PMID- 36940916
OWN - NLM
STAT- MEDLINE
DCOM- 20230411
LR  - 20240402
IS  - 1872-9096 (Electronic)
IS  - 0166-3542 (Print)
IS  - 0166-3542 (Linking)
VI  - 212
DP  - 2023 Apr
TI  - SARS-CoV-2 Omicron (B.1.1.529) shows minimal neurotropism in a double-humanized 
      mouse model.
PG  - 105580
LID - S0166-3542(23)00058-X [pii]
LID - 10.1016/j.antiviral.2023.105580 [doi]
AB  - Although severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) initially 
      infects the respiratory tract, it also directly or indirectly affects other 
      organs, including the brain. However, little is known about the relative 
      neurotropism of SARS-CoV-2 variants of concern (VOCs), including Omicron 
      (B.1.1.529), which emerged in November 2021 and has remained the dominant 
      pathogenic lineage since then. To address this gap, we examined the relative 
      ability of Omicron, Beta (B.1.351), and Delta (B.1.617.2) to infect the brain in 
      the context of a functional human immune system by using human 
      angiotensin-converting enzyme 2 (hACE2) knock-in triple-immunodeficient NGC mice 
      with or without reconstitution with human CD34(+) stem cells. Intranasal 
      inoculation of huCD34(+)-hACE2-NCG mice with Beta and Delta resulted in 
      productive infection of the nasal cavity, lungs, and brain on day 3 
      post-infection, but Omicron was surprisingly unique in its failure to infect 
      either the nasal tissue or brain. Moreover, the same infection pattern was 
      observed in hACE2-NCG mice, indicating that antiviral immunity was not 
      responsible for the lack of Omicron neurotropism. In independent experiments, we 
      demonstrate that nasal inoculation with Beta or with D614G, an ancestral 
      SARS-CoV-2 with undetectable replication in huCD34(+)-hACE2-NCG mice, resulted in 
      a robust response by human innate immune cells, T cells, and B cells, confirming 
      that exposure to SARS-CoV-2, even without detectable infection, is sufficient to 
      induce an antiviral immune response. Collectively, these results suggest that 
      modeling of the neurologic and immunologic sequelae of SARS-CoV-2 infection 
      requires careful selection of the appropriate SARS-CoV-2 strain in the context of 
      a specific mouse model.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Alves, Rubens Prince Dos Santos
AU  - Alves RPDS
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology, La Jolla, CA, USA.
FAU - Wang, Ying-Ting
AU  - Wang YT
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology, La Jolla, CA, USA.
FAU - Mikulski, Zbigniew
AU  - Mikulski Z
AD  - Microscopy and Histology Core Facility, La Jolla Institute for Immunology, La 
      Jolla, CA, USA.
FAU - McArdle, Sara
AU  - McArdle S
AD  - Microscopy and Histology Core Facility, La Jolla Institute for Immunology, La 
      Jolla, CA, USA.
FAU - Shafee, Norazizah
AU  - Shafee N
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology, La Jolla, CA, USA.
FAU - Valentine, Kristen M
AU  - Valentine KM
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology, La Jolla, CA, USA.
FAU - Miller, Robyn
AU  - Miller R
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology, La Jolla, CA, USA.
FAU - Verma, Shailendra Kumar
AU  - Verma SK
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology, La Jolla, CA, USA.
FAU - Batiz, Fernanda Ana Sosa
AU  - Batiz FAS
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology, La Jolla, CA, USA.
FAU - Maule, Erin
AU  - Maule E
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology, La Jolla, CA, USA.
FAU - Nguyen, Michael N
AU  - Nguyen MN
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology, La Jolla, CA, USA.
FAU - Timis, Julia
AU  - Timis J
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology, La Jolla, CA, USA.
FAU - Mann, Colin
AU  - Mann C
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology, La Jolla, CA, USA.
FAU - Zandonatti, Michelle
AU  - Zandonatti M
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology, La Jolla, CA, USA.
FAU - Alarcon, Suzie
AU  - Alarcon S
AD  - Sequencing Core Facility, La Jolla Institute for Immunology, La Jolla, CA, USA.
FAU - Rowe, Jenny
AU  - Rowe J
AD  - Charles River Laboratories Research Models and Services Inc., Wilmington, MA, 
      USA.
FAU - Kronenberg, Mitchell
AU  - Kronenberg M
AD  - Division of Developmental Immunology, La Jolla Institute for Immunology, La 
      Jolla, CA, USA.
FAU - Weiskopf, Daniela
AU  - Weiskopf D
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology, La Jolla, CA, USA.
FAU - Sette, Alessandro
AU  - Sette A
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology, La Jolla, CA, USA; Department of Medicine, Division of Infectious 
      Diseases and Global Public Health, University of California, San Diego, La Jolla, 
      CA, 92037, USA.
FAU - Hastie, Kathryn
AU  - Hastie K
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology, La Jolla, CA, USA.
FAU - Saphire, Erica Ollmann
AU  - Saphire EO
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology, La Jolla, CA, USA.
FAU - Festin, Stephen
AU  - Festin S
AD  - Charles River Laboratories Research Models and Services Inc., Wilmington, MA, 
      USA.
FAU - Kim, Kenneth
AU  - Kim K
AD  - Histopathology Core Facility, La Jolla Institute for Immunology, La Jolla, CA, 
      USA. Electronic address: kenneth@lji.org.
FAU - Shresta, Sujan
AU  - Shresta S
AD  - Center for Infectious Disease and Vaccine Research, La Jolla Institute for 
      Immunology, La Jolla, CA, USA. Electronic address: sujan@lji.org.
LA  - eng
GR  - T32 AI007036/AI/NIAID NIH HHS/United States
GR  - U19 AI142790/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230320
PL  - Netherlands
TA  - Antiviral Res
JT  - Antiviral research
JID - 8109699
RN  - 0 (Antiviral Agents)
RN  - SARS-CoV-2 variants
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - *SARS-CoV-2
MH  - *COVID-19
MH  - Brain
MH  - Antiviral Agents
MH  - Disease Models, Animal
PMC - PMC10027296
OTO - NOTNLM
OT  - Brain
OT  - COVID-19
OT  - Human ACE2
OT  - Human CD34 immune cells
OT  - Mouse model
OT  - NCG
OT  - Neurotropism
OT  - Omicron
OT  - SARS-CoV-2
OT  - T cell
COIS- SF and JR are employed by Charles River Laboratories, Inc. AS is a consultant for 
      Gritstone, Flow Pharma, Arcturus, Immunoscape, CellCarta, Oxford Immunotech, and 
      Avalia. The remaining authors declare no competing interests. SF and JR are 
      employed by Charles River Laboratories, Inc. AS is a consultant for Gritstone, 
      Flow Pharma, Arcturus, Immunoscape, CellCarta, Oxford Immunotech, and Avalia. The 
      remaining authors declare no competing interests.
EDAT- 2023/03/21 06:00
MHDA- 2023/04/11 06:42
PMCR- 2023/03/20
CRDT- 2023/03/20 20:25
PHST- 2023/01/26 00:00 [received]
PHST- 2023/03/08 00:00 [revised]
PHST- 2023/03/15 00:00 [accepted]
PHST- 2023/04/11 06:42 [medline]
PHST- 2023/03/21 06:00 [pubmed]
PHST- 2023/03/20 20:25 [entrez]
PHST- 2023/03/20 00:00 [pmc-release]
AID - S0166-3542(23)00058-X [pii]
AID - 105580 [pii]
AID - 10.1016/j.antiviral.2023.105580 [doi]
PST - ppublish
SO  - Antiviral Res. 2023 Apr;212:105580. doi: 10.1016/j.antiviral.2023.105580. Epub 
      2023 Mar 20.