Mucociliary transport deficiency and disease progression in Syrian hamsters with SARS-CoV-2 infection.

Substantial clinical evidence supports the notion that ciliary function in the airways is important in COVID-19 pathogenesis. Although ciliary damage has been observed in both in vitro and in vivo models, the extent or nature of impairment of mucociliary transport (MCT) in in vivo models remains unknown. We hypothesize that SARS-CoV-2 infection results in MCT deficiency in the airways of golden Syrian hamsters that precedes pathological injury in lung parenchyma. Micro-optical coherence tomography was used to quantitate functional changes in the MCT apparatus. Both genomic and subgenomic viral RNA pathological and physiological changes were monitored in parallel. We show that SARS-CoV-2 infection caused a 67% decrease in MCT rate as early as 2 days postinfection (dpi) in hamsters, principally due to 79% diminished airway coverage of motile cilia. Correlating quantitation of physiological, virological, and pathological changes reveals steadily descending infection from the upper airways to lower airways to lung parenchyma within 7 dpi. Our results indicate that functional deficits of the MCT apparatus are a key aspect of COVID-19 pathogenesis, may extend viral retention, and could pose a risk factor for secondary infection. Clinically, monitoring abnormal ciliated cell function may indicate disease progression. Therapies directed toward the MCT apparatus deserve further investigation.

Ferret Systemic Coronavirus in Alpha-1 Antitrypsin Knockout Ferrets.

Ferret systemic coronavirus (FRSCV) causes a highly fatal disease of ferrets (Mustela putorius furo). It is believed to be a mutated variant of ferret enteric coronavirus (FRECV) and has a clinical presentation similar to that of feline infectious peritonitis virus (FIPV) in cats. The interplay of infectious diseases and host genetics will become a greater issue in the research environment as genetically modified species other than rodents become available due to advances in gene editing technology. In this case series, we present the clinical and histopathologic features of a FRSCV outbreak that affected 5 out of 10 ferrets with α-1 antitrypsin knockout (AAT KO) over an approximately 1-y period. Clinical features varied, with the affected ferrets presenting with some combination of wasting, hind limb paralysis, incontinence or sudden death. Multiple ferrets had gross pathologic lesions consistent with FRSCV, but the lesions were typically mild. Microscopic pyogranulomatous inflammation was present in 4 ferrets. Immunohistochemistry using an anti-feline coronavirus antibody that cross reacts with ferret coronavirus confirmed infection of intralesional macrophages in 4 out of 5 animals with suspected FRSCV infection. PCR testing of formalin fixed tissue was negative for all ferrets. PCR testing of feces from healthy wild-type ferrets indicated that the endemic presence of FRECV genotype 2, while PCR surveillance testing of other in house AAT KO ferrets revealed both enteric coronavirus genotypes 1 and 2. This case series highlights the potential for greater disease incidence in the future as genetically modified ferrets are used more often, and may support exclusion of FRECV and similar viruses from highly susceptible ferret genotypes.

Molecular docking based drug repurposing study of antiviral drugs against COVID-19 virus spike receptor binding domain

Background: Coronavirus disease (COVID-19) has affected more than 30 million people from all over the world. The SARS-CoV-2 is the pathogen of Coronavirus disease (COVID-19). Its infection may cause mild illness, but in certain susceptible persons, it may cause critical condition leading to respiratory failure and even multi-organ failure. The finding of effective curative medicine for the Coronavirus disease (COVID-19) is a huge challenge to the scientists. The drug repurposing with the help of computational simulation may be a one positive step towards the development of an effective curative therapeutic agent for this pathogen. Aim: To evaluate the binding affinity of four antiviral drugs with this COVID-19 virus spike receptor binding domain with the application of molecular docking. Methods: In the present study, four antiviral agents have been selected for the evaluation of binding affinity with the COVID-19 virus spike receptor binding domain. The antiviral drugs included in the study are sofosbuvir, dasabuvir, ledipasvir and daclatasvir while remdesivir is used as standard. The binding affinity was evaluated with the application of molecular docking. Results: In the present study, four antiviral drugs have been evaluated for drug repurposing which included sofosbuvir, dasabuvir, ledipasvir and daclatasvir while remdesivir is used as standard for the result comparison. The docking score (binding affinity) of ledipasvir (-8.12 kcal/mol) and daclatasvir (-7.47 kcal/mol) was more than remdesivir (-6.54 kcal/mol). Conclusion: The antiviral agents used for the management of HCV (positive sense - RNA virus) could also be a potential candidate drugs for the management of Coronavirus disease (COVID-19). © 2020 Lahore Medical And Dental College. All rights reserved.