Oral SARS-CoV-2 Inoculation Causes Nasal Viral Infection Leading to Olfactory Bulb Infection: an Experimental Study

Ueha, Rumi; Ito, Toshihiro; Furukawa, Ryutaro; Kitabatake, Masahiro; Ouji-Sageshima, Noriko; Ueha, Satoshi; Koyama, Misaki; Uranaka, Tsukasa; Kondo, Kenji; Yamasoba, Tatsuya

doi:10.21203/rs.3.rs-1204399/v1

Cited by 3 publications

(9 citation statements)

References 31 publications

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“…The data presented herein do not support hematogenous diffusion of SARS-CoV-2 towards the brain, and supports hypothesis of the olfactory retrograde pathway as a preferential portal of entry (Ueha et al, 2022). Brain infection via the olfactory pathway therefore seems a common feature of coronaviruses (Dubé et al, 2018;Shi et al, 2022), regardless of clinical disease presentations.…”

Section: Discussioncontrasting

confidence: 77%

Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants

Melo

Perraud

Alvarez

et al. 2022

Preprint

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Anosmia was identified as a hallmark of COVID-19 early in the pandemic, however, with the emergence of variants of concern, the clinical profile induced by SARS-CoV-2 infection has changed, with anosmia being less frequent. Several studies have focused on the neuropathogenesis of the original SARS-CoV-2, but little is known about the neuropathological potential of the variants. Here, we assessed the clinical, olfactory and inflammatory conditions of golden hamsters infected with the original SARS-CoV-2, its ORF7-deleted mutant, and three variants: Gamma, Delta and Omicron/BA.1. We show that infected animals developed a variant-dependent clinical disease, and that the ORF7 of SARS-CoV-2 contribute to causing olfactory disturbances. Conversely, all SARS-CoV-2 variants were found to be neuroinvasive, regardless of the clinical presentation they induce. With newly-generated nanoluciferase-expressing SARS-CoV-2, we validated the olfactory pathway as a main entry point towards the brain, confirming that neuroinvasion and anosmia are independent phenomena upon SARS-CoV-2 infection.

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Section: Discussioncontrasting

confidence: 77%

Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants

Melo

Perraud

Alvarez

et al. 2022

Preprint

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“…However, the impact of SARS-CoV-2 on each ORN lineage cell has not been sufficiently verified. We previously reported that all ORN lineage cells are impaired by SARS-CoV-2 (19), and in this study, we verified related longitudinal effects for the first time to our knowledge. In the NS area, SARS-CoV-2 infection caused shedding of almost all cells of the OE and greatly thinned the OE.…”

Section: Discussionsupporting

confidence: 86%

“…SARS-CoV-2 infected animal models were prepared following previously reported methods (19,24). In short, the SARS-CoV-2 strain (JPN/TY/WK-521, provided by the National Institute of Infectious Diseases, Japan) was used.…”

Section: Animal Model Preparationmentioning

confidence: 99%

“…The hamsters were anesthetized with an intraperitoneal injection of pentobarbital (10 mg/mL, 0.8 mL/hamster) before virus inoculation. To the SARS-CoV-2 transoral infection group, 50 μL of virus solution diluted with saline (including 1.0×10 3 pfu of SARS-CoV-2) was administered orally as previously reported (19,24). To the control group, 50 μL of saline was administered.…”

Section: Animal Model Preparationmentioning

confidence: 99%

“…The OE is composed of supporting cells (sustentacular cells), basal progenitor cells, immature olfactory receptor cells (ORNs), and mature ORNs (18). Basal cells and supporting cells are particularly susceptible to damage by SARS-CoV-2 infection, and the entire OE may be denuded depending on the site (10,14,15,19). This OE impairment improves over time, and the OE is nearly normalized within approximately 1 month after SARS-CoV-2 infection, although the regenerative kinetics may differ according to the nose area, such as the nasal septum (14).…”

Section: Introductionmentioning

confidence: 99%

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Delayed SARS-CoV-2 Spread and Olfactory Cell Lineage Impairment in Close-Contact Infection Syrian Hamster Models

Ueha

Ito

Ueha

et al. 2022

Preprint

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Objectives: Close contact with patients with COVID-19 is speculated to be the most common cause of viral transmission, but the pathogenesis of COVID-19 by close contact remains to be elucidated. In addition, despite olfactory impairment being a unique complication of COVID-19, the impact of SARS-CoV-2 on the olfactory cell lineage has not been fully validated. This study aimed to elucidate close-contact viral transmission to the nose and lungs and to investigate the temporal damage in the olfactory receptor neuron (ORN) lineage caused by SARS-CoV-2. Methods: Syrian hamsters were orally administered SARS-CoV-2 as direct-infection models. On day 7 after inoculation, infected and uninfected hamsters were housed in the same cage for 30 minutes. These uninfected hamsters were subsequently assigned to a close-contact group. First, viral presence in the nose and lungs was verified in the infection and close-contact groups at several time points. Next, the impacts on the olfactory epithelium, including olfactory progenitors, immature ORNs, and mature ORNs, were examined histologically. Then, the viral transmission status and chronological changes in tissue damage were compared between the direct-infection and close-contact groups. Results: In the close-contact group, viral presence could not be detected in both the nose and lungs on day 3, and the virus was identified in both tissues on day 7. In the direct-infection group, the viral load was highest in the nose and lungs on day 3, decreased on day 7, and was no longer detectable on day 14. Histologically, in the direct-infection group, mature ORNs were most depleted on day 3 (p < 0.001) and showed a recovery trend on day 14, with similar trends for olfactory progenitors and immature ORNs. In the close-contact group, there was no obvious tissue damage on day 3, but on day 7, the number of all ORN lineage cells significantly decreased (p < 0.001). Conclusion: SARS-CoV-2 was transmitted even after brief contact and subsequent olfactory epithelium and lung damage occurred more than 3 days after the trigger of infection. The present study also indicated that SARS-CoV-2 damages all ORN lineage cells, but this damage can begin to recover approximately 14 days post infection.

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Effects of nasal inflammation on the olfactory bulb

LaFever

Imamura

2022

J Neuroinflammation

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Sinonasal diseases, such as rhinosinusitis, affect up to 12% of individuals each year which constitutes these diseases as some of the most common medical conditions in the world. Exposure to environmental pathogens and toxicants via the nasal cavity can result in a severe inflammatory state commonly observed in these conditions. It is well understood that the epithelial and neuronal cells lining the olfactory mucosa, including olfactory sensory neurons (OSNs), are significantly damaged in these diseases. Prolonged inflammation of the nasal cavity may also lead to hyposmia or anosmia. Although various environmental agents induce inflammation in different ways via distinct cellular and molecular interactions, nasal inflammation has similar consequences on the structure and homeostatic function of the olfactory bulb (OB) which is the first relay center for olfactory information in the brain. Atrophy of the OB occurs via thinning of the superficial OB layers including the olfactory nerve layer, glomerular layer, and superficial external plexiform layer. Intrabulbar circuits of the OB which include connectivity between OB projection neurons, OSNs, and interneurons become significantly dysregulated in which synaptic pruning and dendritic retraction take place. Furthermore, glial cells and other immune cells become hyperactivated and induce a state of inflammation in the OB which results in upregulated cytokine production. Moreover, many of these features of nasal inflammation are present in the case of SARS-CoV-2 infection. This review summarizes the impact of nasal inflammation on the morphological and physiological features of the rodent OB.

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Oral SARS-CoV-2 Inoculation Causes Nasal Viral Infection Leading to Olfactory Bulb Infection: an Experimental Study

Cited by 3 publications

References 31 publications

Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants

Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants

Delayed SARS-CoV-2 Spread and Olfactory Cell Lineage Impairment in Close-Contact Infection Syrian Hamster Models

Effects of nasal inflammation on the olfactory bulb

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