Comparison of Myeloid-Derived Suppressor Cells (MDSC) in children with RSV vs. COVID-19

Abstract

Abstract Introduction Lower respiratory tract infections (LRTI) caused by respiratory syncytial virus (RSV) result in over 100,000 deaths of infants globally. Though adults account for most COVID-19 hospitalizations, children also develop severe disease due to SARS-CoV-2. Children with severe illness due to LRTI demonstrate evidence of impaired adaptive immune function. MDSC are an immature, heterogenous cell population that expands significantly during inflammatory conditions. MDSC suppress T cell proliferation and function resulting in immunosuppression. MDSC subsets (granulocytic (G) MDSC and the monocytic (M-)MDSC) suppress T cells via distinct mechanisms. In a previous study, we observed a significant increase in G-MDSC in children with septic shock. We hypothesize that children with severe LRTI with RSV or COVID-19 will have expansion of MDSC that will be associated with differences in T cell subset composition and worse clinical outcomes. Methods Prospective, observational study in children admitted to the pediatric intensive care unit (PICU) with symptomatic RSV or COVID-19, defined by a positive polymerase chain reaction test. Children with multi-system inflammatory syndrome or positive for both RSV and COVID-19 were excluded. Pre-pandemic healthy control samples were obtained from children requiring IV placement for outpatient MRI. Peripheral blood mononuclear cells were isolated by ficoll gradient and stained for surface markers to identify MDSC (CD45+, HLA-DR-, CD33+ and CD11b+), including G- (CD15+, CD14-) and M-MDSC (CD14+, CD15-), and T cell populations. Clinical and demographic data were collected from the electronic medical record and stored in a secure database. Results We enrolled 30 children, 20 with RSV (50% male, median age 2 [1.2-5] months), 10 with COVID-19 (30 % male, median age 25 [ 3.8 – 215] months), and 30 healthy controls (64% male, median age 73.2 [57.6, 98.4] months. Children with severe LRTI due to RSV or COVID-19 have significantly increased percentage MDSC of PBMC compared to healthy controls (13% [5.6,22] vs 9.9% [5.2, 23] vs 0.95 [0.34, 2.8] respectively). Compared to children with COVID-19, children with RSV had higher percentage M-MDSC of total MDSC (90% [87,97] vs 45% (8.4, 71], p< 0.0001) and lower G-MDSC (1.1% [0.44, 3.0] vs 38% [17,90], p<0.0001). Children with RSV had a larger percentage of T regulatory cells of total CD4+ T cells (8.0% [6.1, 9.0] vs 4.3% [3.3, 5.8], p=0.01) and were more likely require non-invasive or invasive ventilatory respiratory support than those with COVID-19 (75% vs 30%, p=0.04). Conclusions Total MDSC are significantly expanded in children with severe LRTI due to RSV and COVID-19 compared to healthy controls, but with significantly different subset distributions. Children with RSV demonstrate a predominance of M-MDSC, while children with COVID-19 demonstrate significantly higher G-MDSC. Children with RSV were also more likely to have expanded Treg cell population and require higher level respiratory support. These findings suggest that MDSC composition and suppressive mechanisms may be partially driven by viral pathogen. Larger studies are needed to confirm these findings and to investigate the role of MDSC-mediated immune suppression in children with severe LRTI to identify this cell population as a potential therapeutic target.