Viral Infection-Mediated Pulmonary Epigenetics: Comparison
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Respiratory viral infections can trigger chronic lung diseases. Number of studies have shown that respiratory viral infection causes epigenetic changes, which refer to genetic alterations that affect gene expression without any mutational genetic changes.

  • pulmonary pathogen
  • bacteria

1. Introduction

Pulmonary pathogens have been responsible for some of the biggest global health crises in humans for centuries. This is in part due to the efficiency of their mode of transmission. However, their ability to manipulate the human immune system has also been observed as a significant factor. It has already been known that epigenetic alterations play an important role in pathology as well as their ability to modify the immune response [1]. Epigenetic modifications associated with nutrition and the microbiome and their contribution to long-term health development have been well documented [2]. Importantly, the recent research successes show how pulmonary pathogens can modulate the human genome and cause chronic diseases due to the advancement in the OMICS sciences, such as genomics, transcriptomics, proteomics, or metabolomics. For example, genome-wide association studies have revealed genetic changes in different regions of the genome that are primarily associated with complex and nonmalignant respiratory diseases, e.g., chronic obstructive pulmonary disease (COPD), asthma, and pulmonary arterial hypertension (PAH) [3,4,5][3][4][5]. Benincasa et al., have reviewed the epigenetic role in COPD, asthma, and PAH [6]. The epigenetic markers for these common chronic respiratory diseases were identified, e.g., DNA methylation, histone modification, and microRNA (miRNA) [7,8,9,10][7][8][9][10]. There is growing evidence supporting bacterial infection-induced epigenetic modification in the host by different mechanisms [11]. Viruses are intracellular parasites that continuously utilize the subordination and exploitation of cellular machinery for transcription and translation. Thus, it is no surprise that viruses induce modulation of host chromatin dynamics and transcription regulation, and examples of modulated epigenetic mechanisms are DNA methylation, histone post-translational modification, and transcription modification [12,13][12][13]. Bacterial virulence factors can modulate host cell genetic expression rates, limiting the ability of the immune system to adequately respond and allowing replicating bacteria to evade phagocytosis. Multiple virulence factors have been identified in recent studies that may be able to cause lasting pathogenic changes to host cell genomes, some of which may be associated with chronic pathologies such as allergy development, asthma, latent infection, carcinogenesis, and COPD exacerbation. Previously described epigenetic genome modifications, including histone modification, miRNA processing, DNA methylation and acetylation, protein chaperones, and protein degradation processes, all have the potential to upregulate and downregulate host genes at the whim of the invading organism [1,14,15][1][14][15]. These epigenetic changes have potentially chronic or permanent consequences for the host, which can last long after the resolution of the initial infection due to the persistence of some of these changes throughout generations of proliferating cells. Linking the virulence factors of common respiratory infections to consistent host genome modifications and finally to measurable long-term pathogenic outcomes is a potential new front for pulmonary research. The field of infectious epigenetics is still in its early stages, but many authors have already extensively cataloged the most common pathogens and their respective epigenetic targets [1,14,15][1][14][15].

2. Viral Infection-Mediated Pulmonary Epigenetics

Respiratory viral infections can trigger chronic lung diseases [63,64,65][16][17][18]. Asthma is a common chronic disease affecting children in Western countries. Although the pathophysiological changes underlying asthma development are complex and unknown, respiratory syncytial virus (RSV) and human rhinovirus virus (HRV) have been recognized as major etiological factors in wheezing illness, with a significant correlation with asthma development during childhood [66,67][19][20]. A recent number of studies have shown that respiratory viral infection causes epigenetic changes, which refer to genetic alterations that affect gene expression without any mutational genetic changes [64][17]. Here, the research focused on a few common respiratory virus-driven epigenetic changes (Table 1 and Table 2).

2.1. Adenovirus

Adenovirus is a double-stranded DNA virus that commonly causes respiratory infections in humans. It uses a lytic type of life cycle, which is important in its pathophysiology [68][21]. A common theme in adenovirus infection is the suppression of the expression of most host genes except a few that are involved in cell division [69][22]. These profound changes are believed to be caused in part by epigenetic changes. ChIP-sip and ChIP-seq-based data analyses suggested that Adenovirus infection was associated with the modulation of two major epigenetic regulations: the organization of certain histone modifications and transcription factors within infected cells. The adenovirus e1a protein appeared to affect the acetylation of H3K9 and H3K18 and certain transcriptional factors [70,71][23][24]. Adenovirus protein VII is expressed late in the infected cells and translocates into the nucleus, which allows it to associate with host chromatin; consequently, it alters the chromatin composition of the infected cells. [72,73][25][26]. Additionally, the Adenovirus e1A protein is known to localize to host chromatin, alter host histone modifications, and overhaul transcription in infected cells. e1A binds to three different locations on the host’s chromatin. The first site is a region occupied by multiple genes related to the immune response of the host, and e1A binding downregulates these genes [72][25]. The second site of binding for this protein involves genes involved in the cell cycle. These genes were observed to have been upregulated [68,72][21][25]. The genes at the third site of binding are mostly involved in specialization and growth, and these genes were found to have been downregulated. These epigenetic changes hinder the immune system’s ability to respond to an adenovirus infection [72][25].

2.2. RSV

RSV is a negative-sense, single-stranded RNA virus enveloped by a protein coat. Since RSV affects the epithelial cells of the respiratory tract, the epigenetic factors that may induce changes in these cells are of particular interest. Caixia et al., underlined how the epigenetic dysregulation of signaling pathways in epithelial cells of the respiratory tract is related to shortfalls in immunological functions [74][27]. This implies that, through the induction of epigenetic modification, the virus can offset the immune response against it. Some of the signaling pathways that RSV can impact are tyrosine kinase growth factor signaling, the hexosamine biosynthetic pathway, and the extracellular matrix secretory pathways [75][28]. The virus can do this by inducing chromatin remodeling, which involves an increase in the number of nucleosome-free regions. This remodeling affects genes that regulate the aforementioned pathways. The increased accessibility of specific chromatin regions directly affects TGFβ-ECM and HBP pathways, which may explain the airway remodeling that happens in RSV infection [75][28].
Fonseca et al. [76][29] discussed that the disparities in immune responses between adults and infants are caused by epigenetic alterations of inflammatory genes. Histone methylation caused by RSV infection has been seen to enhance the production of Th2 cytokines after diminishing the production of pro-inflammatory cytokines. Other observations that have been made in mouse models suggest that RSV is also able to induce changes in non-coding RNAs [76][29]. These changes were seen to have impacts after the infection had subsided, which involved allergic asthma [76][29]. By having these effects, the virus is able to increase its own virulence while also having lasting effects, especially on vulnerable hosts.

2.3. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

SARS-CoV-2 is a positive-sense, single-stranded RNA virus that was first identified in the city of Wuhan, China. It is the virus responsible for the respiratory disease coronavirus disease 2019 (COVID-19). The virus has been found to alter the epigenetic environment of the host cell to increase its virulence by disrupting the host’s ability to recognize and respond to the pathogen [77][30]. Arguably the most significant regulator of the severity of COVID-19 infection is correlated with the increased expression of the receptor ACE2. DNA methylation is one way in which this receptor can be altered by the virus. Decreased DNA methylation close to the transcription site was found to result in increased expression of ACE2 in lung epithelial cells [77][30]. Chlamydas et al., suggested that the upregulation of the ACE2 receptor on the host cells by the virus is through histone modifications at the DNA packaging histones H3, H3K4me1, H3K4me3, and H3K27Ac [77][30]. Ozturkler et al., summarized how epigenetic changes such as hypermethylation of IFN genes and hypomethylation of inflammatory genes can be induced by the virus, and this change can be cell-specific [78][31]. Corley et al., described how, in severe cases of COVID-19, the epigenetic changes in immune cells varied and DNA methylation decreased in primary neutrophils [79][32].
Table 1.
Common viral pulmonary pathogens and their associated epigenetic changes.
Pulmonary Pathogen Epigenetic Changes Cellular Impact References
[
36
]
TGFβ: tumor growth factor β; IFN: interferon; IFR1: interferon regulatory factor 1; IRF7: interferon regulatory factor 7; SIRT1: sirtuin 1; ACE2: angiotensin converting enzyme 2; CREB1: CAMP responsive element binding protein 1; H3K27: histone 3 at lysine residue in position 27.
Table 2.
Main types of epigenetic changes and virus presence in common respiratory viral diseases.
Types of Epigenetic Change Adenovirus SARS-CoV-2 RSV Influenza Virus Rhino Virus MERS
Adenovirus Histone deacetylase inhibitor suppresses host HDAC proteins Increased global acetylation, transcription modulation [68,72]
Chromatin remodeling Not Identified[21][25]
Not Identified Yes

[75]Yes

[28]		 Yes

[83]		Yes

[36]		 Not Identified Not Identified Respiratory syncytial virus (RSV) Chromatin modifications inducing nucleosome-free regions

Demethylation of Nodal promoter

Increased TGFβ expression		 Impacts tyrosine kinase growth factor signaling,

affects extracellular matrix secretory pathways

Reduced pro-inflammatory cytokines release		 [74,75,76][
Changes in DNA methylation Yes

[68]		Yes

[21]		 Yes

[77,78,79]		Yes

[30][31][32]27][28][29]
Yes

[74]Yes

[27]		 Yes

[81,82]		Yes

[34][35]		 Yes

[64]		Yes

[17]		 Yes

[83]		Yes

[36]		 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) Hypermethylation of IFN related Hypomethylation of inflammatory genes

Perturbation of epigenetic clock

IRF1 and IRF7 were upregulated

Epi-factors HDAC9 and SIRT1 were deregulated.		 Increased level of ACE2 receptor expression

Increased cytokine release		 [77,78   Yes

[80]		Yes

[33]		,79,80][30][31][32][33]
Non-coding RNA Yes

 Influenza virus Post translational histone modification

Decrease in histone acetylation

Demethylation on CREB1 binding region		 Hypercytokinemia [81,82,83][34][35][36]
[74]Yes

[27]		      
Changes in DNA acetylation Yes

[68]		Yes

[21]		 Not Identified Not Identified Yes

[81]		Yes

[34]		 Not Identified Not Identified Rhino virus Modifications in DNA methylation   [64][17]
Middle East respiratory syndrome-related corona virus (MERS) H3K27 methylation Downregulate antigen-presenting molecules [13,77,83][13][30]

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