Introduction

Asthma background

Asthma is currently considered to be a syndrome, its genotype broad and elusive. Its loci and genetic networks overlap with many other diseases & disorders including major depression, primary anxiety, neuroticism. Such wide overlap suggests complex linkage between causes & development of these disorders (Kabesch & Tost, 2020).

Asthma is characterized by a changing obstruction of airflow and hyperresponsive tissues, occurring as chronic bronchiolar inflammation. It occurs primarily in mast cells, eosinophils, T lymphocytes, macrophages, neutrophils and epithelial cells.

Current research state

Historically, asthma was defined only as airway inflammation and bronchospasm, but was expanded to include airway remodelling (NAEPP, 2007). As airway remodelling takes place, the airways narrow and the new epithelial tissues are asthmatic by nature, epigenetically altered by asthmatic triggers, becoming more sensitive and easily triggered. Unanswered questions regarding severe asthma pathophysiology include mechanisms of airway narrowing, if airway remodelling is permanent and if it can be artificially reversed, and what early life events trigger development of severe asthma (King et al., 2018).

Mast cells release immune response cells, including histamine, which triggers contraction of the airway smooth muscle lamina propria. Mast cells infiltrating this muscle was the only difference between asthma and corticosteroid-responsive chronic cough (Brightling et al., 2002), supporting their hypothesis of chemokine-induced mast cell migration toward smooth muscle cells. This suggested targeting the CXCL10/CXCR3 gene axis for treating asthma (Brightling et al., 2005).

Most asthma management methods focus on suppressing immune and inflammatory responses. Some recent studies suggest focussing instead on increasing airway resistance, considering asthma as a disease from impaired barrier function. In asthmatics, certain antioxidant-producing pathways are defective, so inhaled oxidants travel unchecked and disrupt perijunctional actin in tight junctions (TJ) of epithelial barrier cells: more foreign substances enter through the airway epithelium, coming into contact with immune & inflammatory cells (Holgate, 2007).

Indeed, the immune system meeting foreign substances may be fundamental in asthmatic development of trigger sensitization. A biobank genome-wide cross-trait analysis suggests that skin is the immune system’s front line in developing external allergen responses, exacerbating genetic disposition with environmental factors: most of the 30 shared asthmatic loci identified were mainly expressed in skin and other organs with similar epithelium (Sajuthi et al., 2022).

Purpose for this study

The accurate genotype of asthma is a knowledge gap; determining it will provide more potential treatment targets, as in the mast cell studies (Brightling et al., 2002, 2005) and the epithelial tight junctions discovery (Holgate, 2007).

This study looks in asthmatic lung tissues (HAEC, human airway epithelial cells) for differentially-expressed genes in asthmatic response to the asthma trigger HRV16 (human rhinovirus RV‑A16). Functions & pathways of the genes’ products are explored to determine their involvement in asthma and, if so, how they could be used as therapeutic targets in treating, preventing and even curing asthma

STAT2 is relevant because of its relationship with controlling lung epithelial cells’ capacity to generate an immune response (Mathé et al., 2022).

The OAS family are relevant because they’re part of the innate cellular antiviral response, inhibiting protein synthesis and inducing apoptosis thereby preventing virus reproduction; and asthma is commonly both exacerbated and induced by RSV (respiratory syncytial virus) and RV (rhinovirus) (Hansbro et al., 2008). One study strongly linked ORMDL3 with asthma, which induced expression of OAS genes in human bronchial epithelial cells (Miller et al., 2012).

Intent & scope

The principal intention was to answer the question “Could STAT2 and the OAS gene family play a role in the asthmatic inflammatory response?” by examining the genetic expression and functions of STAT2 and OAS family genes, and testing the following hypotheses:

1. There is no significant difference between the expression of STAT2 in the lungs of asthmatic individuals and normal non-asthmatic individuals.

2. There is no significant difference between the expression of the OAS gene family in the lungs of asthmatic individuals and normal non-asthmatic individuals.

The scope of this investigation focusses on only STAT2 and the OAS family, drawing primarily on data from Bai et al. (2015), from 12 human donor samples, deceased by non-asthmatic causes.