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FB1 is a common contaminant of cereal grains that affects human and animal health. It has become increasingly evident that epigenetic changes are implicated in FB1 toxicity. N6-methyladenosine (m6A), the most abundant post-transcriptional RNA modification, is influenced by fluctuations in redox status. Since oxidative stress is a characteristic of FB1 exposure, we determined if there is cross-talk between oxidative stress and m6A in FB1-exposed HepG2 cells. Briefly, HepG2 cells were treated with FB1 (0, 5, 50, 100, 200 µM; 24 h) and ROS, LDH and m6A levels were quantified. qPCR was used to determine the expression of m6A modulators, Nrf2, Keap1 and miR-27b, while western blotting was used to quantify Keap1 and Nrf2 protein expression. Methylation status of Keap1 and Nrf2 promoters was assessed and RNA immunoprecipitation quantified m6A-Keap1 and m6A-Nrf2 levels. FB1 induced accumulation of intracellular ROS (p ≤ 0.001) and LDH leakage (p ≤ 0.001). Elevated m6A levels (p ≤ 0.05) were accompanied by an increase in m6A “writers” [METLL3 (p ≤ 0.01) and METLL14 (p ≤ 0.01)], and “readers” [YTHDF1 (p ≤ 0.01), YTHDF2 (p ≤ 0.01), YTHDF3 (p ≤ 0.001) and YTHDC2 (p ≤ 0.01)] and a decrease in m6A “erasers” [ALKBH5 (p ≤ 0.001) and FTO (p ≤ 0.001)]. Hypermethylation and hypomethylation occurred at Keap1 (p ≤ 0.001) and Nrf2 (p ≤ 0.001) promoters, respectively. MiR-27b was reduced (p ≤ 0.001); however, m6A-Keap1 (p ≤ 0.05) and m6A-Nrf2 (p ≤ 0.01) levels were upregulated. This resulted in the ultimate decrease in Keap1 (p ≤ 0.001) and increase in Nrf2 (p ≤ 0.001) expression. Our findings reveal that m6A RNA methylation can be modified by exposure to FB1, and a cross-talk between m6A and redox regulators does occur.

Variation within the non-coding genome may influence the regulation and expression of important genes involved in immune control such as the human leukocyte antigen (HLA) system. Class I and Class II HLA molecules are essential for peptide presentation which is required for T lymphocyte activation. Single nucleotide polymorphisms within non-coding regions of HLA Class I and Class II genes may influence the expression of these genes by affecting the binding of transcription factors and chromatin modeling molecules. Furthermore, an interplay between genetic and epigenetic factors may also influence HLA expression. Epigenetic factors such as DNA methylation and non-coding RNA, regulate gene expression without changing the DNA sequence. However, genetic variation may promote or allow genes to escape regulation by epigenetic factors, resulting in altered expression. The HLA system is central to most diseases, therefore, understanding the role of genetics and epigenetics on HLA regulation will tremendously impact healthcare. The knowledge gained from these studies may lead to novel and cost-effective diagnostic approaches and therapeutic interventions. This review discusses the role of non-coding variants on HLA regulation. Furthermore, we discuss the interplay between genetic and epigenetic factors on the regulation of HLA by evaluating literature based on polymorphisms within DNA methylation and miRNA regulatory sites within class I and Class II HLA genes. We also provide insight into the importance of the HLA non-coding genome on disease, discuss ethnic-specific differences across the HLA region and provide guidelines for future HLA studies.

With approximately 38 million people living with HIV/AIDS globally, and a further 1.5 million new global infections per year, it is imperative that we advance our understanding of all factors contributing to HIV infection. While most studies have focused on the influence of host genetic factors on HIV pathogenesis, epigenetic factors are gaining attention. Epigenetics involves alterations in gene expression without altering the DNA sequence. DNA methylation is a critical epigenetic mechanism that influences both viral and host factors. This review has five focal points, which examines (i) fluctuations in the expression of methylation modifying factors upon HIV infection (ii) the effect of DNA methylation on HIV viral genes and (iii) host genome (iv) inferences from other infectious and non-communicable diseases, we provide a list of HIV-associated host genes that are regulated by methylation in other disease models (v) the potential of DNA methylation as an epi-therapeutic strategy and biomarker. DNA methylation has also been shown to serve as a robust therapeutic strategy and precision medicine biomarker against diseases such as cancer and autoimmune conditions. Despite new drugs being discovered for HIV, drug resistance is a problem in high disease burden settings such as Sub-Saharan Africa. Furthermore, genetic therapies that are under investigation are irreversible and may have off target effects. Alternative therapies that are nongenetic are essential. In this review, we discuss the potential role of DNA methylation as a novel therapeutic intervention against HIV.

Fumonisin B1 (FB1), a Fusarium-produced mycotoxin, is found in various foods and feeds. It is a well-known liver carcinogen in experimental animals; however, its role in genotoxicity is controversial. The current study investigated FB1-triggered changes in the epigenetic regulation of PTEN and determined its effect on DNA damage checkpoint regulation in human liver hepatoma G2 (HepG2) cells. Following treatment with FB1 (IC50: 200 µM; 24 h), the expression of miR-30c, KDM5B, PTEN, H3K4me3, PI3K, AKT, p-ser473-AKT, CHK1, and p-ser280-CHK1 was measured using qPCR and/or Western blot. H3K4me3 enrichment at the PTEN promoter region was assayed via a ChIP assay and DNA damage was determined using an ELISA. FB1 induced oxidative DNA damage. Total KDM5B expression was reduced, which subsequently increased the total H3K4me3 and the enrichment of H3K4me3 at PTEN promoters. Increased H3K4me3 induced an increase in PTEN transcript levels. However, miR-30c inhibited PTEN translation. Thus, PI3K/AKT signaling was activated, inhibiting CHK1 activity via phosphorylation of its serine 280 residue preventing the repair of damaged DNA. In conclusion, FB1 epigenetically modulates the PTEN/PI3K/AKT signaling cascade, preventing DNA damage checkpoint regulation, and induces significant DNA damage.

[...]the host may silence the integrated viral genome through DNA methylation, inhibiting viral replication. [...]the series of contributions gathered in this Research Topic explores intriguing epigenetic factors that influence host-pathogen interactions. Bacteria, viruses, or fungi can significantly change the pathogen and host’s ncRNA profiles in sepsis. [...]over the past decade, more attention has been given to understanding the role of ncRNAs in disease etiology.Ghafouri-Fard et al. [...]we hope that this Research Topic sparks new ideas in researchers who want to further explore both basic and translational aspects of epigenetic mechanisms in infectious diseases. The authors declare that this study received funding from Novartis and GSK R & D. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.

The coronavirus disease 2019 (COVID-19) has left a devasting effect on various regions globally. Africa has exceptionally high rates of other infectious diseases, such as tuberculosis (TB), human immunodeficiency virus (HIV), and malaria, and was not impacted by COVID-19 to the extent of other continents Globally, COVID-19 has caused approximately 7 million deaths and 700 million infections thus far. COVID-19 disease severity and susceptibility vary among individuals and populations, which could be attributed to various factors, including the viral strain, host genetics, environment, lifespan, and co-existing conditions. Host genetics play a substantial part in COVID-19 disease severity among individuals. Human leukocyte antigen (HLA) was previously been shown to be very important across host immune responses against viruses. HLA has been a widely studied gene region for various disease associations that have been identified. HLA proteins present peptides to the cytotoxic lymphocytes, which causes an immune response to kill infected cells. The HLA molecule serves as the central region for infectious disease association; therefore, we expect HLA disease association with COVID-19. Therefore, in this narrative review, we look at the HLA gene region, particularly, HLA class I, to understand its role in COVID-19 disease.

Infectious diseases such as malaria, tuberculosis (TB), human immunodeficiency virus (HIV), and the coronavirus disease of 2019 (COVID‐19) are problematic globally, with high prevalence particularly in Africa, attributing to most of the death rates. There have been immense efforts toward developing effective preventative and therapeutic strategies for these pathogens globally, however, some remain uncured. Disease susceptibility and progression for malaria, TB, HIV, and COVID‐19 vary among individuals and are attributed to precautionary measures, environment, host, and pathogen genetics. While studying individuals with similar attributes, it is suggested that host genetics contributes to most of an individual's susceptibility to disease. Several host genes are identified to associate with these pathogens. Interestingly, many of these genes and polymorphisms are common across diseases. This paper analyzes genes and genetic variations within host genes associated with HIV, TB, malaria, and COVID‐19 among different ethnic groups. The differences in host–pathogen interaction among these groups, particularly of Caucasian and African descent, and which gene polymorphisms are prevalent in an African population that possesses protection or risk to disease are reviewed. The information in this review could potentially help develop personalized treatment that could effectively combat the high disease burden in Africa. Despite efforts in developing treatments, malaria, tuberculosis (TB), human immunodeficiency virus (HIV), and coronavirus disease of 2019 (COVID‐19) remain a global health burden, especially in Africa. Disease susceptibility and severity varies among individuals. Host genetics potentially contribute a significant portion to disease susceptibility and severity. Common host genes and polymorphisms that associate with these pathogens are reviewed here.

Cancer initiation and progression is an accumulation of genetic and epigenetic modifications. DNA methylation is a common epigenetic modification that regulates gene expression, and aberrant DNA methylation patterns are considered a hallmark of cancer. The human diet is a source of micronutrients, bioactive molecules, and mycotoxins that have the ability to alter DNA methylation patterns and are thus a contributing factor for both the prevention and onset of cancer. Micronutrients such as betaine, choline, folate, and methionine serve as cofactors or methyl donors for one-carbon metabolism and other DNA methylation reactions. Dietary bioactive compounds such as curcumin, epigallocatechin-3-gallate, genistein, quercetin, resveratrol, and sulforaphane reactivate essential tumor suppressor genes by reversing aberrant DNA methylation patterns, and therefore, they have shown potential against various cancers. In contrast, fungi-contaminated agricultural foods are a source of potent mycotoxins that induce carcinogenesis. In this review, we summarize the existing literature on dietary micronutrients, bioactive compounds, and food-borne mycotoxins that affect DNA methylation patterns and identify their potential in the onset and treatment of cancer.

Virulent Enterobacterale strains expressing serine and metallo-β-lactamases (MBL) genes have emerged responsible for conferring resistance to hard-to-treat infectious diseases. One strategy that exists is to develop β-lactamase inhibitors to counter this resistance. Currently, serine β-lactamase inhibitors (SBLIs) are in therapeutic use. However, an urgent global need for clinical metallo-β-lactamase inhibitors (MBLIs) has become dire. To address this problem, this study evaluated BP2, a novel beta-lactam-derived β-lactamase inhibitor, co-administered with meropenem. According to the antimicrobial susceptibility results, BP2 potentiates the synergistic activity of meropenem to a minimum inhibitory concentration (MIC) of ≤1 mg/L. In addition, BP2 is bactericidal over 24 h and safe to administer at the selected concentrations. Enzyme inhibition kinetics showed that BP2 had an apparent inhibitory constant (Kiapp) of 35.3 µM and 30.9 µM against New Delhi Metallo-β-lactamase (NDM-1) and Verona Integron-encoded Metallo-β-lactamase (VIM-2), respectively. BP2 did not interact with glyoxylase II enzyme up to 500 µM, indicating specific (MBL) binding. In a murine infection model, BP2 co-administered with meropenem was efficacious, observed by the >3 log10 reduction in K. pneumoniae NDM cfu/thigh. Given the promising pre-clinical results, BP2 is a suitable candidate for further research and development as an (MBLI).

Globally, SARS-CoV-2 has negatively impacted many lives and industries due to its rapid spread, severe outcomes, and the need for the implementation of lockdown strategies across the world. SARS-CoV-2 disease severity varies among different populations. Host genetics have been associated with various diseases, and their ability to alter disease susceptibility and severity. In addition, Human Leukocyte Antigen (HLA) expression levels and alleles vary significantly among ethnic groups, which might impact the host’s response to SARS-CoV-2. Our previous study highlighted that HLA-A might have an effect on COVID-19 disease severity across ethnicities. Therefore, in this study, we aim to examine the effect of HLA-B and C expression levels on COVID-19 disease severity. To achieve this, we used real-time PCR to measure the HLA mRNA expression levels of SARS-CoV-2-infected individuals from a South African cohort and compared them across ethnic groups, disease outcomes, gender, comorbidities, and age. Our results show (1) that the effect of HLA-B mRNA expression levels was associated with differences in disease severity when we compare symptomatic vs. asymptomatic (p < 0.0001). While HLA-C mRNA expression levels were not associated with COVID-19 disease severity. (2) In addition, we observed that HLA-B and HLA-C mRNA expression levels were significantly different between South African Black individuals and South African Indian individuals (p < 0.0001, p < 0.0001). HLA-B mRNA expression levels among symptomatic South African Black individuals were significantly higher than symptomatic South African Indian individuals (p < 0.0001). In addition, the HLA-B mRNA expression levels of symptomatic South African Black individuals were significantly higher than asymptomatic South African Black individuals (p > 0.0001). HLA-C mRNA expression levels among symptomatic South African Black individuals were significantly higher than among symptomatic South African Indian individuals (p = 0.0217). (3) HLA-C expression levels were significantly different between males and females (p = 0.0052). In addition, the HLA-C expression levels of asymptomatic males are higher than asymptomatic females (p = 0.0375). (4) HLA-B expression levels were significantly different between individuals with and without comorbidities (p = 0.0009). In addition, we observed a significant difference between individuals with no comorbidities and non-communicable diseases (p = 0.0034), in particular, hypertension (p = 0.0487). (5) HLA-B expression levels were significantly different between individuals between 26–35 and 56–65 years (p = 0.0380). Our work is expected to strengthen the understanding of the relationship between HLA and COVID-19 by providing insights into HLA-B and C expression levels across ethnic populations in South Africa among COVID-19-symptomatic and asymptomatic individuals. Our results highlight that HLA-B mRNA expression levels contribute to COVID-19 severity as well as variation in ethnicities associated with COVID-19. Further studies are needed to examine the effect of HLA expression levels across various ethnic groups with contributing factors.