.
Main Methods:
- Transcriptomic analysis of neutrophils and monocytes from CAPM patients, COVID-19 patients, and healthy controls.
- RNA sequencing and differential gene expression analysis using HISAT-2 and DESeq2.
- Gene ontology and metabolic pathway analysis using Shiny GO and R packages.
Main Results:
- CAPM patients exhibited dysregulated immune responses, including altered pattern recognition receptor signaling and downregulated JAK-STAT/IL-17 pathways.
- Elevated mTOR and MAP-kinase signaling were observed in monocytes from CAPM patients.
- Upregulated metabolic pathways in CAPM included glycolysis, pentose phosphate pathway, HIF signaling, and iron metabolism (ferroptosis).
Conclusions:
- Significant alterations in metabolic pathways suggest a potential for cellular iron overload and hyperglycemia in CAPM.
- Immune responses in CAPM patients show altered recognition, signaling, effector functions, and a pro-inflammatory state in monocytes and neutrophils.
