Three distinct immune responses for sicker COVID-19 patients — Penn Institute of Immunology

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Researchers from the Penn Institute of Immunology have discovered three distinct immune responses to the SARS-CoV2 infection that could help predict the trajectory of disease in severe COVID-19 patients and may ultimately inform how to best treat them.

"For patients who are hospitalised with COVID-19, there isn't just one way for the immune system to respond. There's a lot of heterogeneity, which we've distilled down into what we're calling three "immunotypes," said senior author Dr E John Wherry, chair of the department of systems pharmacology and translational therapeutics and director of the Penn Institute of Immunology in the Perelman School of Medicine at the University of Pennsylvania. "We're hopeful we may actually be able to predict, or at least infer, the different immune patterns a patient has based on clinical data. This would allow us to start thinking about enrolling patients to different types of clinical trials investigating treatments."

The coronavirus triggers different immune responses and symptoms in critically ill patients, but how those two correspond has remained poorly understood, making treatment decisions more difficult.

While recent studies reveal details on the immune's response to the virus, most have been single-case reports or focused on a small group of individuals. This is the first study, to the author's knowledge, to offer up a comprehensive immune profile of a large number of hospitalised patients.

The researchers applied deep immune profiling to capture individual responses of 163 patients during the course of their infections. The study included 90 hospitalised patients treated at the Hospital of the University of Pennsylvania, 29 non-hospitalised patients, and 44 healthy donors with no COVID-19 infection. The immune responses varied among the group, but there were patterns that hold clinical promise.

The first immunotype had robust CD4+ T cell activity, with modest activation of CD8+ T cells and peripheral blood lymphocytes. CD4+ and CD8+ act as the main inflammatory immune cells that work to clear viruses. The second immunotype was characterised mainly by a subset of CD8+ T cells known as EM and EMRA and a modest activation of CD8+ T cells, memory B cells, and peripheral blood lymphocytes. The third immunotype showed little to no evidence of an immune response to the infection.

Next, researchers combined the profiling with clinical data to understand the relationships between immune responses and disease. The first immunotype was tied to more severe disease that included inflammation, organ failure, and acute kidney disease. The second correlated not with disease severity but instead pre-existing immunosuppression and mortality. The third type, which had no immune activation, was not associated with specific symptoms or clinical features, though they varied.

The immunotypes developed by Wherry and team represent adaptive immune responses. A second study from researchers at Penn uncovered new details about the innate, or initial, response to SARS-CoV2. "T and B cell activity are informed by innate immune responses," said senior author Dr Michael R Betts, a professor of microbiology and programme leader in the Penn Institute of Immunology, who is also a co-author on the first study. "We believe what's happening with the innate response of the immune system might be what's leading to these three immune phenotypes Wherry's lab identified."

Profiling the blood samples of 42 infected patients (with moderate and severe disease) and 12 healthy donors, the researchers found a similar heterogeneity in immune adaptive responses: robust activation of CD4+ and CD8+ T cells, B cells, along with peripheral blood cells, like neutrophils, monocytes, and "natural killer," or NK, cells.

While the innate responses were also heterogenous, the researchers observed a decrease of CD15 and CD16 molecules on neutrophils and CD16 on NK cells, immature granulocytes, and monocytes, in patients with more severe disease. These two molecules are known players in the immune's response to viral infections that also represent a potential target for immunotherapy. How they are driving and exacerbating the adaptive responses in the three immunotypes is an important question the labs are working to better understand.

COVID-19 studies have been moving at an unprecedented speed as researchers band together to find answers. Among its many efforts, Penn formed lab and clinical research teams from diverse backgrounds to strengthen its focus on the immune system, along with the COVID Processing Unit to manage specimens to profile.

"Understanding the power of the immune system to regulate responses to disease is one of the major advances in medicine in the last decade, and Penn has been at the centre leading that discovery. We are now applying the broad expertise and experience of our more than 200-person immunology community toward the research and treatment of COVID-19," said Dr Jonathan A Epstein, executive vice dean, chief scientific officer, and a professor of cardiovascular research at Penn. "The deep immuno-profiling work the investigators applied here is likely to be useful not only now, for this disease, but into the future for many others."

Abstract 1
COVID-19 is currently a global pandemic, but human immune responses to the virus remain poorly understood. We analyzed 125 COVID-19 patients, and compared recovered to healthy individuals using high dimensional cytometry. Integrated analysis of ~200 immune and ~50 clinical features revealed activation of T cell and B cell subsets in a proportion of patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses reaching >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable to uninfected subjects. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. These analyses identified three “immunotypes” associated with poor clinical trajectories versus improving health. These immunotypes may have implications for the design of therapeutics and vaccines for COVID-19.

Divij Mathew, Josephine R Giles, Amy E Baxter, Derek A Oldridge, Allison R Greenplate, Jennifer E Wu, Cécile Alanio, Leticia Kuri-Cervantes, M Betina Pampena, Kurt D’Andrea, Sasikanth Manne, Zeyu Chen, Yinghui Jane Huang, John P Reilly, Ariel R Weisman, Caroline AG Ittner, Oliva Kuthuru, Jeanette Dougherty, Kito Nzingha, Nicholas Han, Justin Kim, Ajinkya Pattekar, Eileen C Goodwin, Elizabeth M Anderson, Madison E Weirick, Sigrid Gouma, Claudia P Arevalo, Marcus J Bolton, Fang Chen, Simon F Lacey, Holly Ramage, Sara Cherry, Scott E Hensley, Sokratis A Apostolidis, Alexander C Huang, Laura A Vella, The UPenn COVID Processing Unit, Michael R Betts, Nuala J Meyer, E John Wherry

Abstract 2
Although critical illness has been associated with SARS-CoV-2-induced hyperinflammation, the immune correlates of severe COVID-19 remain unclear. Here, we comprehensively analyzed peripheral blood immune perturbations in 42 SARS-CoV-2 infected and recovered individuals. We identified extensive induction and activation of multiple immune lineages, including T cell activation, oligoclonal plasmablast expansion, and Fc and trafficking receptor modulation on innate lymphocytes and granulocytes, that distinguished severe COVID-19 cases from healthy donors or SARS-CoV-2-recovered or moderate severity patients. We found the neutrophil to lymphocyte ratio to be a prognostic biomarker of disease severity and organ failure. Our findings demonstrate broad innate and adaptive leukocyte perturbations that distinguish dysregulated host responses in severe SARS-CoV-2 infection and warrant therapeutic investigation.

Leticia Kuri-Cervantes, M Betina Pampena, Wenzhao Meng, Aaron M Rosenfeld, Caroline AG Ittner, Ariel R Weisman, Roseline S Agyekum, Divij Mathew, Amy E Baxter, Laura A Vella, Oliva Kuthuru, Sokratis A Apostolidis, Luanne Bershaw, Jeanette Dougherty, Allison R Greenplate, Ajinkya Pattekar, Justin Kim, Nicholas Han, Sigrid Gouma, Madison E Weirick, Claudia P Arevalo, Marcus J Bolton, Eileen C Goodwin, Elizabeth M Anderson, Scott E Hensley, Tiffanie K Jones, Nilam S Mangalmurti, Eline T Luning Prak, E John Wherry, Nuala J Meyer, Michael R Betts


Penn Institute of Immunology material


Science abstract


Science Immunology abstract

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