COVID-19 Research: Longitudinal Analysis Of PBMC Proteomics Reveals Metabolic Alterations In COVID-19
Study Finds SARS-CoV-2 Infections Causes Switch From Oxidative Phosphorylation To Glycolysis With Enriched Pentose Phosphate Pathway Abundance
: The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has brought the world to a standstill, impacting millions of lives across the globe. One of the defining characteristics of this disease is its diverse clinical presentation, ranging from asymptomatic or mild cases to severe and critical illness. Even after recovery, some individuals continue to experience lingering symptoms, a condition often referred to as long COVID. Understanding the underlying biological processes that govern these variations in disease progression is of paramount importance.
To gain insight into the intricacies of COVID-19 progression, a new study conducted by researchers at the Universidade Federal de São Paulo in Brazil delved into the realm of proteomics. Instead of focusing solely on plasma, serum, or bronchoalveolar lavage fluid, which have been the primary subjects of previous research, this study explored the alterations in peripheral blood mononuclear cells (PBMCs) in COVID-19 patients. These cells encompass a variety of immune cell types, providing a more comprehensive overview of the host immune system's response to the virus.
The COVID-19 Research
study aimed to shed light on the changes in the cellular proteome over time by collecting samples at distinct stages of the disease, including hospital admission, after 7 days of hospitalization, and 30 days after discharge. The findings from this study could potentially uncover critical insights into the pathophysiology of COVID-19 and inform future treatment strategies.
Clinical and Epidemiological Features
The study encompassed 29 patients with COVID-19 who were admitted to hospital wards and exhibited varying clinical outcomes. The patients had an average age of 69 years, with the majority being male. The average duration of symptoms before hospital admission was approximately 6.7 days, with common symptoms including fever, cough, shortness of breath, and diarrhea. The average length of hospitalization was 19.1 days.
Of the 29 patients, 12 progressed to critical illness, while 17 showed clinical recovery. Notably, at the time of the first sampling (D0), all patients were admitted to the ward, with a subset requiring supplementary oxygen. By the time of the second sampling (D7), some patients had been admitted to the ICU.
Tragically, three patients did not su
rvive their hospitalization. It's crucial to highlight that patients with deteriorating clinical courses exhibited elevated levels of key markers such as neutrophils, neutrophil-lymphocyte ratio, creatinine, and C-reactive protein compared to patients with clinical recovery and shorter hospital stays.
Metabolic Shifts in COVID-19
The study employed a tandem mass tag (TMT)-based quantitative proteomic approach to investigate the presence of altered proteins associated with various dysregulated pathways and biological processes in COVID-19 patients. One of the most striking findings was the broad dysregulation of proteins related to metabolic machinery, which could either signify an antiviral response or viral-induced disruption of host transcripts and translation.
These findings align with previous research that has reported altered metabolic pathways during SARS-CoV-2 infection. Specifically, the study revealed a shift from oxidative phosphorylation (OXPHOS) to glycolysis at D0 and D7, resembling the Warburg effect. This shift plays a crucial role in supporting defense mechanisms against bacterial and viral infections, such as enhanced phagocytosis and antimicrobial responses.
Metabolic pathways related to fatty acid metabolism, OXPHOS, glucose metabolism disorder, and insulin resistance remained altered throughout the hospital stay and even after hospital discharge. Key proteins involved in the TCA cycle and mitochondrial electron transport chain were found to be in low abundance 30 days post-discharge, consistent with previous reports on the long-term effects of COVID-19, characterized by mitochondrial dysfunction and chronic inflammation.
Furthermore, critically ill patients displayed distinct metabolic pathway alterations compared to non-critically ill patients, with non-critical patients showing increased protein abundance in glucose and pentose phosphate pathway (PPP) pathways. The increase in PPP-related proteins was associated with the generation of necessary intermediates for critical cellular functions, including phagocytosis and antimicrobial responses.
On the other hand, critical patients exhibited decreased PPP-related proteins, potentially leading to oxidative damage, cell apoptosis, and inflammatory cytokine release. This observation concurs with previous reports linking PPP-related protein deficiencies to poor outcomes in COVID-19 patients.
Temporal Analysis and Neutrophil-Related Processes
The study also delved into temporal proteomic changes, revealing distinct pathways in critically ill and non-critically ill patients. Specifically, cluster analysis identified clusters enriched in splicing processes and cap processing, with rising protein abundance during follow-up. This pattern was consistent for the entire patient cohort.
In contrast, another cluster related to protein metabolism, including eukaryotic translation elongation and peptide chain elongation, exhibited differences between critical and non-critical patients. Non-critical patients displayed sustained high protein abundance in this cluster, reminiscent of "host-shutoff," a phenomenon linked to viral takeover of host gene expression and protein synthesis.
Notably, the study also identified proteins enriched for neutrophil-related processes, such as azurophilic granule proteins, neutrophil elastase, and neutrophil collagenase. This suggests the presence of low-density neutrophils (LDNs) co-purified with PBMCs, which are associated with various functions, including increased ROS production, heightened phagocytic capacity, neutrophil extracellular trap formation, and suppression of T-cell function. The increase in LDNs may be linked to the severity of infectious diseases like COVID-19 and sepsis.
In conclusion, this longitudinal study of PBMC proteomics in COVID-19 patients has unveiled critical insights into the disease's pathophysiology and progression. The observed metabolic shifts, including the transition from oxidative phosphorylation to glycolysis, provide valuable information about the host's response to the virus and its implications for the immune system.
Moreover, the differences in metabolic pathways between critically ill and non-critically ill patients underscore the significance of tailored therapeutic interventions. The persistence of altered protein abundance even after hospital discharge highlights the potential long-term consequences of COVID-19.
This study emphasizes the importance of longitudinal cellular proteomic research in uncovering disease progression-related pathways and persistent protein changes, ultimately contributing to our understanding of COVID-19 and the development of more effective treatments. As the pandemic continues to evolve, ongoing research in this field remains crucial for mitigating the impact of the virus on global health.
The study findings were published in the peer reviewed journal: iScience.
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