# Computational network biology analysis revealed COVID-19 severity markers: Molecular interplay between HLA-II with CIITA

## TL;DR

This study identifies a molecular network involving HLA class II, CIITA, and CD74 as a marker for severe COVID-19 in the Japanese population using network biology analysis.

## Contribution

A novel computational network biology strategy using Kullback–Leibler divergence to detect severity-specific molecular interplays in gene networks.

## Key findings

- The molecular interplay between HLA class II, CIITA, and CD74 is a severity-specific marker for COVID-19.
- Computational network biology analysis revealed suppression and activation of this interplay as crucial for understanding severity mechanisms.
- Monte Carlo simulations confirmed the effectiveness of the new strategy for differential gene network analysis.

## Abstract

COVID-19, severe acute respiratory syndrome coronavirus 2, rapidly spread worldwide. Severe and critical patients are expected to rapidly deteriorate. Although several studies have attempted to uncover the mechanisms underlying COVID-19 severity, most have focused on the perturbations of single genes. However, the complex mechanism of COVID-19 involves numerous perturbed genes in a molecular network rather than a single abnormal gene. Thus, we aimed to identify COVID-19 severity-specific markers in the Japanese population using gene network analysis. In order to reveal the severity-specific molecular interplays, we developed a novel computational network biology strategy that measures dissimilarity between networks based on the comprehensive information of gene network (i.e., expression levels of genes and network structure) by using Kullback–Leibler divergence. Monte Carlo simulations demonstrated the effectiveness of our strategy for differential gene network analysis. We applied this method to publicly available whole blood RNA-seq data from the Japan coronavirus disease 2019 Task Force and identified differentially regulated molecular interplays between 368 severe and 105 non-severe samples. Our analysis suggests the gene network between HLA class II, CIITA, and CD74 as a COVID-19 severity specific molecular marker. Although the association between HLA class II and COVID-19 has been demonstrated, our data analysis revealed that the molecular interplay of HLA class II with its target and/or regulator is a crucial marker for COVID-19 severity. Our findings from computational network biology analysis suggest that suppression and activation of the molecular interplay between HLA class II, CIITA, and CD74 provide crucial clues to uncover the mechanisms of COVID-19 severity.