Single-Cell and Bulk Transcriptomics Reveal an Epithelial LTF-LRP11 Signaling Axis Associated with Severe COVID-19 Susceptibility

Background/Objectives: The molecular mechanisms underlying susceptibility to severe COVID-19 remain incompletely understood. We aimed to identify the signaling pathways associated with disease severity by integrating transcriptomic data and characterizing ligand–receptor interactions involved in the host response to SARS-CoV-2 infection. Methods: We integrated publicly available bulk RNA-sequencing data from nasopharyngeal (NP) swabs (GSE152075) and single-cell RNA-sequencing data from bronchoalveolar lavage fluid samples (GSE145926). Analyses focused on secreted ligands and their cognate receptors and were performed in relation to demographic and clinical characteristics associated with susceptibility to severe COVID-19, including sex, age, and viral load. Results: Patients with characteristics associated with increased susceptibility to severe disease, including male sex, advanced age, and high viral load, exhibited transcriptional programs enriched for inflammatory and immune-response pathways. In contrast, individuals with lower susceptibility displayed reduced expression of 43 ligand genes compared with matched negative controls, suggesting distinct secretory programs associated with the host response to infection. We identified an association between the expression of lactoferrin (LTF) and its receptor, LDL receptor-related protein 11 (LRP11), and susceptibility to severe COVID-19. LRP11 was predominantly expressed in human pulmonary epithelial cells, and its expression increased during SARS-CoV-2 infection in monkeys. Conclusions: Our findings provide insight into the molecular mechanisms associated with susceptibility to severe COVID-19 through the analysis of ligand and receptor expression in nasopharyngeal swabs and bronchoalveolar lavage fluid samples. The association between LTF and LRP11 highlights a potentially relevant signaling axis in disease pathogenesis and provides a rationale for future functional studies aimed at clarifying its role in COVID-19 severity.