Immunoregulation of Ghrelin in neurocognitive sequelae associated with COVID-19: an in silico investigation

Abstract

Some patients suffering from the new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) develop an exaggerated inflammatory response triggered by a "cytokine storm" resulting in acute respiratory distress syndrome (ARDS) with the concomitant activation of non-specific inflammatory reactivity in the circulatory system and other organs, leading to multiorgan failure, leaky vasculature, coagulopathies and stroke. Impairment of brain functions may also occur as dysregulations in immune function resulting from neuroendocrine interactions. In this study, we explored, by bioinformatics approaches, the interaction between the multiple inflammatory agents involved in SARS-CoV-2 and Ghrelin (Ghre) together with its receptor GHSR-1A, which are described as anti-inflammatory mediators, in order to investigate what could trigger the hyper-inflammatory response in some SARS-CoV-2 patients. In our analysis, we found several interactions of Ghre and GHSR-1A with SARS-CoV-2 interacting human genes. We observed a correlation between Ghre, angiotensin-converting enzyme 2 ACE2, toll-like receptors 9 (TLR9), and Acidic chitinase (CHIA), whereas its receptor GHSR-1A interacts with chemokine receptor 3 (CXCR3), CCR3, CCR5, CCR7, coagulation factor II (thrombin) receptor-like 1 (F2RL1), vitamin D receptor (VDR), Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and DDP4 in receptor dipeptidyl peptidase-4. To our knowledge, our findings show, for the first time, that Ghre and GHSR-1A may exert an immunomodulatory function in the course of SARS-Cov-2 infection.

Keywords: Bioinformatics analysis; COVID-19; Ghrelin receptor; Inflammation; Neuroinflammation; SARS-CoV-2.

Figure 1

Interaction between our genes of interest and the gene networks of SARS-CoV-2 targeted human proteins. The PPI network made by GeneMANIA shows the interconnection for SARS-CoV-2 targeted human proteins and the genes of interest (nodes) connected (with edges) according to the functional association networks from the databases. The edges indicate the type of evidence supporting each interaction by using different colors: co-expression (light purple), physical interaction (pink), genetic interaction (green), shared protein domains (golden yellow), pathway (light blue), predicted (orange), and co-localization (blue).

Figure 2

Gene networks of SARS-CoV-2 targeted human proteins interacting with genes encoding proteins involved in inflammatory processes. The PPI network constructed by GeneMANIA shows the relationships between SARS-CoV-2 targeted human proteins, the genes of interest and Ghrelin and GHSR-1A receptor. The edges between nodes (proteins) indicate interactions according to the GeneMANIA database information. The edges indicate the type of evidence supporting each interaction by using different colors: co-expression (light purple), physical interaction (pink), genetic interaction (green), shared protein domains (golden yellow), pathway (light blue), predicted (orange), and co-localization (blue).

Figure 3

Interaction-specific views of gene networks of SARS-CoV-2 targeted human proteins and their interactions with Ghrelin, and the list of genes of our interest. The figure shows different interaction-specific views of the PPI network constructed by GeneMANIA reporting the interconnection between SARS-CoV-2 targeted human proteins and their interactions with Ghrelin, and the list of genes encoding proteins involved in inflammatory processes. The edges between nodes (proteins) indicate interactions based on GeneMANIA database information. For each network, differently colored ‘edges’ indicate the type of evidence supporting each interaction: co-expression (light purple), physical interaction (pink), genetic interaction (green), shared protein domains (golden yellow), pathway (light blue), predicted (orange), and co-localization (blue).

Figure 4

Immunomodulatory functions exerted by Ghrelin. The figure shows a schematic comparison of the immune-modulating effects exerted by Ghre. Abbreviations: NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; IFN-γR, Interferon gamma; Th, T helper; HMGB1, High Mobility Group Box 1; VCAM-1, Vascular Cell Adhesion Molecule 1; IL, interleukin; TNFα, tumor necrosis factor-a.; TLR, toll-like receptor, PG, prostaglandins; TGFβ, Transforming Growth Factor-β; iNOS, Inducible nitric oxide synthase; ROS, Reactive oxygen species.