PMID- 37762442
OWN - NLM
STAT- MEDLINE
DCOM- 20230929
LR  - 20231003
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 24
IP  - 18
DP  - 2023 Sep 15
TI  - Exploring the Syndecan-Mediated Cellular Internalization of the SARS-CoV-2 
      Omicron Variant.
LID - 10.3390/ijms241814140 [doi]
LID - 14140
AB  - SARS-CoV-2 variants evolve to rely more on heparan sulfate (HS) for viral 
      attachment and subsequent infection. In our earlier work, we demonstrated that 
      the Delta variant's spike protein binds more strongly to HS compared to WT 
      SARS-CoV-2, leading to enhanced cell internalization via syndecans (SDCs), a 
      family of transmembrane HS proteoglycans (HSPGs) facilitating the cellular entry 
      of the original strain. Using our previously established ACE2- or 
      SDC-overexpressing cellular models, we now compare the ACE2- and SDC-dependent 
      cellular uptake of heat-inactivated WT SARS-CoV-2 with the Delta and Omicron 
      variants. Internalization studies with inactivated virus particles showed that 
      ACE2 overexpression could not compensate for the loss of HS in Omicron's 
      internalization, suggesting that this variant primarily uses HSPGs to enter 
      cells. Although SDCs increased the internalization of all three viruses, subtle 
      differences could be detected between their SDC isoform preferences. The Delta 
      variant particularly benefitted from SDC1, 2, and 4 overexpression for cellular 
      entry, while SDC4 had the most prominent effect on Omicron internalization. The 
      SDC4 knockdown (KD) in Calu-3 cells reduced the cellular uptake of all three 
      viruses, but the inhibition was the most pronounced for Omicron. The polyanionic 
      heparin also hindered the cellular internalization of all three viruses with a 
      dominant inhibitory effect on Omicron. Omicron's predominant HSPG affinity, 
      combined with its preference for the universally expressed SDC4, might account 
      for its efficient transmission yet reduced pathogenicity.
FAU - Letoha, Annamaria
AU  - Letoha A
AD  - Department of Medicine, Albert Szent-Gyorgyi Clinical Center, Faculty of 
      Medicine, University of Szeged, 6720 Szeged, Hungary.
FAU - Hudak, Anett
AU  - Hudak A
AD  - Pharmacoidea Ltd., H-6726 Szeged, Hungary.
FAU - Letoha, Tamas
AU  - Letoha T
AUID- ORCID: 0000-0002-6035-4009
AD  - Pharmacoidea Ltd., H-6726 Szeged, Hungary.
LA  - eng
GR  - 2020-1.1.6-JOVO-2021-00012/National Development Agency/
PT  - Journal Article
DEP - 20230915
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Syndecans)
RN  - EC 3.4.17.23 (Angiotensin-Converting Enzyme 2)
RN  - 0 (Heparan Sulfate Proteoglycans)
RN  - 9050-30-0 (Heparitin Sulfate)
RN  - 0 (Extracellular Matrix Proteins)
RN  - SARS-CoV-2 variants
SB  - IM
MH  - Humans
MH  - Syndecans
MH  - *SARS-CoV-2
MH  - Angiotensin-Converting Enzyme 2
MH  - *COVID-19
MH  - Heparan Sulfate Proteoglycans/genetics
MH  - Heparitin Sulfate
MH  - Extracellular Matrix Proteins
PMC - PMC10531417
OTO - NOTNLM
OT  - Delta variant
OT  - Omicron
OT  - SARS-CoV-2
OT  - cellular entry
OT  - endocytosis
OT  - heparan sulfate proteoglycans
OT  - syndecan
COIS- The authors declare no conflict of interest.
EDAT- 2023/09/28 06:42
MHDA- 2023/09/29 06:44
PMCR- 2023/09/15
CRDT- 2023/09/28 01:19
PHST- 2023/08/14 00:00 [received]
PHST- 2023/09/05 00:00 [revised]
PHST- 2023/09/13 00:00 [accepted]
PHST- 2023/09/29 06:44 [medline]
PHST- 2023/09/28 06:42 [pubmed]
PHST- 2023/09/28 01:19 [entrez]
PHST- 2023/09/15 00:00 [pmc-release]
AID - ijms241814140 [pii]
AID - ijms-24-14140 [pii]
AID - 10.3390/ijms241814140 [doi]
PST - epublish
SO  - Int J Mol Sci. 2023 Sep 15;24(18):14140. doi: 10.3390/ijms241814140.