COVID-19 Research: Chinese Doctors Who Discovered SARS Identify New Biomarker For COVID-19 Disease Progression
: A new study led by Dr Nanshan Zhong and Dr Ling Chen of the National Clinical Research Center for Respiratory Disease in China and Dr Jian Han, Faculty Investigator at the Hudson Alpha Institute in Alabama and founder of iRepertoire have identified a potent biomarker for predicting COVID-19 disease progression.
The study team used sequencing to characterize the immune system of patients who survive from COVID-19 infection from symptom onset through recovery. Follow-up studies could lead to the development of a treatment for COVID-19 that is inspired by our own immune system.
The study team said in summary, ”Severe COVID-19 is associated with profound lymphopenia and an elevated neutrophil to lymphocyte ratio. The team applied a novel dimer avoidance multiplexed polymerase chain reaction next-generation sequencing assay to analyze T (TCR) and B cell receptor (BCR) repertoires. Surprisingly, TCR repertoires were markedly diminished during the early onset of severe disease but recovered during the convalescent stage. Monitoring TCR repertoires could serve as an indicative biomarker to predict disease progression and recovery. Panoramic concurrent assessment of BCR repertoires demonstrated isotype switching and a transient but dramatic early IgA expansion. Dominant B cell clonal expansion with decreased diversity occurred following recovery from infection. Profound changes in T cell homeostasis raise critical questions about the early events in COVID-19 infection and demonstrate that immune repertoire analysis is a promising method for evaluating emergent host immunity to SARS-CoV-2 viral infection, with great implications for assessing vaccination and other immunological therapies.”
The study findings were published in the journal: Frontiers in Immunology https://www.frontiersin.org/articles/10.3389/fimmu.2020.582010/full
Dr Nanshan Zhong is one of the doctors who first diagnosed SARS and was instrumental in treating and controlling the disease. Dr Jian Han was previously recognized for his work during the SARS outbreak, earning a Wall Street Journal Technology Innovation Award.
The doctors with their experience and collaborators have taken insights from SARS and used them to take an unprecedented approach to studying COVID-19.
According to the team, for emerging viruses with no vaccine, the only defense is the human immune system. This study provides an unprecedented level of insight into the immune cells of 23 COVID-19 patients over three different stages of the disease.
It is known that in order for our immune system to fight off a new infectious disease, it first has to learn to recognize it. That recognition is coordinated by a family of proteins called receptors that live on the surface of T cells and B cells.
To date, there are seven known types of T cell and B cell receptor proteins, called chains, two of which combine to form the receptors on the surface of each B or T cell. Each individual chain is made up of multiple different segments, enabling millions of different unique B and T cells in every person.
Whenever a new viral infection is introduced, the immune cells that recognize the invading vir
us multiply rapidly, causing a shift in the diversity of B and or T cells.
By detailed studies of an infected person's immune system fingerprint, known as the immune repertoire, we can gain insights into what kind of immune cells will be effective at fighting off the virus.
This new research captured, for the first time, the expansion and contraction of all seven chains in the immune repertoire. The study team discovered that early in COVID-19 infection, T cell discovery is significantly depleted. T cells recovered as patients improved, suggesting that the T cell repertoire might be an important marker for predicting disease progression.
It was found that for B cells, the chain composition of receptors can indicate whether the B cell has become "activated" by an infection. Activated B cells switch their chain type (from D/M to A/M, or G/M) and begin producing antibodies. Determining which specific chains are activated might help identify what antibodies will be effective in treating the infection.
Dr Chen and colleagues discovered that patients infected with COVID-19 exhibit a prominent expansion of their M- and G-type chains, followed by a later transition to A-type chains.
Dr Han told Thailand Medical News, "The next step is to isolate individual B cells that are exhibiting chain switching in order to identify the antibodies produced by patients who recover from infection. We are continuing this work at iRepertoire by performing network analysis on the B-cell data from these patients and identifying responding clones.”
He added, “We are also participating in a local study to use our single cell sequencing technology on samples from infected patients by directly identifying SARS-Cov-2-specific B-cells. Both methods can reveal the identity of neutralizing antibodies of therapeutic value."
Dr Miranda Byrne-Steele, Director of Research and Development at iRepertoire and an author on the paper commented, "What really makes this study interesting is that we profiled all seven chains of the immune repertoire at the same time. Most studies look at one or two chains at a time. By profiling all seven chains, we identified patterns that you wouldn't have noticed in a single chain study."
Those detailed immune patterns have potential clinical significance. For T-cells, the signature observed in patients that recover versus those that progress, could aid in the development of prognostic tests. Such tests might help identify which patients are likely to need or benefit from particular treatments. For B-cells, those that proliferate might point to antibodies that can themselves serve as potential treatments for people who are already infected, but not recovering.
The study team concluded, “Taken together, the results of this study provide a much more detailed view of the immune dynamics of COVID-19 patients. Global and longitudinal analyses of adaptive immunity in COVID-19 patients could provide insights onto the mechanisms of virus infection, providing information for assessment during clinical treatment and assisting in the development of antiviral therapeutics and vaccines.”
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