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Mucociliary Respiratory Epithelium Integrity in Molecular Defense and Susceptibility to Pulmonary Viral Infections.

ABSTRACT: Mucociliary defense, mediated by the ciliated and goblet cells, is fundamental to respiratory fitness. The concerted action of ciliary movement on the respiratory epithelial surface and the pathogen entrapment function of mucus help to maintain healthy airways. Consequently, genetic or acquired defects in lung defense elicit respiratory diseases and secondary microbial infections that inflict damage on pulmonary function and may even be fatal. Individuals living with chronic and acute respiratory diseases are more susceptible to develop severe coronavirus disease-19 (COVID-19) illness and hence should be proficiently managed. In light of the prevailing pandemic, we review the current understanding of the respiratory system and its molecular components with a major focus on the pathophysiology arising due to collapsed respiratory epithelium integrity such as abnormal ciliary movement, cilia loss and dysfunction, ciliated cell destruction, and changes in mucus rheology. The review includes protein interaction networks of coronavirus infection-manifested implications on the molecular machinery that regulates mucociliary clearance. We also provide an insight into the alteration of the transcriptional networks of genes in the nasopharynx associated with the mucociliary clearance apparatus in humans upon infection by severe acute respiratory syndrome coronavirus-2.

SUBMITTER: Adivitiya

PROVIDER: S-EPMC7911113 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Certain riboviruses can cause severe pulmonary complications leading to death in some infected patients. We propose that DNA damage induced-apoptosis accelerates viral release, triggered by depletion of host RNA binding proteins (RBPs) from nuclear RNA bound to replicating viral sequences. Methods: Information theory-based analysis of interactions between RBPs and individual sequences in the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2), Influenza A (H3N2), HIV-1, and Dengue genomes identifies strong RBP binding sites in these viral genomes. Replication and expression of viral sequences is expected to increasingly sequester RBPs - SRSF1 and RNPS1. Ordinarily, RBPs bound to nascent host transcripts prevents their annealing to complementary DNA. Their depletion induces destabilizing R-loops. Chromosomal breakage occurs when an excess of unresolved R-loops collide with incoming replication forks, overwhelming the DNA repair machinery. We estimated stoichiometry of inhibition of RBPs in host nuclear RNA by counting competing binding sites in replicating viral genomes and host RNA. Results: Host RBP binding sites are frequent and conserved among different strains of RNA viral genomes. Similar binding motifs of SRSF1 and RNPS1 explain why DNA damage resulting from SRSF1 depletion is complemented by expression of RNPS1. Clustering of strong RBP binding sites coincides with the distribution of RNA-DNA hybridization sites across the genome. SARS-CoV-2 replication is estimated to require 32.5-41.8 hours to effectively compete for binding of an equal proportion of SRSF1 binding sites in host encoded nuclear RNAs. Significant changes in expression of transcripts encoding DNA repair and apoptotic proteins were found in an analysis of influenza A and Dengue-infected cells in some individuals. Conclusions: R-loop-induced apoptosis indirectly resulting from viral replication could release significant quantities of membrane-associated virions into neighboring alveoli. These could infect adjacent pneumocytes and other tissues, rapidly compromising lung function, causing multiorgan system failure and other described symptoms.

Project description:With the global over 60-year-old population predicted to more than double over the next 35 years, caring for this aging population has become a major global healthcare challenge. In 2016 there were over 1 million deaths in >70 year olds due to lower respiratory tract infections; 13-31% of these have been reported to be caused by viruses. Since then, there has been a global COVID-19 pandemic, which has caused over 2.3 million deaths so far; increased age has been shown to be the biggest risk factor for morbidity and mortality. Thus, the burden of respiratory viral infections in the elderly is becoming an increasing unmet clinical need. Particular challenges are faced due to the interplay of a variety of factors including complex multimorbidities, decreased physiological reserve and an aging immune system. Moreover, their atypical presentation of symptoms may lead to delayed necessary care, prescription of additional drugs and prolonged hospital stay. This leads to morbidity and mortality and further nosocomial spread. Clinicians currently have limited access to sensitive detection methods. Furthermore, a lack of effective antiviral treatments means there is little incentive to diagnose and record specific non-COVID-19 viral infections. To meet this unmet clinical need, it is first essential to fully understand the burden of respiratory viruses in the elderly. Doing this through prospective screening research studies for all respiratory viruses will help guide preventative policies and clinical trials for emerging therapeutics. The implementation of multiplex point-of-care diagnostics as a mainstay in all healthcare settings will be essential to understand the burden of respiratory viruses, diagnose patients and monitor outbreaks. The further development of novel targeted vaccinations as well as anti-viral therapeutics and new ways to augment the aging immune system is now also essential.The reviews of this paper are available via the supplemental material section.

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Mucociliary Respiratory Epithelium Integrity in Molecular Defense and Susceptibility to Pulmonary Viral Infections.

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