Search

Contains fulltext : 283349.pdf (Publisher’s version ) (Open Access), PURPOSE: We sought to describe a disorder clinically mimicking cystic fibrosis (CF) and to elucidate its genetic cause. METHODS: Exome/genome sequencing and human phenotype ontology data of nearly 40 000 patients from our Bio/Databank were analysed. RNA sequencing of samples from the nasal mucosa from patients, carriers and controls followed by transcriptome analysis was performed. RESULTS: We identified 13 patients from 9 families with a CF-like phenotype consisting of recurrent lower respiratory infections (13/13), failure to thrive (13/13) and chronic diarrhoea (8/13), with high morbidity and mortality. All patients had biallelic variants in AGR2, (1) two splice-site variants, (2) gene deletion and (3) three missense variants. We confirmed aberrant AGR2 transcripts caused by an intronic variant and complete absence of AGR2 transcripts caused by the large gene deletion, resulting in loss of function (LoF). Furthermore, transcriptome analysis identified significant downregulation of components of the mucociliary machinery (intraciliary transport, cilium organisation), as well as upregulation of immune processes. CONCLUSION: We describe a previously unrecognised autosomal recessive disorder caused by AGR2 variants. AGR2-related disease should be considered as a differential diagnosis in patients presenting a CF-like phenotype. This has implications for the molecular diagnosis and management of these patients. AGR2 LoF is likely the disease mechanism, with consequent impairment of the mucociliary defence machinery. Future studies should aim to establish a better understanding of the disease pathophysiology and to identify potential drug targets.

Viral infections are a major cause of severe, fatal diseases worldwide. Recently, these infections have increased due to demanding contextual circumstances, such as environmental changes, increased migration of people and product distribution, rapid demographic changes, and outbreaks of novel viruses, including the COVID-19 outbreak. Internal variables that influence viral immunity have received attention along with these external causes to avert such novel viral outbreaks. The gastrointestinal microbiome (GIM), particularly the present probiotics, plays a vital role in the host immune system by mediating host protective immunity and acting as an immune regulator. Bacteriocins possess numerous health benefits and exhibit antagonistic activity against enteric pathogens and immunobiotics, thereby inhibiting viral infections. Moreover, disrupting the homeostasis of the GIM/host immune system negatively affects viral immunity. The interactions between bacteriocins and infectious viruses, particularly in COVID-19, through improved host immunity and physiology are complex and have not yet been studied, although several studies have proven that bacteriocins influence the outcomes of viral infections. However, the complex transmission to the affected sites and siRNA defense against nuclease digestion lead to challenging clinical trials. Additionally, bacteriocins are well known for their biofunctional properties and underlying mechanisms in the treatment of bacterial and fungal infections. However, few studies have shown the role of probiotics-derived bacteriocin against viral infections. Thus, based on the results of the previous studies, this review lays out a road map for future studies on bacteriocins for treating viral infections.