Replicative capacity of SARS-CoV-2 omicron variants BA.5 and BQ.1.1 at elevated temperatures

概要

Correspondence

Replicative capacity of
SARS-CoV-2 omicron
variants BA.5 and BQ.1.1
at elevated
temperatures
After the SARS-CoV-2 omicron variants
replaced the delta variant (B.1.617.2),
omicron subvariants, including BQ.1.1
and XBB, emerged and became the
dominant strain worldwide. Although
the omicron subvariants are more
immunoevasive than earlier variants,1,2
their virological characteristics, such
as replicative capacity in respiratory
organs during pyrexia,3 are not fully
understood.
We compared the replicative
capacity of B.1.617.2, BA.5, and
BQ.1.1 during pyrexia by using
human alveolar epithelial cells
(AECs) in an air–liquid interface
culture, which were generated
from induced pluripotent stem
cells. Human AECs were infected
with 1 × 10⁴ 50% tissue culture
infectious dose (TCID50) of B.1.617.2,
BA.5, and BQ.1.1, and incubated at
two different temperatures, 37°C
(normal human body temperature)
and 40°C (elevated human body
temperature during illness). Samples
were collected daily from the apical
surface of the AECs up to 4 days post
infection (dpi) for viral titration. All
three variants had similar growth
kinetics on human AECs at 37°C,
reaching peak titres of 10⁷ ·⁵–10⁸ ·⁵
TCID50/mL at 2 dpi (appendix p 2).
Notably, although the viral titres of
B.1.617.2 at 2 dpi were 10 times lower
at 40°C (10⁶ ·⁵ TCID 50/mL) than at
37°C (10⁸·² TCID50/mL), viral titres of
BA.5 were 1000 times lower at 40°C
(10⁴·⁶ TCID50/mL) than at 37°C (10⁷·⁵
TCID50/mL), and BQ.1.1 was unable to
replicate at the higher temperature in
human AECs (appendix p 2).

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In Vero E6 cells expressing TMPRSS2
(VeroE6/TMPRSS2), the three
SARS-CoV-2 variants had similar
replication kinetics at 37°C to those in
human AECs at the same temperature,
with peak titres at 2 dpi (appendix p 1).
Virus-infected VeroE6/TMPRSS2 cells
grown at 37°C were dead by 3 dpi due
to virus growth. At 40°C in VeroE6/
TMPRSS2 cells, the titre of B.1.617.2
was again 10 times lower than that at
37°C (appendix p 1). The virus titres for
BA.5 and BQ.1.1 were also substantially
reduced at 40°C compared with titres
at 37°C, showing that the replicative
capacities of BA.5 and BQ.1.1 were
restricted at the higher temperature.
Our data show that omicron
variants—especially BQ.1.1 — can­
not replicate efficiently at high
temperatures, unlike B.1.617.2. Because
pyrexia is one of the most common
symptoms in patients with SARSCoV-2 infection (including the omicron
variant), elevated body temperature
during the illness might substantially
restrict BA.5 and BQ.1.1 replication in
the lungs and could have an important
role in limiting disease severity caused
by the omicron variants. Thus, BA.5
and BQ.1.1 show lower pathogenicity
than B.1.617.2. Further study is needed
to reveal the determinants responsible
for the temperature sensitivity of
SARS-CoV-2 variants, which could
lead to a better understanding of viral
pathogenesis.
YM designed and did infection experiments and data
analysis. ST and SG generated human AECs derived
from induced pluripotent stem cells. PJH, TN, and YK
obtained funding, conceived the study, and wrote
the draft, with all other authors providing editorial
comments. YK is supported by grants from the
Center for Research on Influenza Pathogenesis
(HHSN272201400008C) and from the Center for
Research on Influenza Pathogenesis and
Transmission (75N93021C00014), funded by the
National Institute of Allergy and Infectious Disease;
by a Research Program on Emerging and Reemerging
Infectious Diseases (JP21fk0108552 and
JP21fk0108615), a Project Promoting Support for
Drug Discovery (JP21nf0101632), the Japan Program
for Infectious Diseases Research and Infrastructure

(JP22wm0125002), and a grant (JP223fa627001)
from the Japan Agency for Medical Research and
Development; and has received unrelated funding
support from Daiichi Sankyo Pharmaceutical,
Toyama Chemical, Tauns Laboratories, Shionogi,
Otsuka Pharmaceutical, KM Biologics, Kyoritsu
Seiyaku, Shinya Corporation, and Fuji Rebio. TN is
supported by the JST Core Research for Evolutional
Science and Technology (JPMJCR20HA), the JSPS
Core-to-Core Program A (JPJSCCA20190008), the
Kansai Economic Federation (KANKEIREN), the Joint
Research Project of the Institute of Medical Science at
the University of Tokyo, and the Joint Usage/Research
Center Program of the Institute for Life and Medical
Sciences at Kyoto University. SG is supported by the
Fight Corona Project funded by the COVID-19 Private
Fund (to Shinya Yamanaka, CiRA, Kyoto University),
has received unrelated funding support from Kyorin
Pharmaceutical, and is a founder and shareholder of
HiLung. All other authors declare no competing
interests. We thank Susan Watson for scientific
editing. We also thank Chiho Onishi, Koichi Igura, and
Naoyuki Sone for technical assistance.

Published Online
April 24, 2023
https://doi.org/10.1016/
S2666-5247(23)00100-3

Copyright © 2023 The Author(s). Published by
Elsevier Ltd. This is an Open Access article under the
CC BY-NC-ND 4.0 license.

Yukiko Muramoto, Senye Takahashi,
Peter J Halfmann, Shimpei Gotoh,
*Takeshi Noda, *Yoshihiro Kawaoka
t-noda@infront.kyoto-u.ac.jp;
yoshihiro.kawaoka@wisc.edu
Laboratory of Ultrastructural Virology, Institute for
Life and Medical Sciences, and Laboratory of
Ultrastructural Virology, Graduate School of
Biostudies, Kyoto University, Kyoto 606-8507, Japan
(YM, TN); CREST, Japan Science and Technology
Agency, Saitama, Japan (YM, TN, ST, SG); Center for
iPS Cell Research and Application, Kyoto University,
Kyoto, Japan (ST, SG); Influenza Research Institute,
Department of Pathobiological Sciences, School of
Veterinary Medicine, University of Wisconsin–
Madison, Madison, WI, USA (PJH, YK); Division of
Virology, Institute of Medical Science, University of
Tokyo, Tokyo 108-8639, Japan (YK); The Research
Center for Global Viral Diseases, National Center for
Global Health and Medicine Research Institute,
Tokyo, Japan (YK); The University of Tokyo,
Pandemic Preparedness, Infection and Advanced
Research Center (UTOPIA), Tokyo, Japan (YK)
1
2

3

Imai M, Ito M, Kiso M, et al. Efficacy of antiviral
agents against omicron subvariants BQ.1.1
and XBB. N Engl J Med 2023; 388: 89–91.
Uraki R, Ito M, Furusawa Y, et al. Humoral
immune evasion of the omicron subvariants
BQ.1.1 and XBB. Lancet Infect Dis 2023;
23: 30–32.
Herder V, Dee K, Wojtus JK, et al. Elevated
temperature inhibits SARS-CoV-2 replication
in respiratory epithelium independently of
IFN-mediated innate immune defenses.
PLoS Biol 2021; 19: e3001065. ...