PMID- 35632761
OWN - NLM
STAT- MEDLINE
DCOM- 20220531
LR  - 20240214
IS  - 1999-4915 (Electronic)
IS  - 1999-4915 (Linking)
VI  - 14
IP  - 5
DP  - 2022 May 11
TI  - Neuroinvasion and Neurotropism by SARS-CoV-2 Variants in the K18-hACE2 Mouse.
LID - 10.3390/v14051020 [doi]
LID - 1020
AB  - Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) not only affects the 
      respiratory tract but also causes neurological symptoms such as loss of smell and 
      taste, headache, fatigue or severe cerebrovascular complications. Using 
      transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2), we 
      investigated the spatiotemporal distribution and pathomorphological features in 
      the CNS following intranasal infection with SARS-CoV-2 variants, as well as after 
      prior influenza A virus infection. Apart from Omicron, we found all variants to 
      frequently spread to and within the CNS. Infection was restricted to neurons and 
      appeared to spread from the olfactory bulb mainly in basally oriented regions in 
      the brain and into the spinal cord, independent of ACE2 expression and without 
      evidence of neuronal cell death, axonal damage or demyelination. However, 
      microglial activation, microgliosis and a mild macrophage and T cell dominated 
      inflammatory response was consistently observed, accompanied by apoptotic death 
      of endothelial, microglial and immune cells, without their apparent infection. 
      Microgliosis and immune cell apoptosis indicate a potential role of microglia for 
      pathogenesis and viral effect in COVID-19 and the possible impairment of 
      neurological functions, especially in long COVID. These data may also be 
      informative for the selection of therapeutic candidates and broadly support the 
      investigation of agents with adequate penetration into relevant regions of the 
      CNS.
FAU - Seehusen, Frauke
AU  - Seehusen F
AD  - Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, 
      Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland.
FAU - Clark, Jordan J
AU  - Clark JJ
AUID- ORCID: 0000-0003-1790-7883
AD  - Department of Infection Biology and Microbiomes, Institute of Infection, 
      Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 5RF, 
      UK.
FAU - Sharma, Parul
AU  - Sharma P
AD  - Department of Infection Biology and Microbiomes, Institute of Infection, 
      Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 5RF, 
      UK.
FAU - Bentley, Eleanor G
AU  - Bentley EG
AD  - Department of Infection Biology and Microbiomes, Institute of Infection, 
      Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 5RF, 
      UK.
FAU - Kirby, Adam
AU  - Kirby A
AD  - Department of Infection Biology and Microbiomes, Institute of Infection, 
      Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 5RF, 
      UK.
FAU - Subramaniam, Krishanthi
AU  - Subramaniam K
AD  - Department of Infection Biology and Microbiomes, Institute of Infection, 
      Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 5RF, 
      UK.
FAU - Wunderlin-Giuliani, Sabina
AU  - Wunderlin-Giuliani S
AD  - Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, 
      Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland.
FAU - Hughes, Grant L
AU  - Hughes GL
AUID- ORCID: 0000-0002-7567-7185
AD  - Departments of Vector Biology and Tropical Disease Biology, Centre for Neglected 
      Tropical Disease, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK.
FAU - Patterson, Edward I
AU  - Patterson EI
AUID- ORCID: 0000-0003-3465-0848
AD  - Departments of Vector Biology and Tropical Disease Biology, Centre for Neglected 
      Tropical Disease, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK.
FAU - Michael, Benedict D
AU  - Michael BD
AUID- ORCID: 0000-0002-8693-8926
AD  - Department of Clinical Infection Microbiology and Immunology and NIHR Health 
      Protection Research Unit in Emerging and Zoonotic Infections, Institute of 
      Infection, Veterinary, and Ecological Sciences, University of Liverpool, 
      Liverpool L69 7BE, UK.
AD  - Department of Neurology, The Walton Centre NHS Foundation Trust, Liverpool L9 
      7AL, UK.
FAU - Owen, Andrew
AU  - Owen A
AUID- ORCID: 0000-0002-9819-7651
AD  - Department of Pharmacology and Therapeutics, Centre of Excellence in Long-Acting 
      Therapeutics (CELT), University of Liverpool, Liverpool L3 3NY, UK.
FAU - Hiscox, Julian A
AU  - Hiscox JA
AD  - Department of Infection Biology and Microbiomes, Institute of Infection, 
      Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 5RF, 
      UK.
FAU - Stewart, James P
AU  - Stewart JP
AUID- ORCID: 0000-0002-8928-2037
AD  - Department of Infection Biology and Microbiomes, Institute of Infection, 
      Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 5RF, 
      UK.
FAU - Kipar, Anja
AU  - Kipar A
AUID- ORCID: 0000-0001-7289-3459
AD  - Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, 
      Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland.
AD  - Department of Infection Biology and Microbiomes, Institute of Infection, 
      Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 5RF, 
      UK.
LA  - eng
GR  - MR/W005611/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/T028750/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/V007181//1/MRC_/Medical Research Council/United Kingdom
GR  - WT_/Wellcome Trust/United Kingdom
GR  - MR/V03605X/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/V007181/1/MRC_/Medical Research Council/United Kingdom
GR  - 75F40120C00085/FD/FDA HHS/United States
GR  - ISSF201902/3/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20220511
PL  - Switzerland
TA  - Viruses
JT  - Viruses
JID - 101509722
RN  - EC 3.4.17.23 (ACE2 protein, human)
RN  - EC 3.4.17.23 (Angiotensin-Converting Enzyme 2)
RN  - SARS-CoV-2 variants
SB  - IM
MH  - *Angiotensin-Converting Enzyme 2/genetics
MH  - Animals
MH  - *COVID-19/complications
MH  - *Central Nervous System/physiopathology/virology
MH  - Humans
MH  - Mice
MH  - Mice, Transgenic
MH  - SARS-CoV-2/genetics
MH  - *Viral Tropism
MH  - Post-Acute COVID-19 Syndrome
PMC - PMC9146514
OTO - NOTNLM
OT  - COVID-19
OT  - Severe Acute Respiratory Syndrome Coronavirus 2
OT  - encephalitis
OT  - influenza A virus coinfection
OT  - microgliosis
OT  - mouse model
OT  - virus variants
COIS- The authors declare no conflict of interest.
EDAT- 2022/05/29 06:00
MHDA- 2022/06/01 06:00
PMCR- 2022/05/11
CRDT- 2022/05/28 01:45
PHST- 2022/03/31 00:00 [received]
PHST- 2022/05/07 00:00 [revised]
PHST- 2022/05/09 00:00 [accepted]
PHST- 2022/05/28 01:45 [entrez]
PHST- 2022/05/29 06:00 [pubmed]
PHST- 2022/06/01 06:00 [medline]
PHST- 2022/05/11 00:00 [pmc-release]
AID - v14051020 [pii]
AID - viruses-14-01020 [pii]
AID - 10.3390/v14051020 [doi]
PST - epublish
SO  - Viruses. 2022 May 11;14(5):1020. doi: 10.3390/v14051020.