It’s war. Invaders are afoot. Vigilant sentries spot them, signal for reinforcements, unite with other nearby sentries, and charge into battle. Soon, the “big guns” arrive, a squadron of well-armed, well-trained soldiers who strike deep into the invaders’ ranks.
This drama unfolds on a cellular and subcellular battlefield. It’s the immune system’s response to a SARS-CoV-2 invasion—and investigating how it plays out is crucial for understanding how to prevent death and other poor outcomes in high-risk COVID-19 patients.
Cihan Oguz, Ph.D., a bioinformatics analyst in the Frederick National Laboratory’s (FNL) Biomedical Informatics and Data Science Directorate, is working with a team of scientists at the National Institute of Allergy and Infectious Diseases to study how the immune system responds to SARS-CoV-2 at the molecular level.
Specifically, the team is looking at how one group of “big guns”—white blood cells called T cells—can train the immune system to combat SARS-CoV-2 among a multigenerational group of Italian patients with different severity levels of COVID-19. Their focus is the whole repertoire of T-cell receptors in each patient, which is the collection of molecules on the surfaces of T cells that help the immune system detect and destroy invaders.
Each T cell is outfitted with receptors encoded by genes with specific DNA sequences. These sequences are highly variable and can code for millions of unique receptors thanks to a process called “gene rearrangement.” T-cell receptors determine which pathogens the immune system can attack. (If, for instance, cells lack a receptor specifically designed to mark SARS-CoV-2 as a target, the immune system isn’t likely to attack the virus.)
The body’s response to its sentries’ call—its ability to generate large numbers of T-cell receptors configured to recognize the SARS-CoV-2 proteins—determines how quickly and effectively the immune system counterattacks and destroys the virus.
The team found that patients who experienced COVID-19 for prolonged periods had more diverse sets of T-cell receptors that could recognize SARS-CoV-2 compared to patients with less severe cases in a given age group. On the other hand, patients older than 65 who succumbed to severe COVID-19 had less diverse sets of SARS-CoV-2-specific T-cell receptors. In addition, patients with blood-based malignancies, such as those undergoing chemotherapy due to blood cancers, also had less diverse T-cell receptor repertoires to eliminate SARS-CoV-2.
In other words, in people who had prolonged infections, the immune system is a battle-hardened veteran that’s now more prepared for its next encounter with the virus. Meanwhile, patients with lower levels of the right receptors have immune systems that are less equipped to fight SARS-CoV-2 in future invasions.
“Our findings … can inform development of vaccines geared toward generating a diverse adaptive immune response to prevent full-blown COVID-19 infections,” Oguz said.
Understanding how to generate this diversity and recruit “effective soldiers” in the immune system is a critical part of the vaccine development process. Vaccines simulate an infection and cause the body to train the T cells and other immune system components that can attack the target pathogen. These cells remain in the body and protect against viral infections in the future.
“If confirmed in other [groups of patients], our findings also have important implications regarding potential immunization policies for patients vulnerable to COVID-19 infections due to their low [T-cell receptor] clonotype diversity and inability to mount a quick and robust immune response that is essential to avoid the detrimental effects of COVID-19 on vital organs,” Oguz said.
Moving toward a fuller picture
FNL’s Oguz worked on the project alongside study lead Luigi Notarangelo, M.D.; Ottavia Delmonte, M.D.; and team at the National Institute of Allergy and Infectious Diseases. They were joined by life sciences company Adaptive Biotechnologies. For his part, Oguz analyzed the sequencing data generated from patients’ T-cell receptors to identify the regions that recognize SARS-CoV-2.
That information allowed him and the team to compare the frequencies of the T-cell receptors recognizing the SARS-CoV-2 proteins in different groups of patients and at different times during the infection.
With the results of this first investigation in hand, the team has begun broadening its focus to receptors on B cells, another set of “big guns,” to gain a more complete idea of how the immune system responds to SARS-CoV-2.
Oguz says that characterizing the myriad immune responses against SARS-CoV-2 is a challenging area of research. He acknowledges that it will likely take some time to come up with safe and effective vaccination policies and treatment strategies for COVID-19, but he adds that the work is a “great opportunity” to make meaningful contributions to biomedical research and advance public health.
“With this project, we have a chance to uncover specific immune response signatures that differentiate between patients with different clinical outcomes,” he said. “It is very important to understand the [underlying] mechanisms.”
By Samuel Lopez, staff writer