In a recent article published in the Developmental Cell In the journal, researchers reported that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced anosmia was based on non-cell-independent processes.
An incapacity to smell, known as transient anosmia, is frequently correlated with numerous upper respiratory viral infections, such as SARS-CoV-2. Viral infection induced-nasal congestion usually limits odorants in sensory neurons, resulting in a loss of smell. On the other hand, anosmia arises autonomously from nasal symptoms in Coronavirus disease 2019 (COVID-19) and can remain for months following the resolution of infection. Of note, the fundamental process of anosmia in COVID-19 is still unknown.
According to a paper published in 2020 by Bilinska et al., olfactory sensory neurons (OSNs) did not express the host cell entrance proteins for SARS-CoV-2, making a viral infection of these neurons extremely rare. These molecular and pathological characteristics strengthen 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 “non-cell-autonomous disruption of nuclear architecture as a potential cause of COVID-19-induced anosmia” by Zazhytska et al., published in the Cell journal in 2022.
Zazhytska and her team investigated the non-cell-independent molecular alterations occurring in golden hamsters upon SARS-CoV-2 infection. They gathered olfactory epithelium (OE) from SARS-CoV-2- or sham-infected golden hamsters one, three, and 10 days after infection and conducted single-cell ribonucleic acid (RNA) sequencing (scRNA-seq) to evaluate alterations in gene expression and cellular composition following COVID-19. These researchers also explored transcriptional alterations in OE cells.
Further, Zazhytska et al. obtained serum from SARS-CoV-2-infected hamsters and utilized ultraviolet (UV) irradiation to inactivate the virus before introducing the serum into the nasal cavity of virus-nave hamsters to determine if anosmia was truly non-cell-autonomous. In addition, they used postmortem human tissues to examine the significance of their observations in humans, comparing alterations in gene expression among SARS-CoV-2-infected people and controls.
Results and discussions
Zazhytska et al. discovered 13 distinct cell kinds and found that sustentacular (SUS) cells, expressing the angiotensin-converting protein 2 (ACE2) receptor, accounted for 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, whereas the viability of OSNs was unaltered. Besides, the cellular composition had returned to normal, and the virus had disappeared from all OE cells by day 10.
Zazhytska and her team discovered a substantial drop in genes associated with olfaction, especially transcription factors that govern olfactory receptors (OR) signaling genes and ORs, such as adenylyl cyclase 3 (Adcy3), following COVID-19. They discovered the disruption of wide-range genomic linkages of OR genes one day after SARS-CoV-2 infection utilizing Hi-C assays (a genomic analysis modality) in SARS-CoV-2- and sham-infected hamsters.
Additionally, global, and more extensive chromatin rearrangements occurred by day 3. Surprisingly, OR gene rearrangements continued on day 10 after infection, following the viral clearance, possibly explaining the SARS-CoV-2-linked long-lasting alterations in OR-related gene expression and anosmia.
These findings indicated that anosmia was unlikely to be caused by a direct SARS-CoV-2 mechanism, given OSNs’ limited vulnerability to viral entry and the presence of OR transcriptional and chromatin alterations. Moreover, the experiments with UV-irradiated serum indicated that viral or cellular components released from other infected cells, probably the infected SUS cells, cause widespread alterations in nuclear architecture relevant to OR genes in OSNs.
In human autopsies, Zazhytska et al. discovered a preferential decline in the expression of OR-linked genes, such as Adcy3 and other vital olfactory transcripts. Furthermore, they found an extensive loss of long-distance contacts, many of which were unique to OR-associated genes, when matching Hi-C interaction maps across OSNs from control human autopsies and postmortem specimens from SARS-CoV-2-infected individuals.
Collectively, the authors noted that the findings from the study undertaken by Zazhytska and her team supported the theory that SARS-CoV-2-induced loss of smell was caused by the non-autonomous alteration of wide-range genomic connections of OR-associated genes . Such nuclear architectural abnormalities might not be quickly restored in post-mitotic cells like OSNs, potentially explaining the continuation of anosmia phenotypes and other associated characteristics like parosmia, a distorted perception of the smell, for weeks/months post-infection.
Notably, the research by Zazhytska et al. raised numerous interested concerns. Although the trial showed that the process for the COVID-19-induced loss of smell was non-cell-autonomous and does not necessitate a live virus, the exact components responsible have yet to be discovered.
Further, the authors suggested that the possible molecules included substances released from SARS-CoV-2-infected cells like cytokines, circulating pieces of SUS cells, and nonviable viral fragments. Indeed, the mechanism via such a compound induced dramatic shifts in OSNs’ nuclear architecture was also uncertain.