Pascal Chappert

Bio: Pascal Chappert is an academic researcher from Paris Descartes University. The author has contributed to research in topics: T cell & Cytotoxic T cell. The author has an hindex of 13, co-authored 25 publications receiving 590 citations. Previous affiliations of Pascal Chappert include French Institute of Health and Medical Research & National Institutes of Health.

Vaccine Activation of the Nutrient Sensor GCN2 in Dendritic Cells Enhances Antigen Presentation

Abstract: The yellow fever vaccine YF-17D is one of the most successful vaccines ever developed in humans. Despite its efficacy and widespread use in more than 600 million people, the mechanisms by which it stimulates protective immunity remain poorly understood. Recent studies using systems biology approaches in humans have revealed that YF-17D–induced early expression of general control nonderepressible 2 kinase (GCN2) in the blood strongly correlates with the magnitude of the later CD8+ T cell response. We demonstrate a key role for virus-induced GCN2 activation in programming dendritic cells to initiate autophagy and enhanced antigen presentation to both CD4+ and CD8+ T cells. These results reveal an unappreciated link between virus-induced integrated stress response in dendritic cells and the adaptive immune response.

Maturation and persistence of the anti-SARS-CoV-2 memory B cell response.

Abstract: Memory B cells play a fundamental role in host defenses against viruses, but to date, their role have been relatively unsettled in the context of SARS-CoV-2. We report here a longitudinal single-cell and repertoire profiling of the B cell response up to 6 months in mild and severe COVID-19 patients. Distinct SARS-CoV-2 Spike-specific activated B cell clones fueled an early antibody-secreting cell burst as well as a durable synchronous germinal center response. While highly mutated memory B cells, including preexisting cross-reactive seasonal Betacoronavirus-specific clones, were recruited early in the response, neutralizing SARS-CoV-2 RBD-specific clones accumulated with time and largely contributed to the late remarkably stable memory B-cell pool. Highlighting germinal center maturation, these cells displayed clear accumulation of somatic mutations in their variable region genes over time. Overall, these findings demonstrate that an antigen-driven activation persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection.

“Bioinformatics” 특집을 내면서

Abstract: BIOE 402. Medical Technology Assessment. 2 or 3 hours. Bioentrepreneur course. Assessment of medical technology in the context of commercialization. Objectives, competition, market share, funding, pricing, manufacturing, growth, and intellectual property; many issues unique to biomedical products. Course Information: 2 undergraduate hours. 3 graduate hours. Prerequisite(s): Junior standing or above and consent of the instructor.

Evolution of antibody immunity to SARS-CoV-2.

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with the development of variable levels of antibodies with neutralizing activity, which can protect against infection in animal models1,2. Antibody levels decrease with time, but, to our knowledge, the nature and quality of the memory B cells that would be required to produce antibodies upon reinfection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection with SARS-CoV-2. We find that titres of IgM and IgG antibodies against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 decrease significantly over this time period, with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by fivefold in pseudotype virus assays. By contrast, the number of RBD-specific memory B cells remains unchanged at 6.2 months after infection. Memory B cells display clonal turnover after 6.2 months, and the antibodies that they express have greater somatic hypermutation, resistance to RBD mutations and increased potency, indicative of continued evolution of the humoral response. Immunofluorescence and PCR analyses of intestinal biopsies obtained from asymptomatic individuals at 4 months after the onset of coronavirus disease 2019 (COVID-19) revealed the persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 individuals. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.

Gut Immune Maturation Depends Upon Colonization with Host-Specific Microbiota

Abstract: Gut microbial induction of host immune maturation exemplifies host-microbe mutualism. We colonized germ-free (GF) mice with mouse microbiota (MMb) or human microbiota (HMb) to determine whether small intestinal immune maturation depends on a coevolved host-specific microbiota. Gut bacterial numbers and phylum abundance were similar in MMb and HMb mice, but bacterial species differed, especially the Firmicutes. HMb mouse intestines had low levels of CD4(+) and CD8(+) T cells, few proliferating T cells, few dendritic cells, and low antimicrobial peptide expression--all characteristics of GF mice. Rat microbiota also failed to fully expand intestinal T cell numbers in mice. Colonizing GF or HMb mice with mouse-segmented filamentous bacteria (SFB) partially restored T cell numbers, suggesting that SFB and other MMb organisms are required for full immune maturation in mice. Importantly, MMb conferred better protection against Salmonella infection than HMb. A host-specific microbiota appears to be critical for a healthy immune system.

Synthetic Nanoparticles for Vaccines and Immunotherapy

Abstract: 1.1 Progress and challenges in the new age of engineering immunity The immune system plays a critical role in our health. No other component of human physiology plays a decisive role in as diverse an array of maladies, from deadly diseases with which we are all familiar to equally terrible esoteric conditions: HIV, malaria, pneumococcal and influenza infections; cancer; atherosclerosis; autoimmune diseases such as lupus, diabetes, and multiple sclerosis. The importance of understanding the function of the immune system and learning how to modulate immunity to protect against or treat disease thus cannot be overstated. Fortunately, we are entering an exciting era where the science of immunology is defining pathways for the rational manipulation of the immune system at the cellular and molecular level, and this understanding is leading to dramatic advances in the clinic that are transforming the future of medicine.1,2 These initial advances are being made primarily through biologic drugs– recombinant proteins (especially antibodies) or patient-derived cell therapies– but exciting data from preclinical studies suggest that a marriage of approaches based in biotechnology with the materials science and chemistry of nanomaterials, especially nanoparticles, could enable more effective and safer immune engineering strategies. This review will examine these nanoparticle-based strategies to immune modulation in detail, and discuss the promise and outstanding challenges facing the field of immune engineering from a chemical biology/materials engineering perspective. 1.1.1 Key cellular actors in the immune system A brief summary of the cellular players in the immune response is worthwhile to preface the many immunomodulatory approaches described in this review. The immune system can be viewed at a high level as a collection of mobile cells that include members that traffic throughout the body in search of invading pathogens as well as cells that reside as sentinels at portals of entry (i.e. the airways, skin, gastrointestinal tract, etc.).3 These cells belong to one of two major arms, the innate immune system and adaptive immune system. Innate immune cells such as neutrophils and macrophages are poised to rapidly respond to pathogen invasion, expressing receptors that recognize conserved molecular motifs characteristic of bacteria, viruses, and fungi, to quickly phagocytose (internalize) microbes and secrete reactive oxygen species or cytokines that provide an immediate response to invading pathogens. The adaptive immune system is comprised of T-cells and B-cells, including CD4+ helper T-cells that secrete cytokines to direct the functions of innate cells, killer cells, and B-cells; and CD8+ killer T-cells that recognize and destroy infected or transformed cells. B-cells play a canonical role in vaccine responses by producing antibodies that bind to and neutralize the ability of microbes to invade host cells and/or promote their phagocytosis. The adaptive immune system is so named because of the clonal nature of T and B lymphocytes– each T-cell and B-cell expresses a unique T-cell receptor or B-cell receptor, respectively, which is generated in part by a process of stochastic DNA recombination, enabling the pool of lymphocytes the potential to recognize any microbial antigen they may encounter.4 When a T- or B-cell binds an antigen (essentially, any biological molecule from a microbe that is recognized by a T-cell receptor (TCR) or B-cell receptor (BCR)), this triggers massive proliferation of the antigen-specific cell, generating a pool of effectors within ~7 days following exposure. These effector T-cells and B-cells play an important role in backing up innate immune defenses to clear the invading pathogen. Following pathogen clearance, the majority of these cells (~90%) undergo programmed cell death, leaving a small pool of differentiated memory cells that can remain for the lifetime of the individual, to provide rapid recall protection if the same microbe is ever encountered again.5 A final key group of immune cells are the antigen presenting cells (APCs), and particularly a critical APC known as the dendritic cell, which is responsible for activating naive T-cells (and in some cases B-cells).6,7 Dendritic cells (DCs) are innate-like cells that reside in all peripheral tissues, and which act as sentinels, collecting antigens from the surrounding fluid and staying on constant alert for “danger signals”- molecular motifs signifying tissue damage or pathogen invasion. DCs and other immune cells express a host of receptors that specifically recognize danger signals to trigger their activation; the most studied among these receptors are the Toll-like receptors.8 If activated by danger signals, DCs migrate from their home tissue through the lymphatic vessels to local draining lymph nodes, where they physically present antigen to T-cells and B-cells. For T-cell activation, this is through the loading of short (8–15 amino acids) peptide fragments of antigens into the cleft of major histocompatibility complex (MHC) molecules displayed on the DC surface. These peptides are surveyed by the TCRs of T-cells, and on finding a cognate peptide, T-cells become activated by the DC to proliferate and carry out their effector functions. The vastly complex set of cellular interactions summarized above (greatly oversimplified) is the network of interest to those interested in immune engineering, and in this review we aim to summarize the myriad ways in which materials scientists, chemical engineers, bioengineers, chemists, and physicists (often in collaboration with immunologists) are using nanomaterials as powerful tools to probe or manipulate immune responses for therapeutic ends. To set the stage for the rest of the review, we will briefly discuss two of the areas where synthetic nanoparticles have the prospect to play a significant role in the ongoing revolution of immunology in medicine– vaccines and active immunotherapy.

Molecular signatures of antibody responses derived from a systems biology study of five human vaccines

Abstract: Many vaccines induce protective immunity via antibodies. Systems biology approaches have been used to determine signatures that can be used to predict vaccine-induced immunity in humans, but whether there is a 'universal signature' that can be used to predict antibody responses to any vaccine is unknown. Here we did systems analyses of immune responses to the polysaccharide and conjugate vaccines against meningococcus in healthy adults, in the broader context of published studies of vaccines against yellow fever virus and influenza virus. To achieve this, we did a large-scale network integration of publicly available human blood transcriptomes and systems-scale databases in specific biological contexts and deduced a set of transcription modules in blood. Those modules revealed distinct transcriptional signatures of antibody responses to different classes of vaccines, which provided key insights into primary viral, protein recall and anti-polysaccharide responses. Our results elucidate the early transcriptional programs that orchestrate vaccine immunity in humans and demonstrate the power of integrative network modeling.