SARS-CoV-2: Olfaction, Brain Infection, and the Urgent Need for Clinical Samples Allowing Earlier Virus DetectionClick to copy article linkArticle link copied!
- Rafal Butowt*Rafal Butowt*Address: Department of Molecular Cell Genetics, L. Rydygier Collegium Medicum in Bydgoszcz Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland. Email: [email protected]. Phone 0048-52-5853491.L. Rydygier Collegium Medicum, Nicolaus Copernicus University, Ul. CurieSklodowskiej 9, 85-94 Bydgoszcz, PolandMore by Rafal Butowt
- Katarzyna BilinskaKatarzyna BilinskaL. Rydygier Collegium Medicum, Nicolaus Copernicus University, Ul. CurieSklodowskiej 9, 85-94 Bydgoszcz, PolandMore by Katarzyna Bilinska
Abstract
The novel SARS-CoV-2 virus has very high infectivity, which allows it to spread rapidly around the world. Attempts at slowing the pandemic at this stage depend on the number and quality of diagnostic tests performed. We propose that the olfactory epithelium from the nasal cavity may be a more appropriate tissue for detection of SARS-CoV-2 virus at the earliest stages, prior to onset of symptoms or even in asymptomatic people, as compared to commonly used sputum or nasopharyngeal swabs. Here we emphasize that the nasal cavity olfactory epithelium is the likely site of enhanced binding of SARS-CoV-2. Multiple non-neuronal cell types present in the olfactory epithelium express two host receptors, ACE2 and TMPRSS2 proteases, that facilitate SARS-CoV-2 binding, replication, and accumulation. This may be the underlying mechanism for the recently reported cases of smell dysfunction in patients with COVID-19. Moreover, the possibility of subsequent brain infection should be considered which begins in olfactory neurons. In addition, we discuss the possibility that olfactory receptor neurons may initiate rapid immune responses at early stages of the disease. We emphasize the need to undertake research focused on additional aspects of SARS-CoV-2 actions in the nervous system, especially in the olfactory pathway.
Note
This article is made available via the ACS COVID-19 subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
1. Fast, Sensitive, and Reliable Tests Are Critical to Slow down a Pandemic
2. SARS-CoV-2 Affinity to the Respiratory Epithelium in the Nasal Cavity Is Likely Moderate
Figure 1
Figure 1. Diagram of human nasal cavity with respiratory and olfactory epithelium areas indicated in blue and yellow, respectively.
nasal cavity | hACE2 | hTMPRSS2 | mACE2 | mTMPRSS2 | database |
---|---|---|---|---|---|
respiratory epithelium | + | + | + | ND | Bgee, GEO |
olfactory epithelium | + | ND | + | + | Bgee, GEO |
olfactory receptor neurons | ND | ND | − or low | + | Bgee, GEO |
Data based on Affymetrix and RNAseq. hACE2, human ACE2; hTMPRSS2, human TMPRSS2; mACE2, mouse ACE2; mTMPRSS2, mouse TMPRSS2. +, positive expression; ND, no data available. Note that olfactory receptor neurons are major part of OE; however, OE also contains several types of non-neuronal cells.
3. The Olfactory Epithelium As a Site of SARS-CoV-2 Replication, Accumulation, and Brain Entrance
Figure 2
Figure 2. Basic organization of the olfactory epithelium (OE). Olfactory neurons continuously regenerate through human life and therefore are at different stages of differentiation. Some non-neuronal cells are shown, e.g., progenitors, sustentacular cells, and olfactory ensheathing cells.
age of mice | ACE2 | TMPRSS2 |
---|---|---|
6 weeks old | 49.4 | 78.7 |
6 months old | 61.4 | 89.5 |
www.bgee.org, Affymetrix microarrays, score range 0–10).
4. Olfactory Neurons in OE May Mediate Antiviral Responses
5. Conclusions and Future Directions
Acknowledgments
The authors would like to thank Christopher von Bartheld (University of Nevada, Reno) and Michal Szpinda (Nicolaus Copernicus University) for their valuable and criitical comments.
References
This article references 10 other publications.
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- 7Netland, J., Meyerholz, D. K., Moore, S., Cassell, M., and Perlman, S. (2008) Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J. Virol 82 (5), 7264– 75, DOI: 10.1128/JVI.00737-08Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXovVSltr4%253D&md5=b5d85df75cb9f2ab540c952704ff5377Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2Netland, Jason; Meyerholz, David K.; Moore, Steven; Cassell, Martin; Perlman, StanleyJournal of Virology (2008), 82 (15), 7264-7275CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)Infection of humans with the severe acute respiratory syndrome coronavirus (SARS-CoV) results in substantial morbidity and mortality, with death resulting primarily from respiratory failure. While the lungs are the major site of infection, the brain is also infected in some patients. Brain infection may result in long-term neurol. sequelae, but little is known about the pathogenesis of SARS-CoV in this organ. We previously showed that the brain was a major target organ for infection in mice that are transgenic for the SARS-CoV receptor (human angiotensin-converting enzyme 2). Herein, we use these mice to show that virus enters the brain primarily via the olfactory bulb, and infection results in rapid, transneuronal spread to connected areas of the brain. This extensive neuronal infection is the main cause of death because intracranial inoculation with low doses of virus results in a uniformly lethal disease even though little infection is detected in the lungs. Death of the animal likely results from dysfunction and/or death of infected neurons, esp. those located in cardiorespiratory centers in the medulla. Remarkably, the virus induces minimal cellular infiltration in the brain. Our results show that neurons are a highly susceptible target for SARS-CoV and that only the absence of the host cell receptor prevents severe murine brain disease.
- 8Harberts, E., Yao, K., Wohler, J. E., Maric, D., Ohayon, J., Henkin, R., and Jacobson, S. (2011) Human herpesvirus-6 entry into CNS through the olfactory pathway. Proc. Natl. Acad. Sci. U. S. A. 108 (33), 13734, DOI: 10.1073/pnas.1105143108Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtV2ms7bO&md5=66c218044b70395b7157be1b543ec3ecHuman herpesvirus-6 entry into the central nervous system through the olfactory pathwayHarberts, Erin; Yao, Karen; Wohler, Jillian E.; Maric, Dragan; Ohayon, Joan; Henkin, Robert; Jacobson, StevenProceedings of the National Academy of Sciences of the United States of America (2011), 108 (33), 13734-13739CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Viruses have been implicated in the development of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and multiple sclerosis. Human herpesvirus-6 (HHV-6) is a neurotropic virus that has been assocd. with a wide variety of neurol. disorders, including encephalitis, mesial temporal lobe epilepsy, and multiple sclerosis. Currently, the route of HHV-6 entry into the CNS is unknown. Using autopsy specimens, we found that the frequency of HHV-6 DNA in the olfactory bulb/tract region was among the highest in the brain regions examd. Given this finding, we investigated whether HHV-6 may infect the CNS via the olfactory pathway. HHV-6 DNA was detected in a total of 52 of 126 (41.3%) nasal mucous samples, showing the nasal cavity is a reservoir for HHV-6. Furthermore, specialized olfactory-ensheathing glial cells located in the nasal cavity were demonstrated to support HHV-6 replication in vitro. Collectively, these results support HHV-6 utilization of the olfactory pathway as a route of entry into the CNS.
- 9Baig, A. M., Khaleeq, A., Ali, U., and Syeda, H. (2020) Evidence of the COVID-19 virus targeting the CNS: host-virus interactions and proposed neurotropic mechanisms. ACS Chem. Neurosci. 11, 995, DOI: 10.1021/acschemneuro.0c00122Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXkslGrs70%253D&md5=dfcbb06caaebe5f2aaa273ab981b9b69Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic MechanismsBaig, Abdul Mannan; Khaleeq, Areeba; Ali, Usman; Syeda, HiraACS Chemical Neuroscience (2020), 11 (7), 995-998CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)A review. The recent outbreak of coronavirus infectious disease 2019 (COVID-19) has gripped the world with apprehension and a scare of an epic proportion related to its potential to spread and infect the humans' globe wide. As we are in the midst of an ongoing near pandemic outbreak of the COVID-19, the scientists are struggling to understand how it resembles and varies with the severe acute respiratory syndrome coronavirus (SARS-CoV) at the genomic and transcriptomic level. In a short time following the outbreaks, it has been shown that like SARS-CoV, the COVID-19 exploits the angiotensin-converting enzyme 2 (ACE2) receptor to gain entry inside the cells. This finding raises the curiosity of investigating the expression of ACE2 in neurol. tissue and the possible contribution of neurol. tissues damages to the morbidity and mortality of COIVD-19. Here, we investigate the d. of the expression levels of ACE2 in the CNS, the host-virus interaction and relate it to the pathogenesis and complications seen in the recent cases of COVID-19 outbreak. Also, we debate the need for a model of staging COVID-19 based on neurol. tissue involvement.
- 10Sepahi, A., Kraus, A., Casadei, E., Johnston, C. A., Galindo-Villegas, J., Kelly, C., Garcia-Moreno, D., Munoz, P., Mulero, V., Huertas, M., and Salinas, I. (2019) Olfactory sensory neurons mediate ultrarapid antiviral immune responses in a TrkA-dependent manner. Proc. Natl. Acad. Sci. U. S. A. 116 (25), 12428– 36, DOI: 10.1073/pnas.1900083116Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFyktr3I&md5=9326a472f65e7972e9c4299ae8ad7604Olfactory sensory neurons mediate ultrarapid antiviral immune responses in a TrkA-dependent mannerSepahi, Ali; Kraus, Aurora; Casadei, Elisa; Johnston, Christopher A.; Galindo-Villegas, Jorge; Kelly, Cecelia; GarcAa-Moreno, Diana; MuA±oz, Pilar; Mulero, Victoriano; Huertas, Mar; Salinas, IreneProceedings of the National Academy of Sciences of the United States of America (2019), 116 (25), 12428-12436CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The nervous system regulates host immunity in complex ways. Vertebrate olfactory sensory neurons (OSNs) are located in direct contact with pathogens; however, OSNs' ability to detect danger and initiate immune responses is unclear. We report that nasal delivery of rhabdoviruses induces apoptosis in crypt OSNs via the interaction of the OSN TrkA receptor with the viral glycoprotein in teleost fish. This signal results in elec. activation of neurons and very rapid proinflammatory responses in the olfactory organ (OO), but dampened inflammation in the olfactory bulb (OB). CD8α+ cells infiltrate the OO within minutes of nasal viral delivery, and TrkA blocking, but not caspase-3 blocking, abrogates this response. Infiltrating CD8α+ cells were TCRαβ T cells with a nonconventional phenotype that originated from the microvasculature surrounding the OB and not the periphery. Nasal delivery of viral glycoprotein (G protein) recapitulated the immune responses obsd. with the whole virus, and antibody blocking of viral G protein abrogated these responses. Ablation of crypt neurons in zebrafish resulted in increased susceptibility to rhabdoviruses. These results indicate a function for OSNs as a first layer of pathogen detection in vertebrates and as orchestrators of nasal-CNS antiviral immune responses.
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, 582-603. https://doi.org/10.1177/1073858420956905
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Figure 1
Figure 1. Diagram of human nasal cavity with respiratory and olfactory epithelium areas indicated in blue and yellow, respectively.
Figure 2
Figure 2. Basic organization of the olfactory epithelium (OE). Olfactory neurons continuously regenerate through human life and therefore are at different stages of differentiation. Some non-neuronal cells are shown, e.g., progenitors, sustentacular cells, and olfactory ensheathing cells.
References
This article references 10 other publications.
- 1Ou, X., Liu, Y., Lei, X., Li, P., Mi, D., and Ren, L. (2020) Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat. Commun. 11, 1620, DOI: 10.1038/s41467-020-15562-91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlvFyjt78%253D&md5=6b0b1ef5a68f4a35da4aabecb0f99544Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoVOu, Xiuyuan; Liu, Yan; Lei, Xiaobo; Li, Pei; Mi, Dan; Ren, Lili; Guo, Li; Guo, Ruixuan; Chen, Ting; Hu, Jiaxin; Xiang, Zichun; Mu, Zhixia; Chen, Xing; Chen, Jieyong; Hu, Keping; Jin, Qi; Wang, Jianwei; Qian, ZhaohuiNature Communications (2020), 11 (1), 1620CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)Since 2002, beta coronaviruses (CoV) have caused three zoonotic outbreaks, SARS-CoV in 2002-2003, MERS-CoV in 2012, and the newly emerged SARS-CoV-2 in late 2019. However, little is currently known about the biol. of SARS-CoV-2. Here, using SARS-CoV-2 S protein pseudovirus system, we confirm that human angiotensin converting enzyme 2 (hACE2) is the receptor for SARS-CoV-2, find that SARS-CoV-2 enters 293/hACE2 cells mainly through endocytosis, that PIKfyve, TPC2, and cathepsin L are crit. for entry, and that SARS-CoV-2 S protein is less stable than SARS-CoV S. Polyclonal anti-SARS S1 antibodies T62 inhibit entry of SARS-CoV S but not SARS-CoV-2 S pseudovirions. Further studies using recovered SARS and COVID-19 patients' sera show limited cross-neutralization, suggesting that recovery from one infection might not protect against the other. Our results present potential targets for development of drugs and vaccines for SARS-CoV-2.
- 2Hoffmann, M., Kleine-Weber, H., Schroeder, S., Kruger, N., Herrler, T., Erichsen, S., Schiergens, E. S., Herrler, G., Wu, N.-H., Nitsche, A., Muller, M. A., Drosten, C., and Pohlmann, S. (2020) SARS-CoV-2 cell entry depends on ACE2 and TRMPSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 1– 10, DOI: 10.1016/j.cell.2020.02.052There is no corresponding record for this reference.
- 3Ruiz Garcia, S., Deprez, M., Lebrigand, K., Cavard, A., Paquet, A., Arguel, M.-J., and Zaragosi, L.-E. (2019) Novel dynamics of human mucociliary differentiation revealed by single-cell RNA sequencing of nasal epithelial cultures. Development 146, dev.177428, DOI: 10.1242/dev.177428There is no corresponding record for this reference.
- 4Olender, T., Keydar, I., Pinto, J. M., Tatarskyy, P., Alkelai, A., Chien, M.-S., Fishilevich, S., Restrepo, D., Matsunami, H., Gilad, Y., and Lancet, D. (2016) The human olfactory transcriptome. BMC Genomics 17, 619, DOI: 10.1186/s12864-016-2960-34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFSjur3E&md5=582f6170b76bd2df5222388d5af4161fThe human olfactory transcriptomeOlender, Tsviya; Keydar, Ifat; Pinto, Jayant M.; Tatarskyy, Pavlo; Alkelai, Anna; Chien, Ming-Shan; Fishilevich, Simon; Restrepo, Diego; Matsunami, Hiroaki; Gilad, Yoav; Lancet, DoronBMC Genomics (2016), 17 (), 619/1-619/18CODEN: BGMEET; ISSN:1471-2164. (BioMed Central Ltd.)Olfaction is a versatile sensory mechanism for detecting thousands of volatile odorants. Although mol. basis of odorant signaling is relatively well understood considerable gaps remain in the complete charting of all relevant gene products. To address this challenge, we applied RNAseq to four well-characterized human olfactory epithelial samples and compared the results to novel and published mouse olfactory epithelium as well as 16 human control tissues. We identified 194 non-olfactory receptor (OR) genes that are overexpressed in human olfactory tissues vs. controls. The highest overexpression is seen for lipocalins and bactericidal/permeability-increasing (BPI)-fold proteins, which in other species include secreted odorant carriers. Mouse-human discordance in orthologous lipocalin expression suggests different mammalian evolutionary paths in this family. Of the overexpressed genes 36 have documented olfactory function while for 158 there is little or no previous such functional evidence. The latter group includes GPCRs, neuropeptides, solute carriers, transcription factors and biotransformation enzymes. Many of them may be indirectly implicated in sensory function, and ∼70 % are over expressed also in mouse olfactory epithelium, corroborating their olfactory role. Nearly 90 % of the intact OR repertoire, and ∼60 % of the OR pseudogenes are expressed in the olfactory epithelium, with the latter showing a 3-fold lower expression. ORs transcription levels show a 1000-fold inter-paralog variation, as well as significant inter-individual differences. We assembled 160 transcripts representing 100 intact OR genes. These include 1-4 short 5' non-coding exons with considerable alternative splicing and long last exons that contain the coding region and 3' untranslated region of highly variable length. Notably, we identified 10 ORs with an intact open reading frame but with seemingly non-functional transcripts, suggesting a yet unreported OR pseudogenization mechanism. Anal. of the OR upstream regions indicated an enrichment of the homeobox family transcription factor binding sites and a consensus localization of a specific transcription factor binding site subfamily (Olf/EBF). We provide an overview of expression levels of ORs and auxiliary genes in human olfactory epithelium. This forms a transcriptomic view of the entire OR repertoire, and reveals a large no. of over-expressed uncharacterized human non-receptor genes, providing a platform for future discovery.
- 5Kangeswaran, N., Demond, M., and Nagel, M. (2015) Deep sequencing of the murine olfactory receptor transcriptome. PLoS One 10 (1), e0113170, DOI: 10.1371/journal.pone.0113170There is no corresponding record for this reference.
- 6Saraiva, L. R., Ibarra-Soria, X., Khan, M., Omura, M., Scialdone, A., Mombaerts, P., Marioni, J. C., and Logan, D. W. (2015) Hierarchical deconstruction of mouse olfactory sensory neurons: from whole mucosa to single-cell RNA-seq. Sci. Rep. 5, 18178, DOI: 10.1038/srep181786https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVClt7jM&md5=0509de1a33fe8993fcb877889cfa58a0Hierarchical deconstruction of mouse olfactory sensory neurons: from whole mucosa to single-cell RNA-seqSaraiva, Luis R.; Ibarra-Soria, Ximena; Khan, Mona; Omura, Masayo; Scialdone, Antonio; Mombaerts, Peter; Marioni, John C.; Logan, Darren W.Scientific Reports (2015), 5 (), 18178CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)The mouse olfactory mucosa is a complex chemosensory tissue composed of multiple cell types, neuronal and non-neuronal. We have here applied RNA-seq hierarchically, in three steps of decreasing cellular heterogeneity: starting with crude tissue samples dissected from the nose, proceeding to flow-cytometrically sorted pools of mature olfactory sensory neurons (OSNs), and finally arriving at single mature OSNs. We show that 98.9% of intact olfactory receptor (OR) genes are expressed in mature OSNs. We uncover a hitherto unknown bipartition among mature OSNs. We find that 19 of 21 single mature OSNs each express a single intact OR gene abundantly, consistent with the one neuron-one receptor rule. For the 9 single OSNs where the two alleles of the abundantly expressed OR gene exhibit single-nucleotide polymorphisms, we demonstrate that monoallelic expression of the abundantly expressed OR gene is extremely tight. The remaining two single mature OSNs lack OR gene expression but express Trpc2 and Gucy1b2. We establish these two cells as a neuronal cell type that is fundamentally distinct from canonical, OR-expressing OSNs and that is defined by the differential, higher expression of 55 genes. We propose this tiered exptl. approach as a paradigm to unravel gene expression in other cellularly heterogeneous systems.
- 7Netland, J., Meyerholz, D. K., Moore, S., Cassell, M., and Perlman, S. (2008) Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J. Virol 82 (5), 7264– 75, DOI: 10.1128/JVI.00737-087https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXovVSltr4%253D&md5=b5d85df75cb9f2ab540c952704ff5377Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2Netland, Jason; Meyerholz, David K.; Moore, Steven; Cassell, Martin; Perlman, StanleyJournal of Virology (2008), 82 (15), 7264-7275CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)Infection of humans with the severe acute respiratory syndrome coronavirus (SARS-CoV) results in substantial morbidity and mortality, with death resulting primarily from respiratory failure. While the lungs are the major site of infection, the brain is also infected in some patients. Brain infection may result in long-term neurol. sequelae, but little is known about the pathogenesis of SARS-CoV in this organ. We previously showed that the brain was a major target organ for infection in mice that are transgenic for the SARS-CoV receptor (human angiotensin-converting enzyme 2). Herein, we use these mice to show that virus enters the brain primarily via the olfactory bulb, and infection results in rapid, transneuronal spread to connected areas of the brain. This extensive neuronal infection is the main cause of death because intracranial inoculation with low doses of virus results in a uniformly lethal disease even though little infection is detected in the lungs. Death of the animal likely results from dysfunction and/or death of infected neurons, esp. those located in cardiorespiratory centers in the medulla. Remarkably, the virus induces minimal cellular infiltration in the brain. Our results show that neurons are a highly susceptible target for SARS-CoV and that only the absence of the host cell receptor prevents severe murine brain disease.
- 8Harberts, E., Yao, K., Wohler, J. E., Maric, D., Ohayon, J., Henkin, R., and Jacobson, S. (2011) Human herpesvirus-6 entry into CNS through the olfactory pathway. Proc. Natl. Acad. Sci. U. S. A. 108 (33), 13734, DOI: 10.1073/pnas.11051431088https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtV2ms7bO&md5=66c218044b70395b7157be1b543ec3ecHuman herpesvirus-6 entry into the central nervous system through the olfactory pathwayHarberts, Erin; Yao, Karen; Wohler, Jillian E.; Maric, Dragan; Ohayon, Joan; Henkin, Robert; Jacobson, StevenProceedings of the National Academy of Sciences of the United States of America (2011), 108 (33), 13734-13739CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Viruses have been implicated in the development of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and multiple sclerosis. Human herpesvirus-6 (HHV-6) is a neurotropic virus that has been assocd. with a wide variety of neurol. disorders, including encephalitis, mesial temporal lobe epilepsy, and multiple sclerosis. Currently, the route of HHV-6 entry into the CNS is unknown. Using autopsy specimens, we found that the frequency of HHV-6 DNA in the olfactory bulb/tract region was among the highest in the brain regions examd. Given this finding, we investigated whether HHV-6 may infect the CNS via the olfactory pathway. HHV-6 DNA was detected in a total of 52 of 126 (41.3%) nasal mucous samples, showing the nasal cavity is a reservoir for HHV-6. Furthermore, specialized olfactory-ensheathing glial cells located in the nasal cavity were demonstrated to support HHV-6 replication in vitro. Collectively, these results support HHV-6 utilization of the olfactory pathway as a route of entry into the CNS.
- 9Baig, A. M., Khaleeq, A., Ali, U., and Syeda, H. (2020) Evidence of the COVID-19 virus targeting the CNS: host-virus interactions and proposed neurotropic mechanisms. ACS Chem. Neurosci. 11, 995, DOI: 10.1021/acschemneuro.0c001229https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXkslGrs70%253D&md5=dfcbb06caaebe5f2aaa273ab981b9b69Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic MechanismsBaig, Abdul Mannan; Khaleeq, Areeba; Ali, Usman; Syeda, HiraACS Chemical Neuroscience (2020), 11 (7), 995-998CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)A review. The recent outbreak of coronavirus infectious disease 2019 (COVID-19) has gripped the world with apprehension and a scare of an epic proportion related to its potential to spread and infect the humans' globe wide. As we are in the midst of an ongoing near pandemic outbreak of the COVID-19, the scientists are struggling to understand how it resembles and varies with the severe acute respiratory syndrome coronavirus (SARS-CoV) at the genomic and transcriptomic level. In a short time following the outbreaks, it has been shown that like SARS-CoV, the COVID-19 exploits the angiotensin-converting enzyme 2 (ACE2) receptor to gain entry inside the cells. This finding raises the curiosity of investigating the expression of ACE2 in neurol. tissue and the possible contribution of neurol. tissues damages to the morbidity and mortality of COIVD-19. Here, we investigate the d. of the expression levels of ACE2 in the CNS, the host-virus interaction and relate it to the pathogenesis and complications seen in the recent cases of COVID-19 outbreak. Also, we debate the need for a model of staging COVID-19 based on neurol. tissue involvement.
- 10Sepahi, A., Kraus, A., Casadei, E., Johnston, C. A., Galindo-Villegas, J., Kelly, C., Garcia-Moreno, D., Munoz, P., Mulero, V., Huertas, M., and Salinas, I. (2019) Olfactory sensory neurons mediate ultrarapid antiviral immune responses in a TrkA-dependent manner. Proc. Natl. Acad. Sci. U. S. A. 116 (25), 12428– 36, DOI: 10.1073/pnas.190008311610https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFyktr3I&md5=9326a472f65e7972e9c4299ae8ad7604Olfactory sensory neurons mediate ultrarapid antiviral immune responses in a TrkA-dependent mannerSepahi, Ali; Kraus, Aurora; Casadei, Elisa; Johnston, Christopher A.; Galindo-Villegas, Jorge; Kelly, Cecelia; GarcAa-Moreno, Diana; MuA±oz, Pilar; Mulero, Victoriano; Huertas, Mar; Salinas, IreneProceedings of the National Academy of Sciences of the United States of America (2019), 116 (25), 12428-12436CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The nervous system regulates host immunity in complex ways. Vertebrate olfactory sensory neurons (OSNs) are located in direct contact with pathogens; however, OSNs' ability to detect danger and initiate immune responses is unclear. We report that nasal delivery of rhabdoviruses induces apoptosis in crypt OSNs via the interaction of the OSN TrkA receptor with the viral glycoprotein in teleost fish. This signal results in elec. activation of neurons and very rapid proinflammatory responses in the olfactory organ (OO), but dampened inflammation in the olfactory bulb (OB). CD8α+ cells infiltrate the OO within minutes of nasal viral delivery, and TrkA blocking, but not caspase-3 blocking, abrogates this response. Infiltrating CD8α+ cells were TCRαβ T cells with a nonconventional phenotype that originated from the microvasculature surrounding the OB and not the periphery. Nasal delivery of viral glycoprotein (G protein) recapitulated the immune responses obsd. with the whole virus, and antibody blocking of viral G protein abrogated these responses. Ablation of crypt neurons in zebrafish resulted in increased susceptibility to rhabdoviruses. These results indicate a function for OSNs as a first layer of pathogen detection in vertebrates and as orchestrators of nasal-CNS antiviral immune responses.