In respiratory tract involvement, SARS-CoV-2 causes symptoms from viral pneumonia to ARDS of the upper and lower respiratory tracts (Khoury et al., 2020; Simoneau and Ott, 2020; Youk et al., 2020). ARDS diagnosis is confirmed based on Berlin 2012 criteria: (1) presence of a clinical insult as well as new or worsening respiratory symptoms. (2) bilateral opacities on the imaging that are not fully described as effusion, collapse, or nodule. (3) respiratory failure due to edema that is not due to cardiac failure or volume overload and (4) impaired oxygenation that is described in three levels of mild, moderate, and severe each with its specific cut-offs (Gibson et al., 2020). Since the beginning of the pandemic in 2019, there have been some huge steps toward discovering the mechanism of action and virulence of the virus in order to improve the efficacy of vaccines and drug candidates (Ramezankhani et al., 2020; Zheng et al., 2021). SARS-CoV-2 is composed of four main structural proteins including Spike (S), Membrane (M), Envelope (E), and Nucleocapsid (N). In the mechanism of virus infection, the very first step of pathogenicity is the entrance to the parenchymal lung cells by the interaction between ACE2 receptors and virus surface S protein (Harrison et al., 2020; Li et al., 2020; Ramezankhani et al., 2020; Shang et al., 2020; Simoneau and Ott, 2020; Yang et al., 2020). After that, viral S protein undergoes lysis by transmembrane serine protease 2 (TMPRSS2) of the host cells. This gives the virus genome an opportunity to be translated to viral polymerase and proteases by the host ribosomes (Li et al., 2020; Simoneau and Ott, 2020). The products of this process are viral RNA and structural proteins (Fehr and Perlman, 2015; Li et al., 2020; Simoneau and Ott, 2020). The range of SARS-CoV-2 effects on the respiratory system varies from pneumonia to ARDS. The clinical definition was provided in the previous part. In SARS-CoV-2 infection, the pathological features of ARDS are associated with diffuse alveolar changes such as hyaline membrane formation, interstitial thickening, edema, and fibroblasts proliferation. The associated mechanisms are discussed in the following (Gibson et al., 2020). One of them is the direct cytopathic effect (Ramezankhani et al., 2020). Studies have shown that SARS-CoV-2 causes apoptosis and necrosis in ACE2 positive cells (airway epithelial cells in this case) via cytopathic effect. In addition, cilia movement cessation is another pathologic effect in the airways. Direct virus entrance in some other ACE2 positive cells is one of the possible suggested mechanisms of cell damage (Ramezankhani et al., 2020; Wang et al., 2020). Considering the immunologic effects, the host retinoic acid-inducible gene-I-like (RIG-I) or Toll-like receptors recognize viral pathogen-associated molecular patterns (PAMPs) (Simoneau and Ott, 2020). In the cellular immune system, antigen presenting cells (APC) activate CD4 + cells as well as CD8 + T cells, which destroy infected cells directly. Furthermore, a part of the pro-inflammatory cytokine production (such as interleukin (IL)-1, IL-6, IL-12, interferon(IFN)-γ, and Tumor Necrosis Factor(TNF)-a) is induced by CD4 + T cells, that leads to recruitment of innate immune cells (Costela-Ruiz et al., 2020; Ramezankhani et al., 2020). The uncontrolled production of inflammatory cytokines can also cause cytokine storm, which then leads to ARDS (Molinaro et al., 2020; Ramezankhani et al., 2020). The cytokine storm increases vascular permeability leading to edema as one of the items in ARDS criteria due to damaging the endothelial cell junctions (tight junction protein and the zonula occludens) as well as letting proteins, neutrophils, erythrocytes, and platelets pass into the interstitial tissue. This process is compatible with opacities seen in imaging. Then with the progression of alveolar accumulation with exudate, ventilation to perfusion mismatch is exaggerated and deteriorates impaired oxygenation that results in the progression toward ARDS (Molinaro et al., 2020; Ramezankhani et al., 2020; Suri et al., 2021). Another reason for the hyperinflammatory state is macrophage hyperactivation and neutrophil infiltration. macrophage hyperactivation causes macrophage activation syndrome (MAS) and the latter results in necroinflammation (Cao, 2020; Otsuka and Seino, 2020; Ramezankhani et al., 2020). Interferons (mainly IFN-1) are another group of antiviral factors produced because of antiviral immune response (Boudewijns et al., 2020; Busnadiego et al., 2020; Lei et al., 2020; Simoneau and Ott, 2020). Memory T cells mostly show an immune response to SARS-CoV-2 structural proteins, especially S proteins. Accordingly, structural proteins could be considered as vaccine candidates (Ng et al., 2016; Ramezankhani et al., 2020). SARS-CoV-2 interferes with immune system antiviral actions by using different methods such as causing cell apoptosis and cytopathic effects (Simoneau and Ott, 2020). In addition, SARS-CoV-2 contains enzymes that modify viral and host cell RNAs. This mechanism makes the virus able to escape antiviral receptor detection. Different mechanisms have been proved to be associated with immune system evasion by SASR-CoV-2. SARS-CoV-2 possesses several proteins such as the NSP family, ORF proteins, M, N that are important in evading the immune system through several ways like cleaving host mRNA, inhibiting inflammatory cytokines production, sequestering viral RNA, inducing apoptosis or direct cytopathic effects, and inhibiting host proteins translation. Discussing these mechanisms in detail is beyond the scope of this article (Kasuga et al., 2021). Different factors have been known to be associated with poor prognosis of ARDS in COVID-19 patients, lymphopenia and cytokine storm are the two most important factors (Pourbagheri-Sigaroodi et al., 2020). Cell reduction in lymphopenia happens in T CD4 + and 8 + as well as B cells. The expression of CD38 and human leukocyte adhesion (HLA)-DR in T cells as the hallmark of T cell activation during viral pneumonia, was significantly higher in COVID-19 patients (Hue et al., 2020). PD-1 expression demonstrates immune dysfunction during sepsis. A study showed that during the pathogenesis of the infection, CD8 + T cells express lower levels of PD-1 in comparison to non-COVID ARDS patients (Hue et al., 2020). This finding supports the previous claim that immune system hyper activation is one of the associated mechanisms in ARDS development and probably forecasts its severity during COVID-19 infection (Hue et al., 2020). Higher levels of IL-10, CXCL10/IP-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), and CX3CL1 as well as more severe viral shedding in the examination of nasopharyngeal swabs were also reported in COVID-ARDS patients (Hue et al., 2020). It highlights that immune dysregulation and more severe viral shedding are other negative prognostic factors of COVID-ADRS (Hue et al., 2020). Systemic inflammatory response, as well as multi-organ failure, can affect the susceptibility of developing ARDS. Comorbidities like old age, hypertension, diabetes mellitus, elevated BMI, cardiac and chronic lung diseases are associated with progression to ARDS in COVID-19 infection (Suri et al., 2021). On the other hand, some studies have reported a more severe phenotype of the disease in immunocompromised patients (Belsky et al., 2021). Therefore, we can conclude that hyper inflammatory response of a competent immune system and the cytopathic effect of the virus in the absence of an effective immune system are two possible underlying factors of developing ARDS. However, this deduction is not complete due to the lack of sufficient knowledge in the case of COVID-19 pathogenicity, which reflects the need for designing effective models in order to facilitate studying viral mechanisms of action in more detail (Remy et al., 2020).

Renal involvement in COVID-19 infection is manifested most commonly as Acute Kidney Injury (AKI) which makes the patient prone to other complications (Robbins-Juarez et al., 2020; Arikan et al., 2021). Several pathophysiologic mechanisms have been suggested to be the cause of COVID-19 renal manifestations, which are discussed briefly in the following point. The first one is systemic hemodynamic instability (Legrand et al., 2021). In this state, due to decreased cardiac output or renal venous congestion, renal perfusion is disrupted. The underlying reasons for decreased cardiac output are mentioned under the cardiovascular system subtitle. On the other hand, venous dilation increases renal interstitial and tubular pressure that lead to a hypoxic situation as well as compromising the glomerular filtration rate (Legrand et al., 2021). Another underlying reason is cytokine storm, a life-threatening situation during which the immune system is highly activated and inflammatory cytokines are extensively released, causing organ failure. In addition to systemic inflammation, cytokine release can happen locally in renal tissue. During COVID-19 infection, renal cells start to release inflammatory cytokines such as TNF and FAS that cause renal dysfunction by direct cell injury (Legrand et al., 2021). The virus can also induce cell damage through the cytopathic effect that invades renal cells directly. On the other hand, SARS-CoV-2 inhibits type I IFN production which leads to increased viral replication as well as immune dysregulation. Out-of-control complement release is another underlying reason for hyper-inflammatory state during SARS-CoV-2 infection that induces tissue injury. Adaptive immunity dysfunction such as T cell, plasmacytoid dendritic cell, eosinophil, and natural killer cell depletion has also been reported during the course of infection. The last mechanism is endothelial damage and micro-thrombi formation, the pathophysiology of which is discussed under the “cardiovascular system subtitle” (Legrand et al., 2021).

According to studies, COVID-19 infection does not cause specific retinal involvement, however, conjunctivitis has been reported in some cases with positive PCR (Pirraglia et al., 2020; Seah and Agrawal, 2020). On the other hand, patients with eye comorbidities are at risk of advanced or uncontrolled forms of the disease because of disrupted ophthalmic care delivery during the pandemic (Pujari et al., 2021). However, several ophthalmic symptoms have been reported in animal studies such as retinitis, conjunctivitis, anterior uveitis, chorditis, retinal detachment and, optic neuritis (Seah and Agrawal, 2020). The underlying vacuities during the COVID-19 infection can cause these symptoms (Seah and Agrawal, 2020). Tissue inflammation is also directly induced by viral replication in the retina that causes immune cells to infiltrate and pro-inflammatory cytokines to be released (Seah and Agrawal, 2020). An autoimmune nature of the infection is also suggested in the studies due to the autoantibodies that are produced during the infection against retinal cells that lead to degradation of photoreceptors, ganglion cells, and neuroretina (Seah and Agrawal, 2020). ACE2 protein, which is necessary for the virus entrance, is expressed in the aqueous humor but more studies are needed in order to explore its expression in other structures such as conjunctiva or cornea (Seah and Agrawal, 2020).

Patients with COVID-19 can show several gastrointestinal symptoms such as diarrhea, nausea, vomiting, gastrointestinal bleeding, and abdominal pain (Zhang J. et al., 2020). ACE2 receptor, as well as TMPRSS2, are highly expressed in the gastrointestinal system, thus viral entrance and replication happen extensively in the gut after the respiratory system. Tissue inflammation underlies these symptoms during infection (Steardo et al., 2020; Zhang J. et al., 2020). High levels of fecal calprotectin and IL-6 as inflammatory factors support this claim (Zhang J. et al., 2020). Hyper-inflammatory syndromes such as hemophagocytic lymphohistiocytosis and cytokine storm also are accused of organ failure in the gastrointestinal system like other body organs (Zhang J. et al., 2020). However, based on studies human defensin-5 protein that plays an important role against SARS-CoV-2 in the gut, can be increased during the inflammation (Zhang J. et al., 2020).

Abnormal liver transferase levels can be detected in about 15–43% of COVID-19 patients with more probability in severe cases (Zhang C. et al., 2020). Acute liver injury has also been reported in some studies (Zhang C. et al., 2020). Liver injury can happen during systemic inflammation that is caused by inflammatory cytokine release during the course of infection. High levels of Th17 and 2, IL-2,6,7,10, TNF-a, granulocyte-colony stimulating factor, IFN-inducible protein-10, monocyte chemotactic protein 1and macrophage inflammatory protein 1 alpha in COVID-19 patients support this idea (Li and Fan, 2020). Liver dysfunction can also happen through direct viral invasion in the infection (Zhang C. et al., 2020). In addition, stress- induced liver injury is another pathologic event that can be caused by hypoxia-reoxygenation, activation of oxidative stress mechanisms, intestinal endotoxemia, and activation of the sympathetic nervous and adrenocortical system in COVID-19 patients (Li and Fan, 2020). As cholangiocytes highly express ACE2 receptors, they are suggested to be one of the main cells responsible for liver injury in COVID-19 infection (Zhang C. et al., 2020). However, ACE2 is poorly expressed in the liver, suggesting that there are other entrance paths of the virus to infect the cells (Steardo et al., 2020). Drug toxicity is also mentioned to be another reason for liver dysfunction (Li and Fan, 2020; Zhang C. et al., 2020).

Neurological symptoms of SARS-CoV-2 infection are categorized into two different groups, the first one is anosmia and ageusia that are reported in mild cases and the second group of symptoms consists of mental confusion and cognitive impairment in severe cases (Chigr et al., 2020). ACE2 receptors in the CNS are specifically expressed in the brain stem, subfornical organ, paraventricular nucleus, the nucleus of tractus solitaries, and rostral ventrolateral medulla which are responsible for respiratory and cardiovascular systems regulation, therefore a part of these systems dysfunction can be explained by this claim (Chigr et al., 2020; Steardo et al., 2020). There are different entrance paths to the nervous system. Nasal inoculation of SARS-CoV-2 can infect CNS via the olfactory bulb; other paths are bloodstream (blood-brain barrier (BBB) disruption) and vagus nerve that carries the virus from the respiratory system (Chigr et al., 2020; Steardo et al., 2020). Like other organs, tissue inflammation affects the nervous system. Microglia and astrocyte activation support this issue (Steardo et al., 2020). Astrocytes can be attacked by the virus, cells that play an important role in forming BBB, so by astrocyte involvement, the neuro-infection expands. This situation happens when a systemic cytokine storm is triggered by SARS-CoV-2 (Steardo et al., 2020). BBB disruption leads to neuroinflammation that causes neuronal death (Steardo et al., 2020). Hence, the cognitive disorder, behavioral and personality changes that are reported in severe cases can be explained by this mechanism (Steardo et al., 2020). Persistent neuro-inflammation along with hypoxia is accompanied by more severe presentations such as delirium (Steardo et al., 2020).

As mentioned before, cardiac function can be compromised during SARS-CoV-2 infection leading to decreased cardiac output and in advanced stages, multi-organ dysfunction. Cardiovascular injury can happen through different mechanisms. The first one as was mentioned before is systemic inflammation which involves the cardiovascular system as well as other tissue (Petrovic et al., 2020). Low level of inflammation is the reason for non-specific viral infection symptoms but in severe cases, if the severe inflammatory response syndrome (SIRS) criteria are met, hemodynamic disorders such as shock, disseminated intravascular coagulopathy, and multi-organ failure will lead to cardiac dysfunction (Petrovic et al., 2020). In rare cases, myocardial injury due to hyper-inflammation is reported during COVID-19 infection that compromises cardiac function. Renin–angiotensin system (RAS) activation in the first stages of SIRS to reverse the situation, is responsible for increasing blood pressure through different mechanisms, one of them is vasoconstriction. At first, this condition helps the cardiovascular system to reverse the situation but by the time, hypertension will increase the burden on the cardiovascular system until the heart cannot compensate for the situation (Petrovic et al., 2020). In addition, viral entrance through ACE2 down- regulates its production. This leads to an imbalance between ACE2 and angiotensinogen II levels that is another reason for cardiovascular failure (Petrovic et al., 2020). Hypercoagulable state of the body in COVID-19 as well as plaque instability can exaggerate cardiovascular failure. Hyper-inflammation is one of the triggers of hypercoagulability by disrupting the hematopoietic system (Petrovic et al., 2020). It also plays a negative role in inducing plaque instability. Elevated levels of catecholamines as a result of inflammation may cause plaque rupture that can lead to acute coronary syndrome (Petrovic et al., 2020). Plaque rupture, by exposing its content (foamy macrophage) as well as smooth muscles, induces micro- thrombi formation that can move to other organs and cause organ dysfunction (Petrovic et al., 2020). IL-6, an inflammatory cytokine, can also be released by smooth muscles and worsen the situation.

Regenerative medicine has provided organoids that have many advantages in the field of disease modeling in comparison to in vivo and other in vitro models. Organoids can be generated either from adult stem cells or PSCs. Establishing organoids from PSCs like iPSCs and ESCs needs the media containing growth factors for culturing in a way that mimics the process of developing a particular structure in an embryo. On the other hand, organoids derived from adult stem cells are formed by providing a 3D matrix and growth factors for the resident stem cells of our targeted tissue (Atala et al., 2020; van der Vaart et al., 2021). This novel technology of artificially developed 3D structures is more accessible and a faster tool than animal models. Moreover, they mimic the relevant niche and maintain the genetic profile and physiological characteristics of their original tissue. Hence, since organoids have contributed to gaining more insight into the pathophysiology of different organ dysfunctions and investigating therapeutic approaches, they can serve as valuable models for investigating the SARS-CoV-2 infection and its treatment strategies (Atala et al., 2020; Mahalingam et al., 2021).

As previously discussed, COVID-19 is a new scientific field of study with noticeable gaps that have to be covered especially in testing the efficacy of new therapeutic methods in the field of clinical as well as regenerative medicine. Several animal models can be used with similarities to the human body in some aspects. These species also have been used for testing drug/vaccine candidates of clinical medicine and proved their efficacy, so it is implied that they can be suitable models for regenerative medicine investigations. Different species have been used in this field among which, mice are the most common (Sun et al., 2020). The problem is that mice are resistant to SARS-CoV-2 therefore this issue is resolved by introducing the human ACE2 (hACE2) receptor via an adenovirus into the cells (Atala et al., 2020; Zheng et al., 2021). In a study, cytokeratin 18 (KRT18) promoter, which is an epithelium specific gene, was used for the host cells to express hACE2 (Chow et al., 1997; Zheng et al., 2021). This process causes pneumonia along with weight loss, severe pulmonary pathology, and SARS-CoV-2 replication in the lungs (Sun et al., 2020; Zheng et al., 2021). In some other studies, Lipopolysaccharide has been used to simulate the hyperinflammatory state caused by SARS-COV-2 infection (Molinaro et al., 2020). Mice-based studies confirmed the role of the interferon I (IFN-I) pathway in the clearance of virus as well as the role of interferon II (IFN-II) signaling through signal transducer and activator of transcription 1 (STAT-1) in diminishing clinical severity and hyperinflammatory state of the respiratory system (Sun et al., 2020). In an experiment of Ad5-hACE2 mice, the application of plasma from recovered patients improved the disease severity in addition to increasing the clearance rate of the virus as well as remdesivir (Sun et al., 2020). Leukosomes have been suggested to promote the efficacy of anti-inflammation drugs when applied as a drug delivery system (Molinaro et al., 2020). Ferret is another animal model of SARS-COV-2 infection, which is prone to SARS-COV per se and presents symptoms like cough, rhinorrhea, and lower physical activity (ter Meulen et al., 2004; Park et al., 2020). Positive samples of infectious virus only could be collected through upper respiratory tract washes, and not other collected specimens such as a rectal swab, which was positive of low copy numbers of non-infectious virus (Shi et al., 2020). Then, the application of suggested drugs such as lopinavir-ritonavir, Hydroxychloroquine (HCQ), emtricitabine-tenofovir, and human monoclonal antibodies led to lower severity of clinical presentations (ter Meulen et al., 2004; Park et al., 2020). Another study showed that as well as ferrets, cats, and with less susceptibility, dogs are prone to SARS-CoV-2. In a study using cats as animal models, it was proved that the infection transmits in an airborne state among cats (Shi et al., 2020). Besides, in a study of Syrian hamsters as one of the permissive species to SARS-CoV-2, the STAT-2 signaling mechanism has been considered as one of the mechanisms involved in the virus pathogenesis as well as its protective role as part of the immune system (Boudewijns et al., 2020). Each discussed model has some advantages that make it appropriate to be used as a human body simulator but some disadvantages that make investigations more challenging. However, assessing these disadvantages opens new doors toward developing more efficient animal models. Several types of species models, specific manifestations of each after virus inoculation, and results of suggested drugs/vaccine candidates have been provided in Table 2. Also, pros and cons of each species model are accessible in the Figure 2.

Despite all advantages of the models which were discussed, there are different challenges in the experimental researches on SARS-CoV-2 infection. IPSCs have been widely studied especially for generating organoids, to model the new pandemic disease, but there are some limitations that should be mentioned. For instance, there are some reports that during the reprogramming process, some of the epigenetic memory of donor cells is retained in iPSCs that can result in biased differentiation to target cells. Moreover, there are risks of tumorigenicity in the case of cell transplantation which are contaminated with undifferentiated iPSCs. However, novel protocols for differentiation and the purification process as well as using molecules that cause selective death of these cells have decreased the risks but more follow-up is needed. Besides, differentiating somatic cells from hiPSCs is considered to be expensive and time-consuming (Doss and Sachinidis, 2019; Nolasco et al., 2020). Notable bottlenecks of modeling using iPSC-derived cells are lack of maturity and exhibiting embryonic-like characteristics, especially in late-onset diseases. Some proposed ways to overcome these drawbacks are treatment with mitochondrial stress inducers to provoke aging and direct differentiation of somatic cells like fibroblasts to the relevant cells like neurons that share similar cell markers. On the other hand, novel technological advances like gene editing, organ-on-chip, and “-omics” methodologies can improve the iPSC-based therapeutic approaches (Doss and Sachinidis, 2019). Organoids, as a product of advancements in the fields of PSCs and cell therapy, ECM biology, and tissue engineering, have played a critical role in experimental studies. In the field of RM, organoids have been presented for transplantation instead of organs like the liver, as they recapitulate the main aspects of the organs. Moreover, they represent a step forward to drug screening and a promising tool for personalized medicine. However, there are some obstacles both in the future transplant process and the current modeling area of this novel tool. Some of the challenges and disadvantages of different organoids and iPSC-derived cells are addressed in Table 1. The shape of the organoids, their size, and cell composition and maturation are not completely under control. Additionally, modeling complex and chronic diseases needs a suitable microenvironment and is based on advanced technology in bioengineering (Prior et al., 2019). Major limitations of organoids in studying SARS-CoV-2 infection include their simplicity and lack of immune cells. Therefore, the studies mainly focus on intrinsic pathways. For instance, SARS-CoV-2 causes epithelial damage and inflammatory response in the lung. Hence, the absence of immune cells and stroma are known as major challenges and limitations of lung organoids (Chugh et al., 2021). It is suggested that the organoids can be introduced to immune cells in culture to investigate extrinsic mechanisms of actions (Katsura et al., 2020; Yang et al., 2020; Youk et al., 2020). Accordingly, hESCs were utilized in a study which is pre-print at the time of writing this review, to generate a co-culture of lung cells and macrophages. The results showed a reduction of SARS-CoV-2 N protein expression after adding macrophages, though N protein was detected in the macrophages per se. More studies are required to find the exact role of macrophages, and also other parts of the immune system in the pathogenesis of this virus (Duan et al., 2020; Simoneau and Ott, 2020). In another pre-print study, a mixture of the upper airway and alveolar cells derived from hiPSCs was developed. It showed that the airway cells are more prone to infection than alveolar cells in a manner that was similar to the patients’ lungs. Further, these novel models can be served as beneficial platforms for drug discovery (Simoneau and Ott, 2020; Tindle et al., 2021). In addition, since endothelial dysfunction and vascular impairment like thrombosis and microangiopathy have been found in patients’ lungs, adding endothelial cells to lung organoids may lead to generating more relevant models (Lamers et al., 2021). Due to the complicated behavior of SARS-CoV-2, the involvement of multiple organs, and their interactions with different types of cells and stem cells, more advanced technologies like organ-on chips or complex organoids can be more beneficial (Chugh et al., 2021). Among challenges in brain organoids, the absence of vasculature in choroid plexus organoids and the presence of not fully mature neurons in cortical organoids, which affects the susceptibility to infection, would be worth mentioning (Pellegrini et al., 2020). Moreover, the results of studying SARS-CoV-2 infection in astrocytes, microglia, and cortical neurons are controversial and to some extent, inconsistent. Since these cells have a critical role in CNS homeostasis, developing brain organoids containing these kinds of cells could be useful to take a step forward (Ramani et al., 2021). Besides, the current technology of organoids cannot manifest the communication between different organs and immunological responses in COVID-19 infection. In this context, animal models are more advantageous (Yu, 2021). As one of the most necessary major phases in manufacturing biomedical products, the ideal animal models should be able to simulate the disease in humans and its manifestations as similar to humans as it is possible. For COVID-19 modeling, the animal model must be permissive to the infection. Transgenic mice that express hACE2 are one of the best animal models, yet their availability is limited. Another mouse model is the adeno-associated virus delivery-based model, which expresses ACE2 in non-relevant cells and makes the interpretation of the analyzed data quite hard. Hamsters can model SARS-CoV-2 infection but they can only be used to study the mild forms of the disease because the lung pathology resolves to normal after 14 days post-infection (Kumar et al., 2020). As it was mentioned before, an important point about modeling this disease is that additional risk factors like advanced age and chronic diseases such as diabetes and obesity are associated with increased morbidity and mortality. These comorbidities cause alterations including the dysregulation in body homeostasis and repair mechanisms that make the infection progress to its severe and lethal forms. Hence, developing models with mentioned features to provide a platform for shifting the disease from a curable infection to a multi-organ failure state and ARDS can be beneficial. Accordingly, the results of using aged animals such as aged mice and old macaques showed higher levels of lung injury and inflammation. Other modified models for obesity (e.g., ob/ob and high-fat diet-induced obesity mice), diabetes (e.g., STZ-treated and NOD mice), and immune deficiency/impairment (e.g., SCID and STAT1-knockout mice) might be more easily available to analyze the progression of the severe status of SARS-CoV-2 infection (Croy et al., 2007; Cleary et al., 2020; Payab et al., 2021). Another advantage of using proposed animal models is the possible ability to test the efficacy of interventions and treatments in different stages of the disease. When animal models which can develop multi-organ failure are used, suggested therapies for the mild to severe conditions of the infection can be tested in a pre-clinical setting. Therefore, the safety issues of the drugs and even prophylactic agents might be explored better (Cleary et al., 2020). Collectively, an appropriate model which develops the disease, the body response, and the comorbidities for a comprehensive understanding of the pathogenesis and possible treatments is still elusive. Though, available models have led to invaluable information on the disease and different vaccines (Cleary et al., 2020; Kumar et al., 2020).