Study: Can’t smell the virus: SARS-CoV-2, chromatin organization, and anosmia. Image Credit: huntingSHARK/Shutterstock

Cellular non-autonomous anosmia induced by COVID-19

In a recent article published in the Development Cell journal, researchers reported that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced anosmia was based on non-cell-independent processes.

Study: I can’t smell the virus: SARS-CoV-2, chromatin organization and anosmia. Image Credit: huntingSHARK/Shutterstock

Introduction

An inability to smell, known as transient anosmia, is frequently correlated with many viral upper respiratory infections, such as SARS-CoV-2. Nasal congestion induced by a viral infection usually restricts odorants in sensory neurons, leading to loss of smell. On the other hand, anosmia arises autonomously from nasal symptoms of coronavirus disease 2019 (COVID-19) and may persist for months after the infection resolves. It should be noted that the fundamental process of anosmia in COVID-19 is still unknown.

According to a 2020 paper by Bilinska et al., olfactory sensory neurons (OSNs) did not express host cell entry proteins for SARS-CoV-2, making a viral infection of these neurons extremely rare. These molecular and pathological features reinforce the likelihood that COVID-19 causes anosmia through non-cell-independent processes.

About the study

In the present study, the researchers analyzed a work named “autonomous non-cellular disruption of nuclear architecture as a potential cause of COVID-19-induced anosmia” by Zazhytska et al., published in the Cell reviewed in 2022.

Zazhytska and her team studied non-cell-independent molecular alterations occurring in golden hamsters during SARS-CoV-2 infection. They collected olfactory epithelium (OE) from SARS-CoV-2-infected or sham golden hamsters one, three and 10 days post-infection and performed single-cell ribonucleic acid (RNA) sequencing (scRNA-seq ) to assess alterations in gene expression and cellular composition following COVID-19. These researchers also explored transcriptional alterations in OE cells.

Additionally, Zazhytska et al. obtained serum from hamsters infected with SARS-CoV-2 and used ultraviolet (UV) irradiation to inactivate the virus before introducing the serum into the nasal cavity of virus-naïve hamsters to determine if the anosmia was truly no autonomous cell. Additionally, they used post-mortem human tissue to examine the significance of their observations in humans, comparing gene expression alterations in people and controls infected with SARS-CoV-2.

Results and discussion

Zazhytska et al. discovered 13 distinct cell types and found that sustentacular cells (SUS), expressing the receptor for angiotensin-converting protein 2 (ACE2), represented the most infected cells. Even though microglia and other immune cells showed significant viral uptake, only a tiny percentage of OSNs were infected.

The cellular consequences of direct SARS-CoV-2 infection were demonstrated by a drastic decrease in the proportion of SUS cells, while the viability of OSNs was not impaired. Moreover, the cellular composition had returned to normal and the virus had disappeared from all OE cells by day 10.

Zazhytska and her team found a substantial decline in genes associated with olfaction, particularly transcription factors that regulate olfactory receptor (OR) signaling genes and ORs, such as adenylyl cyclase 3 (Adcy3), following COVID-19. They found the disruption of broad-spectrum genomic linkages of OR genes one day after SARS-CoV-2 infection using Hi-C testing (a modality of genomic analysis) in SARS-infected hamsters. CoV-2 and fictitious.

In addition, global and more extensive chromatin rearrangements occurred on day 3. Surprisingly, OR gene rearrangements continued on day 10 post-infection, after viral clearance, possibly explaining the long-lasting alterations linked to SARS-CoV-2 OR-related gene expression and anosmia.

These results indicated that the anosmia was unlikely to be caused by a direct mechanism of SARS-CoV-2, given the limited vulnerability of OSNs to viral entry and the presence of alterations in OR transcription and chromatin. Moreover, experiments with UV-irradiated serum indicated that viral or cellular components released by other infected cells, probably infected SUS cells, cause widespread alterations in nuclear architecture regarding OR genes in OSNs.

In human autopsies, Zazhytska et al. found a preferential downregulation of OR-related genes, such as Adcy3 and other vital olfactory transcripts. In addition, they found a significant loss of long-distance contacts, many of which were unique to OR-associated genes, when matching Hi-C interaction maps between OSNs from control human autopsies and from human autopsies. post-mortem specimens from individuals infected with SARS-CoV-2.

conclusion

Collectively, the authors noted that the results of the study undertaken by Zazhytska and her team supported the theory that SARS-CoV-2-induced loss of smell was caused by the nonautonomous alteration of genomic connections at large spectrum of genes associated with OR. . Such nuclear architectural abnormalities might not be rapidly restored in post-mitotic cells like OSNs, potentially explaining the continuation of anosmia phenotypes and other associated features like parosmia, distorted odor perception, for long periods of time. weeks/months after infection.

Notably, research by Zazhytska et al. raised many intriguing concerns. Although the trial showed that the COVID-19-induced smell loss process was not cell-autonomous and did not require live virus, the exact components responsible have yet to be discovered.

Additionally, the authors suggested that possible molecules included substances released by SARS-CoV-2 infected cells like cytokines, circulating pieces of SUS cells, and non-viable viral fragments. Indeed, the mechanism via such a compound induces dramatic changes in the nuclear architecture of OSNs was also uncertain.

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