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Shpichka, et al.
SARS-CoV-2 treatment . Nevertheless, ferret dengue virus, Epstein-Barr virus, and Ebola virus
[3]
models have many limitations which include the infections [35,36] . However, such models require
lack of standardized strains, detailed molecular expensive specific handling and housing and are
profiling, and higher handling and housing costs. not flexible to study different viral infections.
Interestingly, there is a pool of studies describing
domestic animals, such as cats and dogs, as a viral 2.3 Tissue models
model. For instance, a recent study has shown that Compared to the above-mentioned models, tissue
cats are susceptible to human SARS-CoV-2 . models can be considered as the most flexible and
[4]
Such findings provide novel insights into virus ethically humane tools to study viral infections.
targets and its lifecycle. However, cat and dog While designing such models, a researcher can use
models have similar issues as ferret ones as well different cell types, biomaterials, and fabrication
as ethical concerns. methods (including bioprinting) that can work with
Cattle, sheep, and pigs are also used to study a wide range of host-specific viruses. Studying
human viruses. Particularly, sheep and cattle are viruses in vitro under controllable conditions allow
susceptible to RSV and have human-like virus better understanding of host-pathogen interactions
spreading due to similar sizes . The application and high-throughput screening of drug candidates.
[27]
of such models is limited by high handling and All tissue models can be divided into three
housing costs and biosafety considerations (e.g., types with ten subtypes: 2D models (monolayer
pigs can be a reservoir for the reassortment and culture of cell lines and primary cells), 2.5D
transgenic shift of influenza viruses). models (suspension culture using microcarriers
The animal model closest to humans is, and simple air-liquid biointerfaces), and 3D
undoubtedly, primates that have similar genetic, models (explants, organoids/spheroids, embedded
anatomical, and physiological features. For cells, cell-seeded scaffolds, bioprinted constructs,
instance, RSV infection of chimpanzees has all and combined systems [organ-on-a chip]).
symptoms and complications (inflammation, Monolayer (2D) cultures are the oldest and the
acute respiratory distress syndrome, lung edema, most widely used model. Cell lines are usually
etc.) that are typical in humans [32,33] . Primates applied to isolate viruses, develop new serological
are perfect candidates for preclinical studies assays, and produce diagnostic reagents or
of vaccines . Despite all of the mentioned vaccines. The current “gold-standard” cell line
[27]
advantages, they cannot be treated as a routine is Vero, an interferon-deficient aneuploid line of
viral model due to extensive economic, ethical, kidney epithelial cells [37,38] . A549 and Madin–
and logistical burdens. Darby canine kidney cell lines are mostly applied
However, in general, virus strains are highly for influenza viruses .The most common cell
[39]
selective and host-specific; therefore, only a line for the foot-and-mouth disease virus is the
subset of data can be extrapolated to humans. mammalian baby hamster kidney cells which
[40]
Phylogenetically close viruses often have have been used since 1964 . Compared to cell
[41]
different hosts and targets, and these viruses lines, primary cell cultures have some advantages.
also cause different pathophysiologic conditions. For instance, cells isolated from ovine pulmonary
Some drugs, whose efficacy was confirmed using adenocarcinoma are a unique platform to reveal
animal models, failed in clinical trials . One mechanisms of epithelial transformation in a
[34]
of the approaches to overcome these issues is case of the lung cancer caused by the retrovirus
humanization. Humanized animals (usually mice) infection . Despite of the availability of cell
[42]
have specific human expression profiles and are variety and easy handling and scaling, 2D cultures
immunodeficient due to the mutation caused by are not capable of recapitulating fully cell-cell and
severe combined immunodeficiency. They are cell-matrix interactions.
widely used to model human immunodeficiency Suspension culture is also the oldest model
viruses (HIV), herpesviruses, cytomegaloviruses, for viral infections and very common for the

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