COVID-19 News: German Study Shows Inflammation-Driven Release Of Soluble HLA In COVID-19 Influences Immunopeptidome Diversity And T-Cell Immunity

COVID-19 News: A new study by researchers from the University of Tübingen and the University Hospital Tübingen - Germany has found that inflammation-driven release of soluble HLA (sHLA) in COVID-19 influences immunopeptidome diversity and T cell immunity!


 
Human leukocyte antigen or HLA-presented antigenic peptides are central components of T cell-based immunity in infectious disease.
 
Aside from HLA molecules on cell surfaces, soluble HLA molecules (sHLA) that are released in the blood also impact cellular immune responses.
 
The study team demonstrated that sHLA levels were significantly increased in COVID-19 patients and convalescent individuals compared to a control cohort and positively correlated with SARS-CoV-2-directed cellular immunity.
 
Importantly, past studies that were covered in various COVID-19 News coverages showed that patients with severe courses of COVID-19 had reduced sHLA levels.
 
Mass spectrometry-based characterization of sHLA-bound antigenic peptides, the so-called soluble immunopeptidome, revealed a COVID-19-associated increased diversity of HLA-presented peptides and identified a naturally presented SARS-CoV-2-derived peptide from the viral nucleoprotein in the plasma of COVID-19 patients.
 
It was also found that sHLA serum levels directly correlated with the diversity of the soluble immunopeptidome.
 
The study findings suggest an inflammation-driven release of sHLA in COVID-19, directly influencing the diversity of the soluble immunopeptidome with implications for SARS-CoV-2-directed T cell-based immunity and disease outcome.
 
The study findings were published in the peer reviewed journal: iScience.
https://www.cell.com/iscience/fulltext/S2589-0042(22)01915-0

The key findings of the study are:

-Soluble HLA serum levels are elevated in COVID-19 patients
 
-This is the first evidence for the association of sHLA with T cell immunity and disease outcome
 
-COVID-19-associated increased diversity in sHLA-presented peptides
 
-Identification of a nucleocapsid-derived sHLA-presented peptide from COVID-19 plasma
 
Numerous past studies have reported elevated levels of sHLA molecules in different pathologies, including infectious, malignant, and autoimmune diseases, and their association with disease severity or outcome.
 
The study team quantified total sHLA class I and -DR serum levels in COVID-19 patients, convalescent individuals and a cohort of healthy control donors showing elevated sHLA levels in COVID-19 patients compared to the control cohort.
 
The findings were in line with recently reported elevated levels of the non-classical sHLA-G in COVID-19 patients20,22.
https://pubmed.ncbi.nlm.nih.gov/34304938/
 
pe=check_update&version=2">https://www.mdpi.com/1422-0067/23/17/9736?type=check_update&version=2
 
It was also found that the amount of sHLA varied considerably among different individuals.
 
Importantly, sHLA class I levels even remained elevated in SARS-CoV-2 convalescents individuals up to six months after infection indicating long-term distorted sHLA release with elevated sHLA class I serum levels associated with persisting COVID-19 symptoms. Patients with post- or long-COVID syndrome suffer from a huge variety of different symptoms including fatigue, shortness of breath or cognitive dysfunction.
 
Initial evidence suggests that uncontrolled inflammation and autoimmunity plays a role in these patients.
https://pubmed.ncbi.nlm.nih.gov/36071155/
https://pesquisa.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/resource/pt/covidwho-2038618
 
It is assumed that in this context, sHLA serum levels might also be elevated in these patients, which would need to be further investigated in large cohort studies.
 
The study team further analyzed the soluble immunopeptidome of a COVID-19 and control cohort to characterize disease-associated alterations in the antigenic peptide repertoire carried by sHLA molecules.
 
An increased diversity of sHLA-presented peptides, attributable to a COVID-19 signature of related source proteins, was observed compared to the healthy control cohort independently of COVID-19-specific therapies. This indicates that the state of intracellular virus replication, inflammation, and immune activation in COVID-19 is directly mirrored in the soluble immunopeptidome.
 
Interestingly, no direct influence on antigen presentation of COVID-19-specific therapies remdesivir and dexamethasone was observed.
 
It should be noted that the study findings demonstrate a direct correlation of sHLA class I serum levels with the diversity of the soluble immunopeptidome

The study team was also able to detect a naturally in vivo presented SARS-CoV-2-derived peptide from the nucleoprotein within the soluble plasma of a COVID-19 patient.
 
Thus far, the identification of naturally presented SARS-CoV-2-derived HLA peptides was limited to immunopeptidomics approaches that use artificial systems with in vitro infected, protein-loaded or protein-overexpressed cells.


Graohical Abstract
 
A key factor for the detection of in vivo presented SARS-CoV-2-derived HLA ligands might be the timepoint of sample collection after infection, which might explain the low frequent detection of SARS-CoV-2-derived peptides within the study cohort, in which the samples were collected several days after infection.
 
A previous study detected SARS-CoV-2-derived HLA peptides in cell lines 3 to 24 hours post infection with a peak of viral peptides at 6 hours indicating rapid HLA presentation of virus-derived peptides that decreases over time.
https://pubmed.ncbi.nlm.nih.gov/34171305/
 
Also, the cells that are primarily targeted by SARS-CoV-2 are not well exposed to the plasma, which might impede the release of sHLA molecules carrying virus-derived peptides by these cells in the plasma.
https://pubmed.ncbi.nlm.nih.gov/34003804/
 
However, especially sHLA class II molecules might not be derived from the SARS-CoV-2 target cells directly, but from antigenpresenting cells and are therefore more reliable to detect within the plasma of the patients.
 
The study team however emphasized that absence of evidence does not equal evidence of absence as the sensitivity of shotgun mass spectrometric discovery approaches, even in the context of immense technical improvements in the last decades, remains for sure limited as the immunopeptidome is a highly dynamic, rich, and complex assembly of peptides.
 
Importantly, the detection of the nucleoprotein-derived peptide within the soluble immunopeptidome proves the soluble immunopeptidome as an interesting and so far under-investigated source for the detection of in vivo presented virus-derived HLA-presented peptides.
 
Interestingly, for tumor patients the soluble immunopeptidome was previously described as a source for the detection of tumor-associated antigens presented by sHLA molecules, which might serve as potential biomarkers.
https://pubmed.ncbi.nlm.nih.gov/20974924/
 
https://pubmed.ncbi.nlm.nih.gov/27862975/
 
The study findings demonstrated elevated sHLA class Iand -DR serum levels in COVID-19 representing a highly diverse and disease-associated soluble immunopeptidome reflecting ongoing SARS-CoV-2-induced inflammation.
 
The findings also demonstrated the association of long-term elevated sHLA class I serum levels with persisting COVID-19 symptoms.
 
The study findings further provided evidence for a positive correlation of anti-SARS-CoV-2-specific T cell responses with sHLA class I levels suggesting a positive role of sHLA molecules for anti-viral cellular immunity and T cell activation.
 
It should be noted that the induction of a potent SARS-CoV-2-directed T cell responses is essential to prevent severe courses of COVID-19.
 
Significantly, patients with critical illness, in terms of required invasive ventilation, exhibited conspicuous low sHLA class I levels.
 
The study teams says that future large cohort studies are needed to further delineate and characterize the functional role of sHLA for T cell immunity and COVID-19 outcome.
 
In conclusion, the study findings indicate an inflammation-driven higher release of sHLA molecules in COVID-19, which directly influence the diversity of the soluble immunopeptidome and positively modulate anti-SARS-CoV-2 cellular immunity.
 
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