The neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2

Bauer, Lisa; Laksono, Brigitta M.; Vrij, Femke M.S. de; Kushner, Steven A.; Harschnitz, Oliver; Riel, Debby van

doi:10.1016/j.tins.2022.02.006

Cited by 154 publications

(142 citation statements)

References 121 publications

(161 reference statements)

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“…Evidence suggests that D614G is neuroinvasive, in at least a subset of patients and experimentally inoculated animals (Meinhardt et al, 2021; de Melo et al, 2021). Although SARS-CoV-2 might enter the central nervous system (CNS) via different routes, evidence suggests that the olfactory nerve is an important route of entry into the CNS (Bauer et al, 2022). The olfactory nerve connects the olfactory mucosa directly with the olfactory bulb in the brain and thus represents a shortcut between the nasal cavity and the brain (Riel et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Differences in neuroinflammation in the olfactory bulb between D614G, Delta and Omicron BA.1 SARS-CoV-2 variants in the hamster model

Bauer

Rissmann

Benavides

et al. 2022

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with various neurological complications. SARS-CoV-2 infection induces neuroinflammation in the central nervous system (CNS), whereat the olfactory bulb seems to be involved most frequently. Here we show differences in the neuroinvasiveness and neurovirulence among SARS-CoV-2 variants in the hamster model five days post inoculation. Replication in the olfactory mucosa was observed in all hamsters, but most prominent in D614 inoculated hamsters. We observed neuroinvasion into the CNS via the olfactory nerve in D614G-, but not Delta (B.1.617.2)- or Omicron BA.1 (B.1.1.529) inoculated hamsters. Neuroinvasion was associated with neuroinflammation in the olfactory bulb of hamsters inoculated with D614G but hardly in Delta or Omicron BA.1. Altogether, this indicates that there are differences in the neuroinvasive and neurovirulent potential among SARS-CoV-2 variants in the acute phase of the infection in the hamster model.

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Section: Introductionmentioning

confidence: 99%

Differences in neuroinflammation in the olfactory bulb between D614G, Delta and Omicron BA.1 SARS-CoV-2 variants in the hamster model

Bauer

Rissmann

Benavides

et al. 2022

Preprint

Self Cite

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“…When some polymorphisms (NSP1 K194R and NSP13 A335V) present in MHV-JHM.SD were introduced into an MHV-JHM.WU-like virus, the viral replication in the liver was diminished, but there is no data on the brain viral titers or overall lethality and weight loss that mice experienced [ 97 ]. Such results are difficult to extrapolate to SARS-CoV-2, which seems not to be as neurovirulent [ 148 ] and does not readily replicate in the liver in most individuals [ 149 ]. In fact, SARS-CoV-2, SARS-CoV MA15 and Urbani and MERS-CoV are primarily respiratory viruses, but MHV-A59 and MHV-JHM have a broader tropism and replicate effectively in the brain, spleen and liver [ 149 ].…”

Section: Discussionmentioning

confidence: 99%

The Reassessed Potential of SARS-CoV-2 Attenuation for COVID-19 Vaccine Development—A Systematic Review

Goławski

Lewandowski

Jabłońska

et al. 2022

Viruses

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Live-attenuated SARS-CoV-2 vaccines received relatively little attention during the COVID-19 pandemic. Despite this, several methods of obtaining attenuated coronaviruses are known. In this systematic review, the strategies of coronavirus attenuation, which may potentially be applied to SARS-CoV-2, were identified. PubMed, Scopus, Web of Science and Embase databases were searched to identify relevant articles describing attenuating mutations tested in vivo. In case of coronaviruses other than SARS-CoV-2, sequence alignment was used to exclude attenuating mutations that cannot be applied to SARS-CoV-2. Potential immunogenicity, safety and efficacy of the attenuated SARS-CoV-2 vaccine were discussed based on animal studies data. A total of 27 attenuation strategies, used to create 101 different coronaviruses, have been described in 56 eligible articles. The disruption of the furin cleavage site in the SARS-CoV-2 spike protein was identified as the most promising strategy. The replacement of core sequences of transcriptional regulatory signals, which prevents recombination with wild-type viruses, also appears particularly advantageous. Other important attenuating mutations encompassed mostly the prevention of evasion of innate immunity. Sufficiently attenuated coronaviruses typically caused no meaningful disease in susceptible animals and protected them from challenges with virulent virus. This indicates that attenuated COVID-19 vaccines may be considered as a potential strategy to fight the threat posed by SARS-CoV-2.

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“…The nasal epithelium is the primary site for the neuroinvasiveness of most neurotropic respiratory viruses [8,[44][45][46][47][48]. It consists of the RE and OE, which are located in the inferioranterior and superior-posterior regions of the nasal cavity, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to airway and pulmonary symptoms, reduction or sudden loss of smell or taste has been reported in approximately half of all COVID-19 patients [3][4][5]. Furthermore, a wide range of central and peripheral neurological symptoms have been observed in patients with severe disease [6,7], suggesting that SARS-CoV-2 may target cells within the central nervous system (CNS) [8]. Currently, few animal models of COVID-19-associated anosmia, ageusia, and SARS-CoV-2 neuroinvasion are available [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

PHEV infection: A promising model of betacoronavirus-associated neurological and olfactory dysfunction

Shi

Zhang

et al. 2022

PLoS Pathog

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Porcine hemagglutinating encephalomyelitis virus (PHEV) is a highly neurotropic coronavirus belonging to the genus Betacoronavirus. Similar to pathogenic coronaviruses to which humans are susceptible, such as SARS-CoV-2, PHEV is transmitted primarily through respiratory droplets and close contact, entering the central nervous system (CNS) from the peripheral nerves at the site of initial infection. However, the neuroinvasion route of PHEV are poorly understood. Here, we found that BALB/c mice are susceptible to intranasal PHEV infection and showed distinct neurological manifestations. The behavioral study and histopathological examination revealed that PHEV attacks neurons in the CNS and causes significant smell and taste dysfunction in mice. By tracking neuroinvasion, we identified that PHEV invades the CNS via the olfactory nerve and trigeminal nerve located in the nasal cavity, and olfactory sensory neurons (OSNs) were susceptible to viral infection. Immunofluorescence staining and ultrastructural observations revealed that viral materials traveling along axons, suggesting axonal transport may engage in rapid viral transmission in the CNS. Moreover, viral replication in the olfactory system and CNS is associated with inflammatory and immune responses, tissue disorganization and dysfunction. Overall, we proposed that PHEV may serve as a potential prototype for elucidating the pathogenesis of coronavirus-associated neurological complications and olfactory and taste disorders.

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The neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2

Cited by 154 publications

References 121 publications

Differences in neuroinflammation in the olfactory bulb between D614G, Delta and Omicron BA.1 SARS-CoV-2 variants in the hamster model

Differences in neuroinflammation in the olfactory bulb between D614G, Delta and Omicron BA.1 SARS-CoV-2 variants in the hamster model

The Reassessed Potential of SARS-CoV-2 Attenuation for COVID-19 Vaccine Development—A Systematic Review

PHEV infection: A promising model of betacoronavirus-associated neurological and olfactory dysfunction

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