Comparing immune landscapes across respiratory infections

From the Lund and Prlic labs, Vaccine and Infectious Disease Division

Although vaccines against SARS-CoV-2 have been rapidly developed, COVID-19 continues to present a global health crisis that necessitates further intervention. Previous research has characterized the immune response to SARS-CoV-2 infection with the goals of illuminating pathogenesis mechanisms and informing development of therapeutics and vaccines. This work suggests that a state of hyper-inflammation is associated with COVID-19, but it is unclear whether this immune dysregulation is unique to COVID-19 or is a hallmark of general viral respiratory infections. To answer this question, Drs. Sarah Vick and Marie Frutoso (Lund and Prlic labs, Vaccine and Infectious Disease Division), along with collaborators from the University of Washington Department of Medicine, designed a study to compare the immune signatures of healthy donors to those of patients hospitalized after SARS-CoV-2 or other respiratory infections. This work is currently available as a preprint on medRxiv.

To profile circulating immune cells across various respiratory infections, the authors collected peripheral blood mononuclear cells (PBMCs)—a representative sample of circulating immune cells— from healthy donors and patients hospitalized after SARS-CoV-2, influenza virus (flu), or respiratory syncytial virus (RSV) infections. Patient samples were further categorized as corresponding to moderate, severe, or critical disease, defined by the level of oxygen supplementation the patient required during hospitalization. The PBMCs were stained with 4 different high-parameter flow cytometry panels to identify expression of various activation and functional markers within major immune cell type populations, followed by unsupervised data exploration with unbiased clustering programs to identify changes in immune clusters between cohorts. These analyses revealed that immune profiles were largely similar between samples from the three respiratory infections, but that this shared phenotype—such as increased expression of markers related to activation on T cells and increased production of pro-inflammatory cytokines— diverged from healthy samples. These findings suggest that various respiratory infections, regardless of the specific virus, trigger a common circulating immune response.

Although broad analysis revealed few changes between the immune landscapes of SARS-CoV-2, RSV, and flu, the authors applied an unbiased analysis tool called Full Annotation Using Shape-constrained Trees (FAUST) to their raw flow cytometry data to further investigate infection-specific immune differences between cohorts. Interestingly, FAUST identified complex phenotypes within regulatory T cells (Tregs) whose frequencies were different across the different infections. Because Tregs are a multi-faceted subset of T cells that coordinate and restrain adaptive immune responses through various suppressive mechanisms, the authors were interested in further investigating Treg phenotypes within COVID-19 disease. The group used high parameter flow cytometry to compare Treg frequencies and expression of known activation and suppressive molecules. They found that samples from the SARS-CoV-2 cohort displayed increased Treg frequencies and activation potential, suggesting that Tregs could be responsible for inhibiting productive anti-viral T cell responses during SARS-CoV-2 infection. However, Treg function is known to be highly contextual and nuanced: although Tregs may limit an effective immune response and allow greater viral dissemination, this necessary evil can protect the host from excessive immune-mediated inflammation and tissue damage. Therefore, in the context of SARS-CoV-2 infection, it is still unclear how Tregs contribute to the balance between immunosuppression and tissue preservation. “We don’t currently know if these suppressive cells are activated in response to the inflammation seen in critical COVID-19 patients, or if these suppressive cells could be dampening a productive immune response leading to more severe disease,” explained the lead authors Drs. Vick and Frutoso. “We are interested in learning more about the role of these cells in disease progression,” Drs. Vick and Frutoso said, as Treg-mediated therapy has been proposed to combat inflammation in SARS-CoV-2 infection.

Graphical abstract of the study design and analysis.
Graphical abstract of the study design and analysis. Figure provided by Sarah Vick and Marie Frutoso.

Overall, this study revealed that a general circulating immune response is shared between several lung infections, suggesting that a common treatment strategy could be effective against multiple infections. “Because our study has a unique cohort of patients hospitalized after SARS-CoV-2, Flu or RSV infection, we were able to determine which of these immune responses is unique to the SARS-CoV-2 virus and which are broadly applicable to respiratory infections,” said Drs. Vick and Frutoso. “These findings are important in order to identify therapeutic avenues which could be beneficial in limiting COVID-19 and could be leveraged to treat other common respiratory infections,” Drs. Vick and Frutoso explained. Looking forward, the development of pan-respiratory immunotherapies could treat a variety of existing infections as well as provide a first-line defense against future pandemic viruses.

This work was supported by the National Institutes of Health.

Fred Hutch/UW Cancer Consortium members Raphael Gottardo, Josh Schiffer, and Martin Prlic contributed to this work.

Vick SC, Frutoso M, Mair F, Konecny AJ, Greene E, Wolf CR, Logue JK, Boonyaratanakornkit J, Gottardo R, Schiffer JT, Chu HY, Prlic M, Lund JM. A differential regulatory T cell signature distinguishes the immune landscape of COVID-19 hospitalized patients from those hospitalized with other respiratory viral infections. medRxiv. 2021 Mar 26;2021.03.25.21254376. doi: 10.1101/2021.03.25.21254376. Preprint