The post-COVID and the long-term-COVID have both tremendously triggered a lot of complications in different human systems. The loss or reduction of smell, among other complications of the nervous system, is an associated symptom for patients affected by different variants of COVID-19 including omicron variant (
Table 1) [
73,
74,
75,
76,
77,
78,
79]. Moreover, studies reported that the prevalence of olfactory dysfunction differs greatly between populations and approaches [
77,
80,
81]. The relationship between the loss of smell and the SARS-CoV-2 infection remains an enigma which could partly explain why the fight against this disorder is difficult. In the emergency context of the pandemic, many COVID-19 vaccines are authorized to help protect and eliminate the virus. Unfortunately, at least, two COVID-19 vaccines have been reported to cause the loss of smell one day after the administration. Also, it remains unclear what drive the occurrence of olfactory dysfunctions as the cases are relatively rare, although the development of a post-vaccine inflammatory reaction in the olfactory neuroepithelium is pointed to play a role in this process [
82,
83]. Therefore, this adds more complexity to compare the molecular signaling of the loss of smell driven by COVID-19 infected patients and individuals benefiting from COVID-19 vaccines and later contracting the disease. The COVID-19 pathology and the cellular mechanism by which the olfactory dysfunction occurs, remain unclear and is still under intensive investigation [
18,
84]. Earlier in the pandemic, reports hypothesized that five potential mechanisms were considered to get insights into the olfactory dysfunction in COVID-19 patients : (1) obstruction/congestion and rhinorrhea of the nasal airway, (2) damage and loss of ORNs, (3) Olfactory center damage in the brain, (4) damage of the olfactory supporting cells in the OE, and (5) Inflammation-related olfactory epithelium dysfunction [
80,
81]. Butowt et
al, have recently reviewed that at least the following hypotheses (1)-(3) turned out to be implausible, for explaining the olfactory dysfunction in patients [
85]. Here, we will particularly review the mechanisms related to the second and the fourth scenarios according the available findings. Healthy sensory cilia of ORNs in the olfactory epithelium are crucial in perceiving odorant molecules before sending the information to the olfactory bulbs and then to the upper parts of the brain [
52]. It has been reported in humans that the SARS-CoV-2 may inderectly affects the olfactory cilia, hindering the smelling system's efficacy [
86]. Reports suggested that ORNs lack to express the entry proteins of SARS-CoV-2 in the OE. The virus seems to establish a first contact in human nasal epithelia by binding its spike S protein to specific cells in the OE [
87]. These reports are confirmed by study based on in-silico data, predicting the that mature ORNs do not express the virus entry protein, the angiotensin-converting enzyme 2 (ACE2), and therefore are not likely to be infected by SARS-CoV-2 [
88]. Furthermore, supporting data by Bryche et
al., showed that SARS-CoV-2 was not detected in the ORNs of golden Siryan hamsters [
89]. However, in few cases, authors suggested that SARS-CoV-2 could infect ORNs in hamsters [
90]. Based on the fact that COVID-19-related loss of smell disappeared within 1-2 weeks, while the regeneration of dead ORNs needs more than 2 weeks, many data tend to conclude that COVID-19-related olfactory dysfunction (OD) is not directly associated with the impairment of the ORNs [
13,
80,
81,
87,
91]. Consequently, studying the entry proteins expression within the cells in the OE will help to understand the sensitivity of the OE to SARS-CoV-2 infection-related to the high prevalence of ODs in patients. Many groups are now interested to the organization of the sustentacular cells in the OE and thought that they might play central role in leading to OD. A high level of expression of ACE2 and the transmembrane serine protease 2 (TMPRSS2) is particularly found on the sustentacular cells suggesting a path to the neurotropism of SARS-CoV-2 in the OE. The ACE2 and TMPRSS2 are respectively known as the SARS-CoV-2 receptor and the SARS-CoV-2 cell entry-priming protease. ACE2 is found mainly on different parts of the sustentacular cells both in human and mouse. The ACE2 and TMPRSS2 genes tend to be co-regulated [
81,
92,
93,
94,
95,
96]. Different approaches using tissues, cells and organ systems in human, golden Syrian hamster, and hACE2 transgenic mouse have been employed to study the pathological impact of the SARS-CoV-2. Here, we discussed findings related particularly to the OE in inducing ODs in human. The spike protein (S protein) of SARS-CoV-2 mediates the passage of the virus into the host cell by fusing the viral and host cell membranes. In fact, via his spike S, SARS-CoV-2 employs the ACE2 as host functional receptor and TMPRSS2 as the cellular priming protease facilitating viral uptake, both signaling being confirmed by Single-cell RNA sequencing (scRNA-seq) datasets from the Human Cell Atlas consortium [
97,
98,
99]. Another study showed that SARS-CoV-2 Nucleocapsid protein (NP), was observed in human OE through the neuronal marker Tuj1, 9 hours post infection. This data further supported the enrichment of ACE2 in human olfactory sustentacular cells [
93,
100]. Earlier in the pandemic, the golden Syrian hamster was used as a model to document the pathology of SARS-CoV-2 in the OE post infection. Reports showed that the sustentacular cells are rapidly infected by SARS-CoV-2. This viral neurtropism is associated with a massive recruitment of immune cells in the OE and lamina propria, which could drive the disorganization of the OE structure [
89]. This study is consistent with high level of TNFα observed in OE samples from COVID-19 suffering patients [
101]. Furthermore, the inflammation induced by SARS-CoV-2 infected supporting cells may play an important role in the onset and persistence of loss of smell in patients. This SARS-CoV-2-associated inflammation status was confirmed by analyzing the expression of selected targets in the olfactory bulb using RNA-seq and RT-qPCR tools. Interestingly, this study showed that the proinflammatory markers Cxcl10, Il-1β, Ccl5 and Irf7 overexpression continued up to 14 dpi, when animals had recovered from ageusia/anosmia (77). These findings are in line with a very recent study showing the implication of immune cell infiltration and altered gene expression in OE in driving persistent smell loss in a subset of patients with SARS-CoV-2. Moreover, this study particularly, demonstrates that T cell–mediated inflammation lasts longer in the OE after the acute SARS-CoV-2 infection has been eliminated from the tissue, suggesting a mechanistic insights into the long-term post–COVID-19 smell loss (78). The OE disorganization is followed by a drastic deterioration of the cilia layer of the ORNs that leads to the impairment of the olfactory capacity of the animal [
89]. Investigations in humans and hamsters using respectively, Transmission Electron Microscopy (TEM) studies and Scanning Electron Microscopy (SEM) analysis showed various levels of cilia height that undergo regeneration in the course of patient recovery, including smell restoration. Data using the golden Syrian hamster showed that the regenerated cilia in the epithelium is accompanied by a decreased expression of FOXJ1
+ highlighting the importance of this marker in the respiratory ciliogenesis. This later finding by Schreiner et
al., could in part shed light on the inquiry of how could we regenerate cilia during patient recovery, although a lot needs to be done in the roadmap of treating loss of smell related to nasal cilia deterioration by SARS-CoV-2 (75, 76) (
Table 1 ;
Figure 2).