A Rare STXBP2 Mutation in Severe COVID-19 and Secondary Cytokine Storm Syndrome.

Daniel D Reiff,Emily A Smitherman,Mingce Zhang,Peter Weiser,Melissa L Mannion,Randy Q Cron,Matthew L Stoll

doi:10.3390/life12020149

Daniel D Reiff, Emily A Smitherman + Show 5 more

Open Access

https://doi.org/10.3390/life12020149

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Journal: Life	Publication Date: Jan 20, 2022
Citations: 6	License type: CC BY 4.0

Affiliation: University of Alabama at Birmingham

Abstract

Background: Primary (familial) hemophagocytic lymphohistiocytosis (pHLH) is a potentially lethal syndrome of infancy, caused by genetic defects in natural killer (NK) cell and CD8 T cell cytotoxicity, leading to hyperinflammation, elevated cytokine levels, and a disorganized immune response resulting in multi-organ system failure and frequently death. Secondary HLH (sHLH) can be triggered in the setting of malignances, diseases of chronic immune system activation, or by infectious etiologies. While pHLH is usually a result of homozygous gene mutations, monoallelic hypomorphic and dominant-negative mutations in pHLH genes have been implicated in sHLH. Coronavirus disease 2019 (COVID-19) has been an omnipresent viral infection since its arrival, and severe cases can present with cytokine storm and have clinical features and laboratory findings consistent with sHLH. Herein, we report an adolescent with severe COVID-19, decreased NK cell function, and features of sHLH. Her genetic evaluation identified a monoallelic missense mutation in the pHLH gene STXBP2, and NK cell assays of her blood showed decreased cytolysis and degranulation ex vivo. Methods: Patient data was extracted through an electronic medical record review. Using a lentiviral approach, the patient’s STXBP2 mutation and wild-type (WT) STXBP2 were separately transduced into the NK-92 human NK cell line. The WT and mutant STXBP2 transduced NK-92 cells were stimulated with NK-sensitive K562 erythroleukemia target cells in vitro, and NK cell degranulation and cytolysis were measured via CD107a expression and Live/Dead near-IR dye, respectively. Results: Compared to WT STXBP2, the patient’s STXBP2 mutation caused significantly decreased NK cell cytolysis and associated degranulation in vitro. Conclusion: These findings add weight to the hypothesis that some severe cases of COVID-19 may be accompanied by sHLH and hyperinflammation, especially in the setting of heterozygous pHLH genetic mutations. This has implications both diagnostically and therapeutically for severe COVID-19.

Highlights

Since its appearance on the world stage in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has affected a wide swathe of the world population, causing a significant burden of morbidity and mortality in infected individuals
Within the subset of severe COVID-19, there is increasing evidence for a hyperinflammatory response similar to that seen in cytokine storm syndromes (CSS) and secondary hemophagocytic lymphohistiocytosis, characterized by thrombocytopenia, lymphopenia, elevated D-dimer levels, low fibrinogen, elevated lactate dehydrogenase (LDH), elevated liver enzymes, elevated ferritin, and elevation in cytokine/chemokine levels—including IL-1β, IL-6, IL-18, and interferon-gamma (IFNγ) [2]. Secondary HLH (sHLH) is associated with conditions of chronic immune dysregulation, including chronic rheumatic diseases (where it is typically called macrophage activation syndrome (MAS)) and hematologic malignancies
We present an 18year-old female with severe COVID-19 and features of HLH, who was found to have a rare (0.036%, Genome Aggregation Database) heterozygous STXBP2 (c.1286C > T, p.Ala429Val) missense mutation and defective natural killer (NK) cell killing

Summary

Introduction

Since its appearance on the world stage in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has affected a wide swathe of the world population, causing a significant burden of morbidity and mortality in infected individuals. We present an 18year-old female with severe COVID-19 and features of HLH, who was found to have a rare (0.036%, Genome Aggregation Database) heterozygous STXBP2 (c.1286C > T, p.Ala429Val) missense mutation and defective NK cell killing Her mutation was further explored by lentiviral over-expression in the human NK-92 cell line and comparing its effect on NK cell degranulation and K562 target cell lysis in vitro, relative to over-expression of wild-type (WT) STXBP2 (control) in NK-92 cells. These findings add to the existing literature of heterozygous pHLH gene mutations contributing to infection-triggered sHLH, improving our understanding of their modulatory effect on the immune response to infectious disease and COVID-19 severity. This has implications both diagnostically and therapeutically for severe COVID-19

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