For the first time in live animals, researchers have captured on video the spread of SARS-CoV-2, tracing the virus as it moved from the noses of infected mice to the lungs, other organs and eventually the brain.
The study and resulting images also offer insight into the role of antibodies, including which properties make them most effective and at which sites they are most likely to halt virus progression.
“We used to think neutralizing the virus was enough to prevent infection, but antibodies have to be present at the right time in the right place in the body and in the right amount,” said Priti Kumar, associate professor of infectious diseases at Yale School of Medicine and a co-corresponding author of the study.
Using bioluminescent tagging and electron microscopy, Kumar and his team tracked the spread of SARS-CoV-2 down to the level of single cells. In mice, the virus took a familiar route with high viral loads first appearing in nasal passages and then spreading—the same way SARS-CoV-2 infects and travels throughout the human body.
According to the paper, published as a pre-proof in Immunity, researchers saw the first signs of infection in mice lungs only one day post-exposure. At day 4, the team recorded an increase in luminescent signal in the brain region. Then, from day 4 to 6, they saw a “steep rise…indicating neuroinvasion and robust virus replication.” This coincided with virus replication in the gut and genital tract, as well as a loss in body weight.
By day 6, the mice died. Microscopy images taken during necropsy revealed maximum luminescent signal activity in the brain, followed by the lung and nasal cavity.
Then, using plasma from human participants who recovered from COVID-19, the researchers isolated two potent neutralizing antibodies—CV3-1 and CV3-25. In testing prophylactic treatments, CV3-1 performed the best. Pretreating mice with the antibody resulted in near complete protection from SARS-CoV-2, including no sign of infection is any organs. By contrast, CV3-25 reduced the intensity of the virus and delayed death by two days, but it did not prevent it. Additionally, recorded viral loads for the CV3-25 mice were similar to the viral loads seen in control mice.
Leveraging CV3-1’s effectiveness, the researchers tested whether the antibody would have a positive effect if given after exposure to SARS-CoV-2. Imaging confirmed that, if given on day 1 or 3 post-infection, CV3-1 could successfully control the spread of the virus, preventing neuroinvasion. Treatment on day 4, however, proved to be too late, as the antibody was unable to control virus spread into the brain, resulting in 75% mortality of the cohort.
“The live reporting of virus spread by imaging can be harnessed to rapidly discern whether treatments will work or not in as little as three to five days, a crucial time-saving feature to develop countermeasures for current and future pandemics,” said study co-author Pradeep Uchil, a research scientist in the Department of Microbial Pathogenesis at Yale.
Running additional tests on CV3-25, the researchers discovered that, to ensure optimal efficacy against SARS-CoV-2, neutralizing antibodies must exhibit “effector functions,” which are necessary to signal the immune system to attack and kill infected cells.
“Antibodies are polyfunctional molecules with several properties,” said study co-author Andrés Finzi from the University of Montreal. “In this study we show their capacity to ‘call for help’ from other cells in the immune system and eliminate infected cells is required to provide optimal protection. Without the effector function, the neutralizing activity alone is not as effective.”