A Systems approach to the implications of perturbed KITLG and KIT receptor in COVID-19

Fluctuations of KITLG (Stem Cell Factor, SCF), a cardinal myeloid and lymphoid regulator, and its cognate receptor KIT (CD117) have been recently detected in a small number of plasma proteomic studies for Sars-CoV-2 infection (COVID-19). In this work, through various biostatistical approaches, we initially corroborated that KITLG and KIT were significantly decreased in COVID-19, and this decrease was inversely analogous to clinical severity (WHO ordinal scale). Furthermore, we discovered that the abovementioned correlations were largely unabated by grave comorbidities and interestingly, early KITLG and KIT expression exhibited noticeable prognostic significance. Next, by analyzing the statistical correlation of plasma proteins and their differential abundance in COVID-19, we designed protein-protein interaction networks and we unveiled that KITLG and KIT operate as hub proteins based on their network topology. Moreover, we unearthed significant associations of KITLG and KIT with the Complement C3d Receptor 2, the Fms-like tyrosine kinase 3 ligand and various cadherins and other cell adhesion molecules. Pathway enrichment of several KITLG/KIT subgraphs unveiled associations in COVID-19 with perturbed hemopoiesis, differentiation of myeloid and lymphoid progenitors, B cell immunity and various signaling cascades. Finally, by integrating plasma proteomic information with relevant COVID-19 transcriptomic studies, we revealed that KITLG and KIT were deregulated across various vital organs during Sars-COV-2 infection and that COVID-19 cases with lower amounts of KITLG contain PBMCs that are skewed towards oxidative stress, neutrophil degranulation and unfavorable myeloid phenotypes. Overall, our herein in-silico approach provides an insight into the previously nascent role of KITLG and KIT in COVID-19, paving the way for novel patient stratification strategies-especially during current vaccination efforts- and for pertinent pharmacological interventions that could save patients in critical condition.