Scientists at La Jolla Institute for Immunology (LJI) and Charles River Laboratories International have announced the launch of a new project geared at uncovering precisely how different cells in the human immune system respond to SARS-CoV-2, the virus behind COVID-19. According to the collaborators, this work is aimed at helping scientists worldwide to better capture how the body responds to the virus, starting on the first day of infection.
Heading up the work at LJI is Sujan Shresta, member of the LJI Center for Infectious Disease and Vaccine Research. Her laboratory will provide the first in-depth characterization of an ACE2i humanized mouse model of SARS-CoV-2 infection, made available by Charles River in conjunction with Gempharmatech, including a close look at human immune responses; Shresta’s lab also will work with Kenneth Kim, director of the LJI Histopathology Core.
“With the urgent need for animal models in the early stages of the emerging pandemic, Charles River initiated development with our licensee partner for the NCG (triple immunodeficient) mouse, GemPharmatech,” Steve Festin, senior director of scientific and commercial development with Charles River, explained to Outsourcing-Pharma. “We immediately reached out to Dr. Shresta based on her recognized reputation as a leading researcher using animal models to study infectious disease and the advanced laboratory capabilities of LJI.”
Festin added that Shresta and Kim “were very excited about the opportunity to work with a novel mouse model replacing the mouse ACE2 gene with a hACE2 (the known receptor for SARS-CoV2) capable of hosting human immune an integrated human immune cell system.”
This new mouse model has been engineered to express human ACE2, the receptor that SARS-CoV-2 uses to infect human cells and include the same immune cells made by the human body. As Shresta explained, these mice may offer a window into understanding COVID-19 not feasible in human studies.
Previously, researchers have found that the incubation period for SARS-CoV-2 is usually four to five days. In severe cases, patients tend to show signs of the disease for 10 to 12 days before they are hospitalized.
"At the time of hospitalization, people have already been infected for two weeks," Kim explained.
"With human patients, we can only look at the immune response after there have been signs of infection," Shresta added. "We need these animal models to understand the early time points in infection and get a window into the human immune response in tissues such as the lungs."
Shresta’s lab plans to investigate how susceptible these mice are to SARS-CoV-2. The researchers will also measure viral loads in the mice and analyze lung tissues with help from the LJI Histopathology Core.
The goal for Charles River’s Research Model and Services business was to obtain and develop a model to solve the problem of understanding the role of human immune cells in early, acute SARS-CoV-2 infection. The best solution, the team discovered, was to increase the susceptibility of the NCG mouse model, which is capable to be immuno-humanized, by engineering human ACE2 receptor (known now to be the receptor of many variant strains of SARS-COV-2) into the mouse ACE2 locus of NCG, named hACE2-NCG(1) leading to a scientific partnership and collaboration with Shresta’s lab to better define the utility of the model and to understand better mechanisms of early infection in an immuno-humanized mouse.
Shresta is a renowned expert in using mouse models to study immune responses to infectious diseases. Her laboratory has led research into virus-host interactions in a range of diseases, including dengue, Zika, and Japanese encephalitis. This work reportedly has shed light on the precise balance of immune cell types needed to fight off these potentially deadly viruses.
Shresta is also a member of the LJI Coronavirus Task Force and has worked to establish COVID-19 research partnerships in Nepal, Vietnam, and the Philippines. She thinks the new mouse models from Charles River Laboratories will provide a critical window into what is happening in human patients.
"I'm really excited about this collaboration," says Shresta. "This brand-new mouse model is a tremendous opportunity for my lab to study the human immune response on a timescale which is just not possible with clinical studies."