YSM Issue 95.1

Immunobiology
FOCUS
Who is Mr. G?
Mr. G is a genetically engineered mouse
with a human-like immune response to
COVID-19: through him (and mice like
him), researchers may be able to better
test both existing and new potential treatments
against the virus. Mouse models
like Mr. G can be crucial to answering key
questions about how the virus works and
how we can combat it.
Over four hundred million cumulative
cases of COVID-19 have been recorded
in the past six months. Roughly eighty
percent of them have been classified as
“mild”. The remaining twenty percent of
cases are “severe,” with symptoms including
respiratory failure, blood clotting, and
multi-organ dysfunction.
Why do some people experience only
mild cases while others face life-threatening
ones? Through Mr. G, Yale School of Medicine
Sterling Professor of Immunobiology
Richard Flavell and Esen Sefik, a post-doctoral
fellow in his lab, aimed to find out.
“Some [COVID-19 treatments] worked
in a subset of patients, but not all of them,”
Sefik said. “There were a lot of unknowns
at the time, and we thought that if we had a
model, we could help.”
The Challenges of an Animal Model
Scientists have traditionally relied on
animal models to evaluate the safety and
efficacy of vaccines and antiviral candidates.
However, while a plethora of animals
– ranging from rabbits to primates – have
been studied for their immune response to
SARS-CoV-2, no standard laboratory animals
have developed the severe respiratory
failure, organ failure, or cytokine storms,
which are intense inflammatory processes,
seen in severe human cases. Some animals
barely show any symptoms.
But the lack of symptom overlap with
humans does not mean that these animal
models lack usefulness as a starting
point for study. Animals are affected by
SARS-CoV-2; the difference merely lies
in how they respond. With this in mind,
if researchers could alter the response of a
COVID-infectable species to match the human
immune response, they could create a
suitable animal model to study the disease.
Of the animal species that do get infected,
mice stand out as the most promising
for this type of study. Mice have
been used in biomedical research for
nearly a century, and, as a result, scientists
understand their physiology with
near genomic-level precision. We also
share about ninety-five percent of our
DNA with mice, so our biological responses
to disease are typically similar
enough for findings to be translatable to
humans. In addition, practically speaking,
mice are small, easy to transport, and
have a fast reproduction time with an accelerated
lifespan, making them incredibly
cost-effective and efficient for studying
infectious disease processes.
However, the differences in the immune
response to COVID-19 between
humans and mice still represent a major
obstacle for researchers. In humans, inhaled
SARS-CoV-2 travels to the alveoli
in the lungs, where the exchange of carbon
dioxide for fresh oxygen in the blood
occurs. There, the virus hooks onto a
protein called the angiotensin-converting
enzyme type 2 receptor (ACE2), which
provides an entry point into the alveolar
cell lining. Once taken in, the virus
breaks the cell apart, releasing millions
of new viral particles and inflammatory
cytokines. These cytokines cause plasma
and immune cells in the blood to leak
into the alveoli, blocking gas exchange
and causing fluid buildup in the lungs.
However, unlike humans, standard laboratory
mice infected with SARS-CoV-2
do not show major signs of infection.
This is partly because the ACE2 receptor
in mice is structurally different from the
ACE2 receptor in humans, enough so that
SARS-CoV-2 generally cannot effectively
bind to the mouse receptor, enter alveolar
cells, and cause chronic infection. To
address this difference, Flavell and Sefik
turned to Akiko Iwasaki, the Waldemar
Von Zedtwitz Professor in the Department
of Immunology at Yale, who found
a way to use gene therapy to induce mice
to transiently express the human version
of ACE2. By delivering the human-ACE2
gene through a mild adeno-associated virus
(AAV) injected into the trachea, her
team successfully transferred the gene
into cells into the lung tissue of mice.
“Humanizing” a Mouse
While mice with just the human-ACE2
gene get sick, they do not necessarily exhibit
severe COVID-19 symptoms. The
immune systems of mice and humans are
just different enough that “humanized
mice,” or mice adapted to have a human
immune system, have become crucial
HUMANIZING MOUSE
MODELS By Ryan Bose-Roy
www.yalescientific.org
March 2022 Yale Scientific Magazine 17