Mucociliary Transport Deficiency and Disease Progression in Syrian Hamsters with SARS-CoV-2 Infection

Abstract

Substantial clinical evidence supports the notion that ciliary function in the airways plays an important role in COVID-19 pathogenesis. Although ciliary damage has been observed in both in vitro and in vivo models, consequent impaired mucociliary transport (MCT) remains unknown for the intact MCT apparatus from an in vivo model of disease. Using golden Syrian hamsters, a common animal model that recapitulates human COVID-19, we quantitatively followed the time course of physiological, virological, and pathological changes upon SARS-CoV-2 infection, as well as the deficiency of the MCT apparatus using micro-optical coherence tomography, a novel method to visualize and simultaneously quantitate multiple aspects of the functional microanatomy of intact airways. Corresponding to progressive weight loss up to 7 days post- infection (dpi), viral detection and histopathological analysis in both the trachea and lung revealed steadily descending infection from the upper airways, as the main target of viral invasion, to lower airways and parenchymal lung, which are likely injured through indirect mechanisms. SARS-CoV-2 infection caused a 67% decrease in MCT rate as early as 2 dpi, largely due to diminished motile ciliation coverage, but not airway surface liquid depth, periciliary liquid depth, or cilia beat frequency of residual motile cilia. Further analysis indicated that the fewer motile cilia combined with abnormal ciliary motion of residual cilia contributed to the delayed MCT. The time course of physiological, virological, and pathological progression suggest that functional deficits of the MCT apparatus predispose to COVID-19 pathogenesis by extending viral retention and may be a risk factor for secondary infection. As a consequence, therapies directed towards the MCT apparatus deserve further investigation as a treatment modality.

Neutrophils initiate the destruction of the olfactory epithelium during SARS-CoV-2 infection in hamsters

“…Since we observed that these treatments did not impair SARS-CoV-2 replication in vitro , we hypothesize that neutrophils may have a counterproductive effect by releasing infected cells into the lumen of the nasal cavity. These infected cells could allow the virus to spread more easily in the nasal cavity due to impairment of mucociliary clearance that has been recently shown to be reduced during SARS-CoV-2 infection ( 53 ). Such a hypothesis is consistent with our results showing that cyclophosphamide and IcatC XPZ-01 treatment significantly reduced the amount of infected desquamated cells filling the lumen of the nasal cavity.…”

COVID-19 Causes Ciliary Dysfunction as Demonstrated by Human Intranasal Micro-Optical Coherence Tomography Imaging

“…The copyright holder for this preprint (which this version posted July 11, 2022. ; https://doi.org/10.1101/2022.07.08.499336 doi: bioRxiv preprint tracheobronchial epithelial (HTBE) cells (7,10,29), nasal ciliated cells from human and non-human primates (5), Syrian hamsters (11,30,31), and SARS-CoV-2 infected human nasal organoids. (32) In addition, diminished mucociliary clearance by SARS-CoV-2 has been demonstrated in HTBE cells by tracking polystyrene beads (10) and in Syrian hamsters by µOCT imaging.…”

“…Similarly, pCC was not affected by the duration of illness (R 2 <0.01). (Figure S1) SARS-CoV-2 infection in experimental animals and in vitro is known to cause shortening and misshapen ciliary structure, thus contributing to alterations in function (10,11), but this has not yet been assessed in symptomatic COVID-19 patients. µOCT demonstrated ciliary beat frequency was severely diminished in COVID-19 patients compared to controls (12.32 ± 2.58 Hz healthy controls vs 7.57 ± 2.56 Hz COVID-19, P= 0.011).…”

“…This finding is consistent with data in hamsters where our group found that fewer motile cilia combined with abnormal ciliary motion of residual cilia contribute to delayed MCT in SARS-CoV-2 infection. (11) Due to the severity of the abnormalities in the mucociliary transport apparatus, and frequent areas where the epithelium had complete absence of cilia, it was challenging to ascribe the motion of motile particles to mucociliary transport in majority of the COVID-19 subjects. In subjects where quantification was possible, mucociliary transport rates showed a pronounced reduction in the COVID-19 cohort as compared to controls, although this was not statistically significant (7.2 ± 2.9 mm/min healthy controls, n=7 vs 1.6 ± 0.3 mm/min COVID-19, n=2, P= 0.056 by Mann Whitney).…”

“…Several in vitro and in vivo studies have demonstrated proclivity for SARS-CoV-2 virus to ciliated cells, evidenced by prominent ciliary abnormalities (7)(8)(9) and impaired mucociliary clearance (10,11) in these model systems. Perhaps consequently, hyper viscous mucus in bronchoalveolar lavage (BAL) fluid (12)(13)(14) and in the airways (15,16) of COVID-19 patients have been reported, suggesting the clinical importance of these events.…”