The cold snap of autumn is a harbinger of a surge in respiratory infections for physicians across the country. Among the culprits responsible for these infections is respiratory syncytial virus (RSV). While almost all kids will be infected by RSV at least once before the age of two, some of them have an infection so severe that it lands them in the hospital.
Melody Duvall, a pediatric critical care physician at Boston Children’s Hospital, wanted to figure out why. “The kinds of kids that drew me in were the ones who were ventilated and super sick in the intensive care unit with lung inflammation, often from viral infections,” she said.
In a study recently published in Science Translational Medicine, Duvall and her team found that a certain population of immune cells — natural killer (NK) cells — were decreased in the blood of infected kids compared to healthy controls (1). When they took a closer look at these NK cells, they saw that the cells had impaired cytotoxic properties, meaning that they were less able to kill other cells. These results might help explain how the immune system becomes dysregulated during severe RSV infection and could lead to future therapeutic interventions that target these cells.
NK cells are an important part of the immune response. “They’re one of the earliest responders, and they have two main functions,” said Rosie Reilly, now an MD-PhD student at Washington University in St. Louis and a coauthor on the study. One function, she said, is to produce cytokines or other proteins that signal to the body that there is an infection. The other function is cytotoxicity, where the NK cells recognize and kill infected cells.
Duvall, Reilly, and the team wanted to see what was happening with the NK cells during a severe RSV infection. But because the kids were so sick that they required advanced respiratory support like ventilation, getting any samples from their breathing tubes was very difficult. Ultimately, the team collected airway samples from 10 patients and blood samples from 37 patients who were hospitalized in the intensive care unit with RSV.
When they counted the number of NK cells in the airway versus the blood, the scientists found that “the children who were most sick with RSV had many more NK cells in the airway than children who were either uninfected or had mild cases of RSV,” said Duvall. “That was in direct contrast to what we found in the peripheral blood, where numbers were suppressed.”
Finding that there were lower numbers of NK cells in the blood was consistent with previous studies. One hypothesis for why, said Duvall, is that the NK cells might be recruited to the lungs since that is the primary site of an RSV infection — leading to lower numbers in the blood.
The scientists decided to probe further into the NK cells from the patients’ blood. By looking at the levels of a certain protein on the NK cells, the team saw that the NK cells seemed to be the type of cells that would secrete cytokines instead of being cytotoxic.
When the team mixed the NK cells from the patients’ blood with target cells in a petri dish, they found that the NK cells could not kill the target cells as effectively as those from healthy controls. This meant that the cytotoxic response in these NK cells was not working as well during an RSV infection.
Did the RSV cause the NK cells to become dysfunctional, or did [the kids] have something different about their NK cells that contributed to the disease pathogenesis?
- Rosie Reilly, Washington University in St. Louis
Normally, an NK cell can eliminate a sick cell through a process Duvall called the “kiss of death.” The NK cell will attach to the sick cell and then reorganize its cytoskeleton — the NK cell’s internal scaffolding — so that a collection of toxic granules can enter the sick cell to kill it.
To figure out exactly what was going wrong in patient NK cells, the scientists used confocal microscopy. When they zoomed in on the NK cells from the RSV patients’ blood, they found that the NK cells’ normal cytoskeletal reorganization did not occur properly — potentially keeping the NK cells’ toxic granules from entering the target cell. This may be why NK cells were not successfully killing the target cells.
“This is a very neat story that shows that in kids with RSV, yes, their cells are getting to the lungs, but in the blood, the makeup of these cells and how they work has been altered,” said Simon Drysdale, a pediatric infectious disease physician at the University of Oxford who was unaffiliated with the study. “Perhaps that’s why these kids are getting more severe disease.”
This finding leads to many more questions down the road for kids with RSV. “Did the RSV cause the NK cells to become dysfunctional, or did [the kids] have something different about their NK cells that contributed to the disease pathogenesis?” Reilly said.
Duvall also wants to see if there is a way to fix what is going wrong in these NK cells or to help mitigate immune responses that have gone haywire. She does recognize, however, that much remains to be solved. “We’re beginning to speak with a more educated voice about immune pathology,” she said. “Perhaps if we identify pathways that are overactive, underactive, or separately active, that can give us some targets to think about for therapies in the future.”
Reference
1. Reilly, R.B. et al. An altered natural killer cell immunophenotype characterizes clinically severe pediatric RSV infection. Sci Transl Med 16, eado6606 (2024).
