Can cilia provide an entry gateway for SARS-CoV-2 to human ciliated cells?

Abstract

A worldwide coronavirus pandemic is in full swing and, at the time of writing, there are only few treatments that have been successful in clinical trials, but no effective antiviral treatment has been approved. Because of its lethality, it is important to understand the current strain's effects and mechanisms not only in the respiratory system but also in other affected organ systems as well. Past coronavirus outbreaks caused by SARS-CoV and MERS-CoV inflicted life-threatening acute kidney injuries (AKI) on their hosts leading to significant mortality rates, which went somewhat overlooked in the face of the severe respiratory effects. Recent evidence has emphasized renal involvement in SARS-CoV-2, stressing that kidneys are damaged in patients with COVID-19. The mechanism by which this virus inflicts AKI is still unclear, but evidence from other coronavirus strains may hold some clues. Two theories exist for the proposed mechanism of AKI: 1) the AKI is a secondary effect to reduced blood and oxygen levels causing hyperinflammation and 2) the AKI is due to cytotoxic effects. Kidneys express angiotensin-converting enzyme-2 (ACE2), the confirmed SARS-CoV-2 target receptor as well as collectrin, an ACE2 homologue that localizes to the primary cilium, an organelle historically targeted by coronaviruses. Although the available literature suggests that kidney damage is leading to higher mortality rates in patients with COVID-19, especially in those with preexisting kidney and cardiovascular diseases, the pathogenesis of COVID-19 is still being investigated. Here, we present brief literature review supporting our proposed hypothesis of a possible link between SARS-CoV-2 cellular infection and cilia.

Keywords: ACE2; COVID-19; cilia; corona virus.

Figure 1.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) structure and proteins. Used with permission from Ref. .

Figure 2.

General depiction of coronavirus life cycle. The steps in the coronavirus lifecycle are 1) binding of the virion to the cell via the S1 spike protein receptor interaction; 2) proteolytic cleavage of S protein into S1 and S2, followed by fusion of cellular and viral membranes and release of viral genome; 3) viral genomic RNA translation into replicase; 4) viral RNA synthesis; 5) viral structural proteins are translated; 6) moved into the endoplasmic reticulum (ER); 7) then into the Golgi-ER compartment and assembly of virions; 8) virions bud from Golgi-ER compartment; and 9) leave cell via exocytic pathway (23, 24). Used with permission from Ref. .

Figure 3.

Cilia Classification. A: motile cilia have an axoneme structure of nine concentrically arranged doublets anchored to a central pair of microtubules via dynein arms. B: primary cilia lack the radial spokes, dynein arms, and central pair of microtubules resulting in a 9 + 0 structure and reduced motion and flexibility. Used with permission and modified from Ref. .

Figure 4.

Angiotensin-converting enzyme-2 (ACE2) localization to primary cilia in respiratory system and collecting duct cells. A: immunofluorescence staining using anti-ACE2 and anti-acetylated α-tubulin (ACTUB; cilia marker) antibodies show ACE2 localization to primary cilia of normal mouse nasal turbinate and trachea. B: immunofluorescent staining of ACE2, cilia marker ADP-ribosylation factor-like protein 13B (ARL13B), and cilia centrosome marker FGFR1 Oncogene Partner (FOP) (top); ACE2, and cilia markers ACTUB and ARL13B in a ciliated mouse cell line, Inner Medullary Collecting Duct 3 (IMCD3) (bottom). Modified from Ref. . Scale bars: 20 μm (A, top); 5 μm (A, bottom); 2 μm (B).

Figure 5.

Proposed coronavirus entry into cells through primary cilia pathway. Detailing entry through endocytosis in the ciliary pocket as well as exocytosis of the mature virions through ciliary mechanisms. Created with BioRender.com.