3.1 Mouse Model:
Mice are the most widely used animal models in infectious disease
research. Many inbred mouse strains have been tested for SARS-CoV
infections. BALB/c mice, C57BL/6 (B6) and 129SvEv mice were challenged
intranasally with Urbani strain (Glass, Subbarao, Murphy, & Murphy,
2004; Roberts et al., 2005). This resulted in a productive infection
with peak titers on day 3 but there was an early clearance of the virus.
Furthermore, mice did not lose weight, display signs of clinical
disease, or develop pulmonary pathology that were observed in humans
(Yin & Wunderink, 2018). Mutant mice such as B6, Beige, and
CD1−/− (lack NK cell function and NK-T cells) and
RAG1−/− mice (lack T and B lymphocytes) did not
develop clinical disease (Glass et al., 2004).
STAT1−/− mice showed some clinical signs of weight
loss and bronchiolitis but were unable to show the pathological signs
and mortality as observed in human cases (Frieman et al., 2010).
Examination of the amino acid sequence of mouse and rat revealed
differences in the amino acids at positions 353 and 82. Mice have
histidine and humans have lysine at position 353 (F. Li, Li, Farzan, &
Harrison, 2005) which may explain the reason why SARS-CoV replicated
less efficiently in murine cells (W. Li et al., 2004). At position 82,
mice ACE2 has serine whereas human ACE2 has methionine, but this
difference did not prevent the S-protein of SARS-CoV to bind mice cells
and internalize but reduced permissiveness of these cells to infection,
thus, making it semi-permissive to the SARS-CoV. Therefore, there is a
need to generate ”transgenic” mice or mouse should be adapted to become
permissive to SARS-CoV infection.
Various transgenic mouse models like mice expressing the human ACE2
(hACE2) receptor and transgenic hACE2 under the control of an epithelial
cell-specific promoter K18, showed infectivity with disease pathogenesis
similar to that in humans (Bao et al., 2020; McCray et al., 2007),
making them suitable for pathogenesis studies and evaluation of vaccines
and other therapeutics against SARS-CoVs. The genetically engineered
mice expressing the human ACE-2 (hACE2) were suitable for SARS-CoV
infection and produced mortality (Dediego et al., 2008). Different
contract research companies have produced hACE-2 expressing mice models
and are already supplying it for SARS-CoV-2 studies. Taconic
Biosciences, Rensselaer, New York, is supporting CoV research by
providing ACE2-expressing mice that have been transplanted with human
leukocyte antigen (HLA). The Jackson Laboratory (JAX), Maine, Florida is
working to provide transgenic mouse expressing hACE-2 that were
originally developed by Dr. Stanley Perlman at the University of Iowa. A
study by Bao et. al . have used the mice model for SARS-CoV-2 and
reported that transgenic hACE2 mice, when inoculated with
BetaCoV/Wuhan/IVDC-HB-01/2020|EPI_ISL_402119 strain,
developed clinical signs of COVID-19, including weight loss and
interstitial pneumonia with histopathological signs in lungs(Table 1) (Bao et al., 2020). Another study by Sheahan
et. al. showed that an orally bioavailable broad-spectrum,
ribonucleoside analog β-D-N4-hydroxycytidine (NHC, EIDD-1931), is able
to inhibit SARS-CoV-2 replication. Following intranasal challenge with a
mouse-adapted 2019-nCoV/USA-WA1/2020 strain of SARS-CoV-2 virus;
resulted in such as nasal congestion & difficulty in breathing that
have been reported in COVID-19 patients (Sheahan et al., 2020).(Table 1) . Researchers at the University of Pittsburgh School
of Medicine have developed a vaccine candidate “PittCoVacc” (Pittsburgh
CoV Vaccine) using in vitro -generated fragments of viral protein.
Administration of the vaccine to transgenic BABL/c mice resulted in the
successful production of neutralizing antibodies against SARS-CoV-2 (E.
Kim et al., 2020). Researchers at the NIH tested a mRNA vaccine
developed by Moderna in Phase I clinical trials and confirmed immune
responses by natural infection, which is now in its Phase II trial
(”Moderna Moderna announces funding award from CEPI to accelerate
development of messenger RNA (mRNA) vaccine against novel coronavirus;
2020. [accessed 2020 February15]
,”). administration of an inactivated SARS-CoV-2 vaccine, PiCoVacc, to
ten BALB/c mice at multiple doses on day-0 and day-7 produced a good
amount of SARS-CoV-2 spike and Receptor Binding Domain -specific
immunoglobulin G (Ig G) responses (Q. Gao et al., 2020). All these
studies signify the importance of mouse models in the testing of
vaccines against SARS-CoV-2.
The major limitation with mice is that they are partially permissive to
SARS-CoV infection due to the differences in the residues in ACE2 that
are required for the cellular attachment and entry of SARS-CoV (F. Li et
al., 2005). Mice adapted SARS-CoV-2 strains are suitable for use in
pathogenesis, vaccine and therapeutic studies (Table 2) .
Altogether certain genetically engineered mice models can be useful in
pathogenesis studies and testing vaccines and antivirals because of
their small size, body weight, easy availability, and cost effectiveness
for initial studies including high throughput screening.