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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 5  |  Page : 18-23

An insight into the use of transgenic animal models for conducting research on coronavirus


Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysore, Karnataka, India

Date of Submission04-May-2020
Date of Decision05-May-2020
Date of Acceptance11-May-2020
Date of Web Publication04-Jun-2020

Correspondence Address:
Dr. Prashant Akila
Department of Biochemistry, Leader: SIG Human Genomics and Rare Disorders, JSS Medical College, JSS Academy of Higher Education & Research, Mysore, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijhas.IJHAS_86_20

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  Abstract 


Novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV2) outbreak, which is a causal agent for coronavirus disease-19 (COVID-19), has gotten a pandemic in a very short timeframe and represents a global health threat. Since this virus crossed species boundaries, it has put the whole humanity at risk for the infection. We may expect to see the emergence of many other novel coronaviruses like this in future. It is of vital importance that effective standardized care protocols for serious cases are globally recommended to tackle the COVID-19 pandemic. As of now, there are no clinically approved vaccines for COVID-19, but the Phase1 vaccine development approach is on the way. In future, we may expect a dozen vaccines but to test the vaccines and to understand their role, animal models which reflect the clinical symptoms, replication of the virus and disease pathology as in the humans are in great demand. The vaccine development for SARS-CoV2 would depend on the immunological data collected from the severe acute respiratory syndrome coronavirus (SARS-CoV) that emerged late in 2003. Because the SARS-CoV and newly emerged SARS-CoV2 share ninety percent of sequence homology, previously used transgenic animal models to study the spread of the virus and the therapeutic response could be used for the development of systematic therapeutic drugs for SARS-CoV2. Here, in this review, we have summarized some of the animal models which were considered from the previous studies on SARS-CoV and the comparison between these animal models could be a good consideration for further developments in the treatment of COVID-19.

Keywords: COVID-19, novel coronavirus, severe acute respiratory syndrome coronavirus 2, transgenic animal models


How to cite this article:
Bevinakoppamath S, Ramachandra SC, Akila P. An insight into the use of transgenic animal models for conducting research on coronavirus. Int J Health Allied Sci 2020;9, Suppl S1:18-23

How to cite this URL:
Bevinakoppamath S, Ramachandra SC, Akila P. An insight into the use of transgenic animal models for conducting research on coronavirus. Int J Health Allied Sci [serial online] 2020 [cited 2020 Sep 18];9, Suppl S1:18-23. Available from: http://www.ijhas.in/text.asp?2020/9/5/18/285973




  Introduction Top


The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus (SARS-CoV2) has become an extraordinary public health emergency of international concern,[1] as declared by the World Health Organization (WHO) on January 30, 2020. The WHO also declared this as pandemic on March 11, 2020.[2] SARS and middle east respiratory syndrome coronavirus (MERS) are the two animal coronavirus strains that have been shown to cross the species boundary. The virus emerged in late 2002 and started spreading throughout Asia to North America.[3] SARS coronavirus is mostly spread through civet cats, infected by Chinese horseshoe bats (Rhinolophu sinicus)[4],[5] which were sold in food markets and consumed in southern China.[3],[6]

Coronaviruses are the largest RNA viruses encoding 16–32 kb of genome size among all known viruses.[7] Based on the genome structure and phylogenetic relationship, there are four genera of coronavirus, namely, alphacoronavirus, betacoronavirus, deltacoronavirus, and gammacoronavirus. Till now, only alphacoronavirus and betacoronavirus are known to infect humans. SARS and MERS are the syndromes caused by SARS-CoV and MERS-CoV, respectively. These viruses belong to betacoronaviruses genera, which are highly pathogenic to humans causing interstitial pneumonia.[8]


  Covid-19 in Humans Top


In the current scenario, COVID-19 is caused by one of the betacoronaviruses, 2019 novel coronavirus (2019 nCoV), and later named as SARS-CoV2 by The International Committee on Taxonomy of Viruses (ICTV).[9] As of April 30, 2020, a total of 1,999,037 cases have been reported to be active for COVID-19, causing about 229,179 deaths throughout the world.

Recent data have shown that the symptoms vary according to the age group and persists from being asymptomatic carriers to severely fatal disease. Angiotensin-converting enzyme (ACE2) is the receptor for the virus through which the virus enters into the cells.[10] The expression of ACE on the cell surface increases as age advances when it is also accompanied by the decrease in the individual's immune response. Due to the high expression of ACE and low immunity, the elderly population has higher chances of having severe clinical symptoms.[11] Among the people with severe infection, diarrhea, confusion, increased levels of inflammatory biochemical markers, low levels of lymphocytes, hepatic, and renal dysfunction have been reported apart from respiratory failure.[12] Patients with comorbidities such as hypertension, cardiovascular disease, lung disorders, and diabetes may need special care since they exhibit severe clinical symptoms when infected with SARS-CoV2.[13] Human–to-human contact, travel histories have led to the spread of SARS-CoV2. In the absence of a clinically approved vaccine against Covid-19, the only way to control the spread is by social distancing and quarantining, which has led to a huge loss in the world's economy.[14] Immunizations have a long history of achievement in diminishing viral infection loads. They have shown undeniable success against formerly fearsome diseases that are now rare in most of the developed countries.

The supervised and detailed studies needed to elucidate pathogenesis and the production of vaccines and antiviral agents against SARS-CoV involve small and inexpensive animal models. There is very little knowledge currently available against COVID-19 and the animal models used to study the disease. Preclinical SARS experiments may give insight into economic and helpful animal models for COVID-19 experiments. Because no efficient therapy is currently available to treat the disease, numerous drugs have been attempted off late in the treatment, which includes antimalarial drug hydroxychloroquine as a potential drug against SARS-CoV. Diabetic patients treated with hydroxychloroquine need timely monitoring of hematological parameters.[15] Hence, developing a vaccine against the novel SARS-CoV-2 is recognized as an urgent problem. Effective vaccination against the virus could eliminate the virus from the human population.[16] In this review, we summarize the different types of animal models used for the research on SARS-CoV2, causing COVID-19 and the limitations observed in their usage.


  Mouse as a Model Top


It is necessary to use bred mice or transgenic mice for the research of SARS-CoV2 because normal mice are resistant to the virus.


  Tmprss2knockout Mice Top


TMPRSS2 is a membrane-associated serine protease expressed in the epithelium of the human respiratory tract, regulating the airway surface liquid volume by proteolytic cleavage of epithelial sodium channels. In Tmprss2−/− knock-out mice, the exons 10–13 of the transmembrane protease is being replaced by loxP-flanked neo cassette, abolishing the gene function. A study evaluated the potential for producing steadily constricted inversion safe, immunogenic strains of known and recently recognized CoVs to be utilized as immunizations in both immunocompetent and immunocompromised populations. The fidelity of coronavirus is roughly 20-fold more noteworthy than that of other RNA infections and is intervened by a 3′→5′ exonuclease (ExoN) activity probably involved in RNA proofreading. The ExoN inactivation genotype and mutator phenotype are steady and do not return to virulence, much after sequential entry or long-haul persevering infection in vivo.[17] Inhibition of Tmprss2 protein that is essential for the virus to enter into the cells may give insights into the development of new therapeutic strategies to develop vaccines.


  Expression of Human Angiotensin-Converting Enzyme in Mice Top


ACE2 is present in many human tissues, including the vascular endothelial cells of many organs, and the epithelial cells of the lung, small intestine, and kidney. The exact physiological function of the ACE2 molecule remains unknown. Bao et al. observed that in the mouse with human angiotensin converting enzyme (hACE), SARS-CoV replicated more efficiently and expressed interstitial pneumonia. Lymphocyte and monocyte infiltration were seen in the alveolar cavities. Hence, it was identified as a major functional receptor for SARS-CoV, facilitating the entry and replication of the virus.[1] This has indicated the use of mouse transgenic for hACE as important animal models for SARS-CoV.


  Human Angiotensin-Converting Enzyme 2 Transgenic Mice Top


Transgenic mouse model has been developed by introducing the human gene of ACE2, driven by mouse ACE2 promoter, into the mouse genome. The response of wild type and transgenic mice to SARS-CoV inoculation was evaluated, which showed that the lungs of the transgenic mice replicated the virus more efficiently than the wild-type mice. Tissue distribution of the hACE2 protein, viral replication, and pathologic changes in the transgenic mice was similar to those in humans. These findings support the validity of this SARS mouse model, despite the absence of mortality in transgenic mice when infected with SARS-CoV.[18] Lack of detectable viral antigen in organs with marked pathologic changes has revealed that hACE2 may not be the only receptor for SARS-CoV, but its entry may require several co-factors as well. SARS-CoV infection results in ACE2 downregulation through binding of SARS-CoV spike protein to ACE2, contributing to the severity of lung pathologies. This may lead to the use of recombinant ACE2 protein as a treatment of choice to block the spreading of SARS-CoV.[19]


  Stat 1 Knockout Mice (Stat1−/−) Top


The primary sites of SARS-CoV infection are bronchioles. Stat1 knockout mice develop inflammation throughout the lungs and alveoli through the infiltration of lymphocytes, neutrophils, and eosinophils throughout the lungs. In contract to interstitial pneumonia and acute bronchiolitis, the infection has been shown to spread to other organs as well. Loss of Stat1 prevents wound healing, promotes fibrosis, and develops lethal diseases after the infection by SARS-CoV.[7],[20],[21] The exact mechanism compromising the ability of the animal to clear SARS-CoV infection remains unclear. However, it has been suggested that alpha/beta interferon inhibits the replication of SARS-CoV in vitro. The innate immune reaction is indeed a vital initial point of contact with the invasive pathogen. It is based on numerous cellular signaling pathways and receptors, which eventually stimulate hundreds of antiviral proteins. It establishes a sub-optimal replication and spreading environment for intrusive pathogens.[22],[23] Therapeutic strategies may be designed that augment the innate immune response in the context of interferon action.


  Balb/c, C57bl/6 and 129s6 Top


They are the young inbred mice models, which may likewise be helpful in considering them for COVID-19 vaccine and virulence studies.[24] SARS-CoV replication in the respiratory tract of BALB/c mice allows an assessment of the adequacy of immunizations and immunotherapeutic and treatment techniques[25] though they do not show clinical symptoms. Age-related mortality could be studied using aged C57BL/6 and 129S6 strains of mice and C57BL/6 strains of mice for lung injury-related complications associated with COVID-19.[26] The availability of vast knowledge on immunology and genetics makes mice an adequate model for antiviral and vaccine studies.

Vaccine development has become complicated due to the differences in the antigens exhibited by the major histocompatibility complex proteins, which are known as human leukocyte antigen (HLA). HLA genes are present in wide varieties in humans. Transgenic mice carrying such genes may be helpful in vaccine development against COVID-19. Model human peripheral blood mononuclear cells- NOD/Shi-scid IL2rgnull (NOG) grafted in immunodeficient NOG mice is also helpful in studying the SARS-CoV2 vaccine response in mice in contrast to humans.


  Nonhuman Primates Top


African green monkey, Cynomolgus macaques, and Rhesus macaques are the species currently under laboratory usage to understand the SARS-CoV pathogenesis. Clinical symptoms for these species vary due to the genetic variation among the different subspecies.[27],[28] Furthermore, the severity of the infection depends on the methodology, dosage, and route of infection. Pneumonitis is common in these species.[29],[30] Cynomolgus macaque develops mild symptoms which are similar to the symptoms seen in younger children.[29]

Monkeys infected through the trachea with MERS-CoV showed an increase in the temperature post infiltration. Yao et al. showed that the viral particles were not found in other organs but lungs, which suggest that MERS-CoV infected only lungs. Histopathology and immunohistochemistry showed the presence of interstitial pneumonia and the presence of Type 1 and 2 pneumocytes and alveolar macrophage antigens. Furthermore, the absence of viral particles in nasal turbinate and oropharyngeal homogenates suggested that the only lower respiratory tract gets infected by the virus.[5] MERS-CoV replication occurs in interstitial pneumocytes causing interstitial pneumonia. The lower respiratory tract is the key site for the replication of the virus.[31] Rhesus macaques develop neutralizing antibodies after the infection. Secondary infection in the lungs does not occur.[6] Marmosets are the effective MERS-CoV lethal disease model to study the pathogenesis of the virus. Viral titers detected by RT-PCR demonstrated the induction of immune and inflammatory pathways. The infection of MERS-CoV promotes consistent pulmonary fibrosis and tissue differentiation and may be used as a model to assess the efficacy of the vaccines and other treatment strategies along with elaborate pathogenesis studies.[32]

Although nonhuman primates mimic the symptoms of the disease and infection as in humans, they are to be handled in biosafety level 3 facilities which are not available in most of the Institutes. Apart from this, they are very expensive compared to the other model organisms.


  Ferrets as Models Top


Ferrets are a very good model to study the transmission of SARS-CoV. Previous studies have shown that the ferrets having close contact with the infected ones develop infection more rapidly before the symptoms actually show up, that is within 2–3 days of primary infection exemplifying human-to-human contact.[33] One of the markers of the infection is increased temperature. Clinical symptoms in ferrates include diarrhea, sneezing, lung lesions, dehydration, and there are no significant changes in hematology evaluation. MERS-CoV does not replicate in ferrets[34] due to which this model is not adequate to study MERS-CoV pathogenesis. However, it supports SARS-CoV infection, which makes it a very good model to study the pathogenesis and development of therapeutic vaccines.


  Syrian Hamsters Top


ACE2 protein of the Syrian hamster is highly similar to that of humans and shows the highest binding affinity towards SARS-CoV2, almost similar to SARS-CoV. Viral N proteins and infiltration were detected throughout the epithelial layers and submucosal glands. SARS-CoV2 triggers the immune system.[35] Treatment of SARS-CoV infected Syrian hamsters with monoclonal antibodies reduced viral titers and interstitial pneumonia.[36] Mb201 has been shown to have therapeutic and prophylactic potential in treating the models for coronavirus, and it could be a phase 1 trial in humans.

Previous studies have searched the available epitope data of SARS-CoV to identify similar B and T-cell epitopes and found that, among 120 T-cell epitopes 25 of them were having similar sequences to the SARS-CoV2 and among 298 B-cell linear epitopes 49 of them showed similarity toward SARS-CoV2. N and E protein sequences of SARS-CoV are 90% similar to that of SARS-CoV2, but the S protein shows lesser similarity. Considering the fact that only a little percent similarity is found in T- and B-cells between SARS-CoV and SARS-CoV2 and no observable mutation was observed in these epitopes provides strong evidence of antibody or T cell response in SARS-CoV.


  Discussion Top


Counteraction and treatment techniques can be created dependent on principles that apply to different pathogens; however, assessment of the adequacy of these methodologies requires creature models. Be that as it may, their utility in the investigation of the clinical movement of ailment is constrained by the intrinsic contrasts between small animal models and humans in anatomical structure, respiratory physiology, and appearance of the clinical ailment. However, human studies should be conducted with a large sample size with demographical information based on the copathogens, sex, age, and origin, which may be practically impossible. The unexpected development of respiratory diseases and causal viral pathogens; underscores the requirement for new, comprehensive immunization procedures that quickly and normally weaken the emerging zoonoses, particularly to secure helpless population from future outbreaks. Even though there is a great sequence homology score of SARS-CoV2 with SARS-CoV and MERS-CoV to some extent, vaccines developed against SARS-CoV and MERS-CoV are not anticipated to produce a satisfactory quantity of antibodies against SARS-CoV2. There is a great need to engineer new vaccines for SARS-CoV2, including antigens of the SARS-CoV2 strain of the virus. Information on the virus such as gene expressions, epidemiology, and immune response against SARS-CoV2 is lacking, and this has become a challenge for the development of the therapeutic vaccine. Pharmacological agents did not show satisfactory results in the treatment towards respiratory disease; thus preclinical identification of the patients earlier in the treatment would ease the management of the COVID-19.

Still, there is a lot to explore about this novel coronavirus, its pathogenic mechanisms, genetics, and immunology are to be well understood to develop effective therapeutic vaccines. Based on the previous studies, several animal models such as transgenic mice, ferrets, golden Syrian hamsters, and nonhuman primates are used to understand the disease spread, immune response, mortality, and morbidity. An ideal animal model should reproduce the viral entry, multiplication, pathology, and clinical features, as seen in humans. Hence, sound knowledge of all the potential animal models would be beneficial to carry out research on COVID 19.


  Conclusion Top


Transgenic animal models of various disease conditions serve a strong benefit to the scientific community. Similarly, they can be used to understand the disease pathophysiology, test new therapeutic drugs, and vaccines against the novel coronavirus causing COVID-19. They are generally used for the production of recombinant human protein and monoclonal antibodies. There are several methods for the production of the transgenic animal; however, care should be taken that the animal has very minimal or, if possible, no suffering while maximizing the medical benefit.

Acknowledgment

We acknowledge JSS Academy of Higher Education and Research for allowing us to form the Special Interest Group – Human Genomics and Rare Disorders and giving us an opportunity to work in this field.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
Introduction
Covid-19 in Humans
Mouse as a Model
Tmprss2knockout Mice
Expression of Hu...
Human Angiotensi...
Stat 1 Knockout ...
Balb/c, C57bl/6 ...
Nonhuman Primates
Ferrets as Models
Syrian Hamsters
Discussion
Conclusion
References

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