The coronavirus disease 2019 (COVID-19) pandemic, caused by the rapid outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has significantly affected the global healthcare system and economy.
The strategy of early diagnosis of SARS-CoV-2 infection and subsequent isolation from healthy people has been followed by most governments across the world to prevent further transmission of the infection.
One of the early symptoms of COVID-19 is anosmia, which is associated with partial or complete loss of smell. This condition has been utilized as a predictor of SARS-CoV-2 infection.
Nevertheless, the underlying mechanism linked to the rapid onset of anosmia has remained debatable. Surprisingly, a large number of COVID-19 patients suffered from anosmia without the occurrence of nasal congestion.
The SARS-CoV-2 virus infects the host via the binding of the viral spike protein to the host ACE2 receptor, which is present on the cell surface. As ACE2 is not expressed in olfactory sensory neurons (OSNs), it has been proposed that the sense of smell is affected by a viral infection of non-neuronal cell types in the olfactory epithelium (OE).
Moreover, sustentacular (SUS) cells that provide structural support to OE contain a high level of viral receptors. Therefore, the viral infection of SUS cells may cause impairment of the metabolic and structural functions essential for proper OSN functioning.
Since most COVID-19 patients with anosmia recovered their sense of smell within a couple of weeks, infection of SUS cells is less likely to be as drastic as leading to OSN cell death. Nevertheless, inflammatory response in the OE, induced by the innate immune system, can cause olfaction impairments. This statement has been supported by several studies that reported detecting high levels of IL-6 and pro-inflammatory cytokines TNF-α in the OE of COVID-19 patients.
Additionally, cytokines can also change the cellular microenvironment, which interferes with ONS function or triggers premature apoptosis.
Humans contain 376 functional olfactory receptor genes (ORs) distributed across eighteen chromosomes. On maturation, each mature OSN (mOSNs) expresses one allele of a randomly selected OR gene. The tendency of ORs to colonize in constitutive heterochromatin (cHC) or facultative heterochromatin (fHC) regions may be associated with the selection of genes. Additionally, the downregulation of lamin-B receptors (LBR) in OSNs may lead to decondensation of the cHC block, affecting OR gene expression.
About the study
A recent study posted on the bioRxiv* preprint server evaluated how SARS-CoV-2 infection leads to anosmia via chromatin structure disruption and OR dysregulation. For this purpose, publicly available Hi-C data of OSNs of SARS-CoV-2-infected and control human subjects were used. The organization of OR clusters were considered and the Hi-C data to detect fine structural chromatin units and their associated functions were assessed.
Two methods were used to characterize the chromatin structural differences between SARS-CoV-2 patients and the healthy control group. The first method involved the analysis of large-scale structural shifts via spatial reconstructions at the genome level. In contrast, the other method involved determining the fine-scale organization of key gene clusters.
A Markov State Model (MSM) was used to identify Mb-scale structural units, followed by a stochastic embedding procedure (SEP) to attain a genome-level reconstruction of the chromatin ensemble. Furthermore, to better understand chromatin organization and packing at the local level, a new method was formulated. This method helped analyze the strong associations of localized structural units at the ~30 to 200-500 kbp scale.
The current study hypothesized that the disruption of the OR functioning could be due to the chromatin reorganization that occurs during SARS-CoV-2 infection. The whole chromatin genome was reconstructed using SEP. Although the relative positions of chromosomal territories (CTs) in COVID-19 patients and healthy individuals were similar, a strong intermingling tendency of chromosomes containing most OR genes with the interchromosomal OR aggregation was observed.
Nevertheless, in SARS-CoV-2 patients, the intermingling of chromosomes 1 and 9 were significantly reduced by its detachment from the rest of the chromosomes.
OR-containing structural units were found to have consistently strong mutual interactions than OR-free units in all samples. The strong interaction between OR-containing units drives the formation of larger structural units in COVID-19 patients. This finding indicated the disruption of chromatin organization within OR clusters in SARS-CoV-2 infected patients.
The current study provided the first insight into how disruptions of OSN chromatin structure could be an important missing link in the manifestation of anosmia in COVID-19 patients.
A significant change in both inter- and intrachromosomal levels in the chromatin of the SARS-CoV-2 infected patients was noted, compared to healthy individuals.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.