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"I’ve been working with iTL over the past 5 years in the production of 3 different genetically altered mice. Not only did iTL help in the design of the mice, […]” - Raghu Mirmira, MD, PhD University of Chicago.
Since the initial reports surfaced in China in late 2019, researchers have been working around the clock to understand the molecular mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In parallel, they have been repurposing currently available antiviral drugs to aid in recovery while developing new therapies and vaccines against coronavirus disease 2019, or COVID-19.
SARS-CoV-2 is a beta-coronavirus closely related to SARS-CoV, the virus that caused a smaller global outbreak in the early 2000s. As with SARS-CoV, SARS-CoV-2 binds the human ACE2 receptor on epithelial cells. Serine proteases such as TMPRSS2 are required for entry into the cell, facilitated by endocytosis.
SARS-CoV-2 binds with greater affinity to human ACE2 than does SARS-CoV, likely contributing to the higher infectivity of SARS-Cov-2. The infection begins with an incubation period of about 5 days, with illness typically developing by 11 days. It is in the early phase that symptoms are mild and mostly confined to the upper respiratory tract, with most people remaining asymptomatic, although there is still the capability of transmitting infection. When symptoms do begin, they tend to be typical of viral respiratory illness and can include fever, cough, and fatigue. Approximately 80% of people will remain with mild symptoms and the disease will not extend to the lower respiratory tract. However, in about 20% of cases, patients develop more severe symptoms which can include pneumonia, severe gas exchange problems, acute lung injury and progress onto acute respiratory distress syndrome (ARDS).
When COVID-19 first hit, many people were not too fearful because the initial statements were that it was not deadly unless you met certain criteria: being an older individual, being of a certain blood type, gender or ethnicity, or having a chronic illness. However as people communicated their experiences on social media, it became apparent that death was not limited to a certain defined group, and that people much younger, with no chronic conditions and that were perfectly healthy individuals were dying from COVID-19. It became very real very fast and within one year, there have been over 140 million cases and 3 million deaths from COVID-19. In addition to the death toll, we are now learning about long-term effects from those who survived COVID-19, who will have lifelong complications from the viral infection. With new variants on the rise as well as disparities in treatment capabilities around the world, it has become even more important to develop better therapies and vaccines. Preclinical animal models play a vital role in this endeavor.
A wide spectrum of laboratory and domestic animal species have been challenged with SARS-CoV-2 in an effort to find suitable preclinical models for studying COVID-19, but only a few, such as hamsters, cats, ferrets and monkeys, are susceptible to the virus. Unfortunately, many of these species are neither accessible nor practical for the vast majority of researchers to make progress rapidly enough to help the global pandemic.
When it comes to preclinical models in general, mice constitute about 70% of all the laboratory animal species used in biomedical research. The advantage of their small size and short life cycle makes them easier to work with and maintain, and their anatomical, physiological, and genetic similarity to humans make them a top choice for researching human disease. However, SARS-CoV-2 does not infect mice the same way it does humans and does not lead to significant disease in mice as seen in humans. Luckily, there is a wealth of genetic tools that are available for modifying the mouse to express human ACE2, offering researchers a unique opportunity to create versatile preclinical tools for COVID-19 research that are susceptible to SARS-CoV-2 infection.
In order to generate ACE2 transgenic mice, the human ACE2 gene (hACE2) is placed under the control of a promoter of choice in order to induce expression of hACE2 in a specific tissue or cell type in the mouse. These strains are readily susceptible to SARS-CoV-2 infection and are invaluable tools for studies on pathogenesis and antiviral therapies for COVID-19.
For example, one ACE2 transgenic mouse line used the human cytokeratin 18 (K18) promoter to express a full-length hACE2 cDNA in epithelial cells. The transgene was injected into pronuclei of fertilized mouse eggs to generate transgenic embryos, which were then implanted into surrogate mother mice and the progenies were studied. It was shown that K18 directed expression of human ACE2 in the lung, colon, liver, and kidney of the transgenic offspring. Three to five days following the SARS-Cov infection, the ACE2 transgenic mice began to lose weight and become lethargic with labored breathing. Within seven days, all the transgenic mice in the original study died, supporting that transgenic expression of hACE2 in epithelial cells can lead to a moderate SARS-CoV infection that can progress into a fatal disease.
Standard infection of ACE2 transgenic mice is via intranasal inoculation of SARS-CoV or SARS-CoV-2. A recent study showed that infection with SARS-CoV-2 in the ACE2 transgenic mice resulted in high levels of viral infection in lungs, with spread to other organs. A decline in lung function occurred several days after peak viral titer and correlated with the infiltration of immune cells. SARS-CoV-2-infected lung tissues showed a massively upregulated innate immune response similar to what is seen in humans. Thus, the ACE2 transgenic mouse model of SARS-CoV-2 infection is one model that can be used to study lung disease and test immune and antiviral-based therapies.
Although ACE2 transgenic mice have been promising for COVID-19 research, they lack some of the tissue-specificity seen in humans and might not replicate COVID-19 precisely, limiting their applications in certain studies. Therefore, precise genetic editing to express human ACE2 specifically at the mouse ACE2 locus in order to observe an endogenous pattern of expression and an infection that progresses similar to what is seen in humans is imperative.
Many research labs and commercial companies are working toward using gene targeting and editing to make specifically-targeted human ACE2 mouse models, including ingenious targeting laboratory. We have developed our own exclusive, large-scale humanized mouse model that provides a targeted, hybrid human/mouse ACE2 receptor which supports viral infection of a human host while conserving intracellular signaling functionality of the mouse. It is our hope that our model will enable relevant studies of infectivity, viral life cycle, and disease progression by means of a new, virally-susceptible murine experimental platform that can be used to develop better therapies and vaccines.
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