COVID-19 - Coronavirus disease 2019

Study of immune crosstalk in COVID-19 – COVIMUNE

Study of immune crosstalk in COVID-19 – COVIMUNE

We hypothesize that antigen presenting cells determine, based on human leucocyte antigens (HLAs) and viral antigens to activate T cell response, whether infection leads to disease pathogenesis or a protective immune response resulting in milder disease and/or long-term protection to SARS-CoV-2.

We aim to better understand how human-viral interactions polarize the adaptive immune response through interaction of antigen presenting cells and T lymphocytes.

Coronavirus disease 2019 (COVID-19) is caused by «severe acute respiratory syndrome coronavirus 2« (SARS-CoV-2). First identified in 2019 in Wuhan, China, it has since spread globally, resulting in the pandemic. While the majority of cases result in mild symptoms, some progress to severe pneumonia and multi-organ failure. Recent clinical data suggested that severe Covid-19 is due to overreacting immunity leading to a cytokine storm. Although the innate immune response is critical in preventing viruses from establishing infection, it is adaptive immunity that determines the outcome of infection and clearance of the viruses. Little is known about how pathogens activate the human immune system and in certain circumstances lead to a cytokine storm. Previous reports from China show that a dysregulated T cell response might be implicated in the pathological process of COVID-19. These data highlight the importance of dissecting the spectrum of CD4 T cell responses to SARS-CoV-2 and discovering the underlying reason why SARS-CoV-2 causes high inflammation in affected individuals as compared to seasonal coronaviruses.

In this proposal, we had an objective to create an in vitro model using primary immune cells to understand how human-viral interactions polarize the adaptive immune response through the interaction of antigen-presenting cells (APCs) and T lymphocytes. Our concept was that APCs determine, based on human leukocyte antigens (HLAs) and viral antigens to activate T cell response, whether infection leads to disease pathogenesis or a protective immune response resulting in milder disease and/or long-term protection to SARS-CoV-2. To characterize the immune response of COVID-19 patients, we recruited 69 COVID-19 individuals admitted to four hospitals in the Paris area, France from June 2020 to April 2021 (COVIMUNE cohort). Patients were segregated into four clinical groups based on the disease severity.

We observed that APCs were moderately activated by SARS-CoV-2 in vitro. Surprisingly basophils, as major cells involved in respiratory tract infection, could also be activated by SARS-CoV-2 in vitro. These results suggest that basophil cytokine responses to SARS-CoV-2 might help in reducing the inflammation and also promote antibody responses to the virus. We characterized the CD4 T cell polarization in the convalescent COVID-19 patients and the correlation with their disease severity. Also, we determined how HLA haplotype can influence CD4 T cell polarization after SARS-CoV-2 infection.

Concerning the identification of sequences of the virus that significantly activated T cells in convalescent COVID-19 patients (the viral T cell epitopes), the sequences located in the Spike glycoprotein (S), the Membrane protein (M), and the Nucleocapsid protein (N) regions of the virus. The human leukocyte antigen (HLA) haplotype of the responding patients was determined. A further characterization needs to be performed to correlate the specific immune response with the patients' HLA and the severity of the disease they developed. The mapping of viral T cell epitopes allowed us to synthesize and efficiently transfect a polySARS-CoV-2 epitope using mRNA/lipoprotein complexes. After identification of DOSSRI as the most efficient in transfecting mRNA and validating the maturation of human antigen-presenting cells after transfection, we succeed in inducing a significant T cell response in convalescent patient samples. Other experiments will be essential to validate the use of the COVIMUNE mRNA technology as a T-cell targeted vaccine. Our results are the first proof-of-concept of the design of an efficient mRNA encoding for the positive peptides that we identified in the COVIMUNE cohort.

These results allow us to publish one manuscript, one manuscript submitted and several in preparation., and one declaration of invention, In addition, the partners of this project wrote seven reviews on the topic.

Coronavirus disease 2019 (COVID-19) is caused by "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). First identified in 2019 in Wuhan, China, it has since spread globally, resulting in the pandemic. While the majority of cases result in mild symptoms, some progress to severe pneumonia and multi-organ failure. The rate of deaths per number of diagnosed cases ranges from 0.2% to 15% depending on age and other health problems. Recent clinical data suggested that severe Covid-19 is due to over reacting immunity leading to a cytokine storm. Although the innate immune response is critical in preventing viruses from establishing infection, it is adaptive immunity that determines the outcome of infection and clearance of the viruses. Little is known on how pathogens activate the human immune system and in certain circumstances lead to a cytokine storm. Recent reports from China show that a dysregulated T cell response might be implicated in the pathological process of COVID-19. These data highlight the importance of dissecting the spectrum of CD4 T cell responses to SARS-CoV-2 and to discover the underlying reason on why SARS-CoV-2 causes high inflammation in affected individuals as compared to seasonal corona viruses. In this proposal, we will create an in vitro model using primary immune cells to understand how human-viral interactions polarize the adaptive immune response through interaction of antigen presenting cells (APCs) and T lymphocytes. Our concept is that APCs determine, based on human leucocyte antigens (HLAs) and viral antigens to activate T cell response, whether infection leads to disease pathogenesis or a protective immune response resulting in milder disease and/or long term protection to SARS-CoV-2. Our hypotheses are i) SARS-CoV-2 induces distinct T cell response as compared to seasonal Corona virus; ii) The distinct T cell response induced by SARS-CoV-2 is dependent on the certain virus-specific PAMPs and HLA; iii) Regulatory T cells (Treg) play a critical role in balancing protective immune responses and inflammation to SARS-CoV-2; iv) Immune cells from diabetes and cardiovascular disease patients are polarized toward over-reactive immunity and, thus, predispose these patients to severe COVID-19 after SARS-CoV-2 infection. To address these hypotheses, we will study the HLA-viral antigen interaction influencing CD4 T cell polarization after SARS-CoV-2 infection and explore underlying molecular pathways involved. We will investigate the role of Tregs in modulating this immune response. In addition, we will study CD4 T cell polarization in patients with diabetes, which is one the risk factors for severe COVID-19. Unraveling the role of T cells in the disease pathogenesis by cellular and molecular approaches is critical for designing appropriate therapeutic strategies and repurposing the therapeutic molecules that are already available to re-establish the balanced T cell response in SARS-CoV-2-infected patients. Specifically, lipidic derivatives of natural sugar-based immunomodulators, shown by us to be capable of increasing the Treg frequency and anti-inflammatory cytokines including IL-10, have been shown to be compatible with lung aerosolisation using human medical nebulizers. These immunomodulators could therefore be delivered to the lungs to increase the Treg frequency and to produce locally IL-10 to reverse the inflammatory state of the lungs of SARS-CoV-2-infected patients. Finally, investigation of innate and adaptive CD4 T cell response to various PAMPs of SARS-CoV-2 will help in the identification of vaccine candidates.

Project coordination

Anavaj Sakuntabhai (INSTITUT PASTEUR)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IP INSTITUT PASTEUR

Help of the ANR 199,800 euros
Beginning and duration of the scientific project: June 2020 - 18 Months

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