A pharmacological interactome between COVID-19 patient samples and human sensory neurons reveals potential drivers of neurogenic pulmonary dysfunction

Abstract

The SARS-CoV-2 virus infects cells of the airway and lungs in humans causing the disease COVID-19. This disease is characterized by cough, shortness of breath, and in severe cases causes pneumonia and acute respiratory distress syndrome (ARDS) which can be fatal. Bronchial alveolar lavage fluid (BALF) and plasma from mild and severe cases of COVID-19 have been profiled using protein measurements and bulk and single cell RNA sequencing. Onset of pneumonia and ARDS can be rapid in COVID-19, suggesting a potential neuronal involvement in pathology and mortality. We sought to quantify how immune cells might interact with sensory innervation of the lung in COVID-19 using published data from patients, existing RNA sequencing datasets from human dorsal root ganglion neurons and other sources, and a genome-wide ligand-receptor pair database curated for pharmacological interactions relevant for neuro-immune interactions. Our findings reveal a landscape of ligand-receptor interactions in the lung caused by SARS-CoV-2 viral infection and point to potential interventions to reduce the burden of neurogenic inflammation in COVID-19 disease. In particular, our work highlights opportunities for clinical trials with existing or under development rheumatoid arthritis and other (e.g. CCL2, CCR5 or EGFR inhibitors) drugs to treat high risk or severe COVID-19 cases.

Figure 1.

Our work identifies that: 1) Several proinflammatory cytokines and chemokines are upregulated in the COVID-19 BALF samples that are known to be translationally-regulated via MNK-eIF4E signaling. This offers a unique opportunity to disrupt activity of many inflammatory proteins via MNK inhibitors. 2) Many upregulated COVID-19 inflammatory mediators interact with receptors potentially expressed on thoracic sensory neurons that innervate the lung. Activation of these sensory neurons may cause them to release neuropeptides back into the lung environment to cause vasodilation, immune cell recruitment, neurogenic inflammation, and potentially even pain upon breathing. 3) It is currently unknown if ACE2, the receptor through which SARS-CoV-2 can infiltrate cells, is expressed in sensory neurons.