Oxford Led Study Shows That Most Fatal COVID-19 Cases Are Due To Weak Immune Responses And Elevated MAIT Cell Activation
COVID-19 Mortality: A new research led by scientist from Oxford University-UK that also involved researchers from St. George’s University of London-UK, St. George’s Hospital NHS Trust-UK and the Massachusetts Institute of Technology-USA has found that most fatal COVID-19 cases are due to weak immune responses and elevated MAIT(elevated mucosal associated invariant) cell activation.
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The study team examined the immune abnormalities linked to critical illness and death in COVID-19 patients on ICU, performing immunophenotyping of viral antigen-specific and unconventional T cell responses, together with studies of neutralizing antibodies, and serum proteins.
The team compared these findings to a parallel set of patients with severe influenza.
Importantly From this screen the study team identified mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19. MAIT cell activation correlated with several other mortality-associated immunologic measures including elevated levels of cytokines and chemokines, such as GM-CSF and CXCL10.
MAIT cell activation is also a predictor of disease severity in influenza. Single-cell RNA-sequencing revealed a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 –a feature not observed in severe influenza.
Overall the study team observed key potential biomarkers and targetable pathways in critical viral illness, many shared between influenza and COVID-19 and some unique to each infection.
The study findings were published in the peer reviewed journal: PLOS Pathogens.
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009804
To date it has been found that the mortality rate of COVID-19 patients requiring mechanical ventilation is 30-40%, however, the immunological factors associated with death in critically ill COVID-19 patients are poorly understood.
The study findings suggest an association between systemic inflammation responses and increased mortality of COVID-19 patients.
Although antibodies and T cells play a critical role in protection from viral illness, however the exact role of T cell and antibody responses in SARS-CoV-2 infection is unclear.
In order to better understand the immune abnormalities linked to critical illness and death in COVID-19 patients on ICU, the study team conducted a prospective observational study investigating the association of T cell and antibody responses with fatal outcome in severe COVID-19.
The team analyzed serum samples from 41 mechanically ventilated COVID-19 patients, performing immunophenotyping of T cell responses and a range of experiments analyzing antibody responses. They then compared their findings to a parallel set of 18 mechanically ventilated influenza patients, as well as to 12 mild COVID-19 patients and 12 healthy controls.
The study team found that fatal COVID-19 infections were correlated with poorly coordinated systemic immune responses and elevated mucosal associated invariant (MAIT) cell activation were the strongest predict
or of a fatal outcome.
Mucosal associated invariant T cells (MAIT cells) make up a subset of T cells in the immune system that display innate, effector-like qualities. In humans, MAIT cells are found in the blood, liver, lungs, and mucosa, defending against microbial activity and infection. The MHC class I-like protein, MR1, is responsible for presenting bacterially-produced vitamin B2 and B9 metabolites to MAIT cells. After the presentation of foreign antigen by MR1, MAIT cells secrete pro-inflammatory cytokines and are capable of lysing bacterially-infected cells. MAIT cells can also be activated through MR1-independent signaling. In addition to possessing innate-like functions, this T cell subset supports the adaptive immune response and has a memory-like phenotype. Furthermore, MAIT cells are thought to play a role in autoimmune diseases, such as multiple sclerosis, arthritis and inflammatory bowel disease.
The
COVID-19 Mortality study was however limited in that it only analyzed samples in a cross sectional manner and did not observe how immune responses changed over the course of the infection.
More detailed future studies are needed to explain in depth how mortality-associated immune characteristics may develop over time.
Lead author Dr Jonathan Youngs from the Institute for Infection & Immunity, St. George’s University of London told Thailand Medical News, "Our study findings yield an enhanced understanding of the differential immunopathogenic processes driving critical COVID-19 and influenza, which can translate into improved immunotherapeutic approaches in patients with severe viral pneumonitis."
He further added, "In critically ill patients on ICU with COVID-19 and influenza, an unbiased analysis of the antiviral immune response revealed activation of a specific immune subset: Mucosal-associated invariant T (MAIT) cells as a strong immunological predictor of death. Survival in critical COVID-19 is associated with focused immune responses driven mainly by one cytokine ie interferon alpha in contrast to the very broad pro-inflammatory responses seen in those with fatal disease. This cytokine pattern linked to death versus survival separates critical COVID-19 from influenza."
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