FOCUSImmunobiologyART BY SOPHIA ZHAOAmid the COVID-19 pandemic, a figure crawls from the darkness. Bornfrom the collaborative efforts of investigators at the Yale School of Medicine,he represents a crucial scientific weapon for COVID-19 researchers—abridge between understanding the disease and effectively treating it. He isa hero that wears no cape, and his name…is Mr. G.Okay, his full name is MISTRG6.And he is a mouse.16 Yale Scientific Magazine March 2022 www.yalescientific.org
ImmunobiologyFOCUSWho is Mr. G?Mr. G is a genetically engineered mousewith a human-like immune response toCOVID-19: through him (and mice likehim), researchers may be able to bettertest both existing and new potential treatmentsagainst the virus. Mouse modelslike Mr. G can be crucial to answering keyquestions about how the virus works andhow we can combat it.Over four hundred million cumulativecases of COVID-19 have been recordedin the past six months. Roughly eightypercent of them have been classified as“mild”. The remaining twenty percent ofcases are “severe,” with symptoms includingrespiratory failure, blood clotting, andmulti-organ dysfunction.Why do some people experience onlymild cases while others face life-threateningones? Through Mr. G, Yale School of MedicineSterling Professor of ImmunobiologyRichard Flavell and Esen Sefik, a post-doctoralfellow in his lab, aimed to find out.“Some [COVID-19 treatments] workedin a subset of patients, but not all of them,”Sefik said. “There were a lot of unknownsat the time, and we thought that if we had amodel, we could help.”The Challenges of an Animal ModelScientists have traditionally relied onanimal models to evaluate the safety andefficacy of vaccines and antiviral candidates.However, while a plethora of animals– ranging from rabbits to primates – havebeen studied for their immune response toSARS-CoV-2, no standard laboratory animalshave developed the severe respiratoryfailure, organ failure, or cytokine storms,which are intense inflammatory processes,seen in severe human cases. Some animalsbarely show any symptoms.But the lack of symptom overlap withhumans does not mean that these animalmodels lack usefulness as a startingpoint for study. Animals are affected bySARS-CoV-2; the difference merely liesin how they respond. With this in mind,if researchers could alter the response of aCOVID-infectable species to match the humanimmune response, they could create asuitable animal model to study the disease.Of the animal species that do get infected,mice stand out as the most promisingfor this type of study. Mice havebeen used in biomedical research fornearly a century, and, as a result, scientistsunderstand their physiology withnear genomic-level precision. We alsoshare about ninety-five percent of ourDNA with mice, so our biological responsesto disease are typically similarenough for findings to be translatable tohumans. In addition, practically speaking,mice are small, easy to transport, andhave a fast reproduction time with an acceleratedlifespan, making them incrediblycost-effective and efficient for studyinginfectious disease processes.However, the differences in the immuneresponse to COVID-19 betweenhumans and mice still represent a majorobstacle for researchers. In humans, inhaledSARS-CoV-2 travels to the alveoliin the lungs, where the exchange of carbondioxide for fresh oxygen in the bloodoccurs. There, the virus hooks onto aprotein called the angiotensin-convertingenzyme type 2 receptor (ACE2), whichprovides an entry point into the alveolarcell lining. Once taken in, the virusbreaks the cell apart, releasing millionsof new viral particles and inflammatorycytokines. These cytokines cause plasmaand immune cells in the blood to leakinto the alveoli, blocking gas exchangeand causing fluid buildup in the lungs.However, unlike humans, standard laboratorymice infected with SARS-CoV-2do not show major signs of infection.This is partly because the ACE2 receptorin mice is structurally different from theACE2 receptor in humans, enough so thatSARS-CoV-2 generally cannot effectivelybind to the mouse receptor, enter alveolarcells, and cause chronic infection. Toaddress this difference, Flavell and Sefikturned to Akiko Iwasaki, the WaldemarVon Zedtwitz Professor in the Departmentof Immunology at Yale, who founda way to use gene therapy to induce miceto transiently express the human versionof ACE2. By delivering the human-ACE2gene through a mild adeno-associated virus(AAV) injected into the trachea, herteam successfully transferred the geneinto cells into the lung tissue of mice.“Humanizing” a MouseWhile mice with just the human-ACE2gene get sick, they do not necessarily exhibitsevere COVID-19 symptoms. Theimmune systems of mice and humans arejust different enough that “humanizedmice,” or mice adapted to have a humanimmune system, have become crucialHUMANIZING MOUSEMODELS By Ryan Bose-Roywww.yalescientific.orgMarch 2022 Yale Scientific Magazine 17