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2016-2017 IMS Lecture Series Schedule

Lectures are held Thursdays @ 4:00 - 5:00 pm in The Committee Lecture Hall of the Molecular Biology Building at The Scripps Research Institute in California, unless otherwise noted. All lectures will be followed by a reception in the Skaggs Atrium, where all attendees may interact with our guests.

Faculty will have the opportunity to meet with speakers over the course of the day and a small number of students and fellows will be able to join the speaker in an informal lunch. 

Scripps students and fellows can reserve a space for lunch with the speaker by emailing Ivy Chester.

 

2016 Schedule

Eric J. Topol, M.D.

The Scripps Research Institute

Director, Scripps Translational Science Institute 

"Towards Individualized Medicine"

Abstract: That each of us is truly biologically unique, extending to even monozygotic, "identical" twins, is not fully appreciated. Now that it is possible to perform a comprehensive "omic" assessment of an individual, including one's DNA and RNA sequence and at least some characterization of one's proteome, metabolome, microbiome, autoantibodies, and epigenome, it has become abundantly clear that each of us has truly one-of-a-kind biological content. Well beyond the allure of the matchless fingerprint or snowflake concept, these singular, individual data and information set up a remarkable and unprecedented opportunity to improve medical treatment and develop preventive strategies to preserve health.

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09/15/16

Ganes Sen, Ph. D.

Cleveland Clinic Lerner Research Institute

Department of Immunology

"Novel Observations on Intracellular Pattern Recognition Receptor Signaling"

Abstract: Innate immune response to microbial infections is triggered by the pattern recognition receptors (PRRs), which recognize not only microbial products but also host damage-associated molecular patterns. Our research focuses on the intracellular nucleic acid recognizing PRRs: how they signal and how specific proteins induced by them, impair virus replication and tumor growth. Signaling by the cytoplasmic RLRs activates IRF3, which in turn, induces many antiviral proteins; one such protein, Ifit2, protects mice from neuropathy caused by the rhabdovirus, VSV. RLR signaling can also activate IRF3 by a different pathway, called RIPA, which causes apoptosis of the infected cells; both RIPA and the antiviral proteins protect the host from viral pathogenesis. Another important family of PRRs constitutes the endosomal membrane-bound TLRs, such as TLR3 and TLR9. We observed that receptor tyrosine phosphorylation triggers their signaling and the tyrosine kinase activity of the EGF receptor is essential for the process. Consequently, EGFR inhibitors that are commonly used in cancer therapy, block signaling by TLR3 and TLR9 both in vitro and in vivo. Finally, STING is an ER-bound receptor for cyclic di-nucleotides, produced in response to cytoplasmic DNA. Recently, we made the surprising observation that, TRIF, the adaptor for TLR3 and TLR4, is essential for STING signaling. TRIF promotes STING dimerization and membrane translocation, by directly interacting with STING. As a consequence, like STING-/- mice, TRIF-/- mice are susceptible to HSV-1 pathogenesis. The above observations revealed avenues of possible cross-talks between unrelated signaling pathways, such as, EGFR and TLR or TLR and STING pathways.

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09/29/16

Pamela J. Bjorkman, Ph. D.

Cal Tech

Division of Biology and Biological Engineering

"A Molecular Arms Race: The Immune System Versus HIV"

Abstract: Over 30 years after the emergence of HIV, there is no effective vaccine, and AIDS remains a threat to global public health. Following HIV infection, the human immune response is unable to clear the virus, partly because the virus rapidly mutates to evade antibodies, one of our most important defenses against pathogens. In the absence of treatment with anti-retroviral drugs (unfortunately not readily available in the developing world), an HIV-infected person’s immune system gradually collapses and he/she cannot fight off normally innocuous pathogens in the environment. Antibodies, which we readily produce against other viruses, don’t work well against HIV. We hypothesize this is partly because antibody arms, which can both normally “hang on” to a virus until it is destroyed, don’t have the right dimensions to stay attached to HIV. We seek to alter natural antibodies using molecular engineering so that HIV is powerless to mutate against them. One engineering project involves designing and creating new antibody architectures with arms that can remain attached to HIV even as it mutates. We also engineer the antibody combining site by using chemical principles to improve the interface between antibodies bound to HIV proteins, starting with experimentally-determined three-dimensional structures of antibody/HIV complexes, and using bioinformatics to predict common pathways of HIV escape. The goal is to create potent antibody reagents that can be delivered to prevent or treat HIV/AIDS.

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10/06/16

La Jolla Immunology Conference @ The Salk Institute 

October 11-13, 2016

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10/11/16

John Boothroyd, Ph. D.

Stanford University School of Medicine

Department of Microbiology and Immunology

“The Challenge of Living in a Bubble: How the Intracellular Parasite, Toxoplasma gondii, Communicates with its Host from Inside a Parasitophorous Vacuole.”

Abstract: Infectious agents that reproduce only inside a host cell face very special challenges. On the one hand, they grow within an environment that is rich in all the essentials of life; on the other hand, such environments are often fiercely protected by a myriad of host defenses. Toxoplasma gondii is a eukaryotic, single-celled “parasite” that infects an extraordinarily broad range of cell types in an equally broad range of mammalian and avian host species. In this talk, I will explore how Toxoplasma communicates with these different hosts and host cell types, deploying a range of effectors that mediate the interaction.

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11/03/16

Erica Ollmann Saphire, Ph. D.

Faculty Lecure Series 

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11/09/16

Carolina B. Lopez, Ph. D. 

University of Pennsylvania School of Veterinary Medicine

Department of Pathobiology

"Defective viral genomes: Understated drivers of the host response to viral infections"

Abstract: The Lopez laboratory investigates the mechanisms involved in the recognition and control of RNA viruses that infect the respiratory tract, including parainfluenza virus and respiratory syncytial virus (RSV). Work from the laboratory revealed that replication defective forms of viral genomes (DVGs) that accumulate naturally during infections are the primary stimulators of the immune response to various RNA viruses in vivo and are critical determinants of infection outcome. We identified DVGs as the primary triggers of the antiviral response during viral infection and in a pilot study, we not only confirmed the presence of DVGs in human respiratory secretions, but also demonstrated a strong correlation of DVG levels and levels of expression of genes with known antiviral activity in patients infected with RSV. Work from the laboratory have elucidated molecular mechanisms mediating the potent immunostimulatory activity of DVGs and has most recently revealed an unexpected role for DVGs in promoting cell survival during infection. 

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11/17/16

Elina Zuniga, Ph. D.

University of California, San Diego

"The Art Of Coexistence: Immune Adaptations During Chronic Viral Infections"

Abstract: Chronic infections, including human immunodeficiency virus (HIV), mycobacterium tuberculosis and malaria, represent a major health burden. Immunosuppression is a hallmark of chronic infections and limits the ongoing antimicrobial immune response and secondary responses to unrelated pathogens or cancers. Such immunosuppression can be seen, however, as an evolutionary adaptation of the host and microbe to enable long-term co-existence. Indeed, hosts with genetic ablation of core immunosuppressors often die after infection (despite enhanced microbial control) while pathogens depleted of their immunosuppressive capacity fail to persist. While a significant advance has been made on the understanding of cellular adaptations in T cells, which undergo functional exhaustion during chronic infections and cancer, much less is known on the mechanisms mediating long-term adaptation in the innate immune system. It is also unclear how innate exhaustion could be sustained for long term given that (in contrast to T cells) innate cells are generally short-lived. I will be presenting new data that help understanding how innate adaptation is induced and sustained during chronic infection.

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12/01/16

Gwendalyn J. Randolph, Ph. D.

Washington University in St. Louis School of Medicine

Division of Immunology

"Lymphatic Transport and Inflammation"

Abstract: The lymphatic vasculature controls immune cell and molecular transport out of tissues. As the field of lymphatic vessel biology grows, it becomes evident that altered transport through the interstitium and lymphatic vasculature is a key feature in several chronic inflammatory diseases. This lecture will present an overview of the lymphatic vasculature and will then delineate specific changes in transport that appear to be linked to inflammatory bowel disease and more briefly to atherosclerosis and psoriasis.

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12/08/16

Stefan Kunz, Ph. D.

Lausanne University Hospital

Institute of Microbiology

"Novel Strategies to Combat Pathogenic Arenaviruses"

Abstract: Arenaviruses, chiefly Lassa virus cause severe hemorrhagic fevers with high mortality in humans and represent serious public health problems. Considering the limited therapeutic options at hand, the development of novel drugs against pathogenic arenaviruses is an urgent need. The goal of our research is the identification of cellular factors required for productive infection with arenaviruses and their evaluation as potential drug targets. Characterization of the virus-receptor interaction and cell entry of Lassa virus revealed the ability of the pathogen to mimic receptor recognition of endogenous ligands and to induce receptor-mediated signaling. Upon receptor binding, Lassa virus enters the cell via an unusual pathway related to macropinocytosis and is capable of hijacking the endosomal sorting machinery implicated in degradation of cellular membrane receptors. During the arenavirus life cycle, maturation the viral envelope glycoprotein precursor by the cellular proprotein convertase subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P) is crucial for productive infection. We and others validated SKI-1/S1P as a “druggable target for anti-viral intervention, providing proof-of-concept. Apart from its role in arenavirus infection SKI-1/S1P is at the crossroads of major human disorders, including cancer and metabolic diseases. Using the viral glycoprotein as a “molecular probe”, we uncovered novel and unique aspects of SKI-1/S1P maturation, substrate recognition, and evolution. Based on viral substrates, we developed a new cell-based molecular sensor for SKI-1/S1P that is currently implemented in screens for novel small molecule inhibitors. 

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12/15/16

2017 Schedule



Marie Pancera, Ph. D.

The Fred Hutchinson Cancer Research Center

"Structural Characterization of HIV-1 Env with Small Molecule HIV Entry Inhibitors and Germline Precursors of Broadly Neutralizing Antibodies"

Abstract: The HIV-1 envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a post-fusion state. As the sole viral antigen on the HIV-1 virion surface, Env is both a target of neutralizing antibodies and small molecule HIV-1 entry inhibitors.

First, I will present crystal structures of HIV-1-Env trimer with BMS-378806, a small molecule HIV-1 entry inhibitor, and its derivative, BMS-626529, for which a prodrug version is currently in Phase III-clinical trials. Together with biophysical and antigenicity characterizations, the structures illuminate the allosteric and competitive mechanisms whereby these small-molecule leads inhibit CD4–induced structural changes in Env.

Second, I will describe our recent study of germline pre-immune precursor forms of broadly neutralizing antibodies and their interaction with Env. This study revealed that not all humans are equally predisposed to generate VRC01-class antibodies, not all predicted progenitor VRC01-expressing B cells can bind to Env, and the CDRH3 region of germline VRC01 antibodies influence their ability to recognize HIV-1. 

01/26/17

Robert Seder, M.D.

Cellular Immunology, Vaccine Research Center

National Institutes of Health 

"Modulating Vaccine Immunity Against Infections and Tumors with Chemically Programmable Polymers Nanoparticles and TLR 7/8 ligands"

Abstract: Development of vaccines against infections and tumors will require vaccine approaches that can induce broad-based antibody and T cell immunity. Accordingly, protein and peptide based vaccines are one approach that can be used for these indications. A critical aspect using protein/peptide vaccines is how they are formulated and delivered to optimize innate immunity and antigen processing and presentation.  Accordingly, the seminar will show recent data for how synthetic polymers can be used to formulate and delivery protein/peptide antigens as nanoparticles in the context of co-delivery with TLR 7/8 agonists. Specific applications using this approach will be presented in the context of HIV vaccine development for  inducing HIV antibodies using V3 glycans as an immunogen or personalized therapeutic tumor vaccines for induction of protective T cell immunity with neo-antigen peptides.

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02/02/17

Bernard Fields Lecture:

Herbert Virgin, M.D., Ph.D.

Edward Mallinckrodt Professor and Chairman, Department of Pathology and Immunology

Washington University School of Medicine

Dorian McGavern, Ph. D.

Senior Investigator, NIH, NINDS, Viral Immunology and Intravital Imaging Section, Bethesda

National Institute of Neurological Disorders and Stroke

02/07/17

Richard Flavell, Ph. D. FRS

Yale School of Medicine

Department of Immunobiology

"Innate Immune Sensing of Genomic Integrity"

Abstract: Genomic instability is a hallmark of cancer, and policing this is therefore essential to life. For this and many other reasons, extensive DNA repair mechanisms are encoded in our genome. All of these require sensing of DNA damage as a prerequisite for action. Acute exposure to ionizing radiation induces massive cell death and severe damage to tissues containing actively proliferating cells, including bone marrow and the gastrointestinal tract. However, the cellular and molecular mechanisms underlying this pathology remain controversial. We found that mice deficient in the double-strand DNA (dsDNA) sensor AIM2 are protected from irradiation-induced death. AIM2 mediates caspase-1-dependent death in response to dsDNA breaks caused by ionizing radiation and chemotherapeutic agents. Mechanistically, we found that AIM2 senses radiation-induced DNA damage in the nucleus to mediate inflammasome activation and cell death. Thus AIM2 is a sensor of genomic integrity.

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02/16/17

Frank Dixon Lecture

Klaus Rajewsky, Ph. D. 

Max Delbruck Center for Molecule Medicine 

02/23/17

Ye Zheng, Ph. D.

Salk Institute for Biological Studies

Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis

"T lymphocytes in autoimmune and metabolic diseases"

Abstract: Regulatory T cells (Treg) are a specialized subset of T cells that play a critical role in suppression of over-exuberant immune response and maintenance of immune system homeostasis. Abnormal Treg function has been linked to multiple autoimmune diseases, such as arthritis, type-1 diabetes, lupus, and multiple sclerosis, as well as inefficient tumor immunity. Research in the Zheng lab is focused on the molecular and cellular mechanisms of regulatory T cell development and function in the context of autoimmune and metabolic diseases. Foxp3, a member of the forkhead transcription factor family, is expressed specifically in regulatory T cells, and plays a pivotal role in Treg development and function. We discovered an intronic enhancer at Foxp3 genomic sequence named CNS2, which is a “signal hub” for protection of Treg identity. We found that the activation of Tregs is a key event that triggers CNS2:promoter looping activity to stabilize Foxp3 expression. In addition to Treg’s role in preventing autoimmune diseases, We recently revealed that Treg is also involved in the development of metabolic diseases. We demonstrated that accumulation of adipose tissue resident Treg cells is associated with insulin resistance in aged mice. This study highlighted a novel role of the immune compartment in contributing to key aspects of adipose health and disease.

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03/02/17

Scott C. Weaver, Ph. D.

University of Texas Medical Branch, Galveston National Laboratory 

Institute for Human Infections and Immunity

Departments of Pathology and Microbiology & Immunology

"Emergence of Zika Congenital Syndrome in the Americas”

Abstract: Zika virus, a mosquito-borne flavivirus discovered in Uganda in1947 but which remained obscure until 2007, has caused a recent series of explosive outbreaks in the Pacific Ocean basin, and arrived for the first time in the Americas in late 2013. Since 2015, Zika virus has initiated its first major Western Hemispheric epidemic with spread to most countries and territories including the United States (local transmission in Florida and Texas) and the recognition that it is causes several severe neurologic diseases including Guillain Barré syndrome (GBS) and congenital microcephaly. Although most Zika virus transmission involves the peridomestic mosquito vector, Aedes aegypti and possibly also the invasive species A. albopictus, chronic sexual transmission, mainly from men to women, has also been documented in travelers returning to non-endemic regions. In the Americas, Zika virus Infections have been associated with hundreds of GBS cases and also with over 1,600 confirmed cases of fetal microcephaly coincident in time and space with Zika virus circulation. I will review the origins and history of Zika virus as determined by molecular genetic studies, along with the factors involved in its recent, rapid spread. I will also discuss epidemiologic and basic research being conducted to test competing hypotheses to explain Zika virus’ dramatic spread and the sudden appearance of nervous system disease, to predict future trends, and to develop control measures as well as therapies to protect against severe outcomes of infection. Finally, the risk for further transmission and spread within the U.S. and elsewhere will be discussed along with strategies to control the pandemic.

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03/09/17

Marc K. Jenkins, Ph. D.

University of Minnesota

Department of Microbiology and Immunology

"Composition and function of the pre-immune lymphocyte repertoire"

Abtract: Vertebrates are thought to make strong adaptive immune responses because of exposure to large amounts foreign antigen in an inflammatory context. For certain foreign antigens, however, strong immunity also results from a high frequency of antigen-specific lymphocytes in the pre-immune repertoire. My talk will focus on the mechanisms that create large foreign antigen-specific lymphocyte populations even before the host is exposed to the relevant antigen.

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03/16/17

Barney Graham, M.D., Ph. D.

Senior Investigator, Vaccine Research Center, NIAID, NIH. He is an immunologist, virologist, and clinical trials physician whose primary interests are viral pathogenesis, immunity, and vaccine development.

"RSV Vaccine Development: A Paradigm for Structure-Guided Antigen Design"

Abstract: Respiratory syncytial virus (RSV) is a pneumovirus in the family Paramyxoviridae. The putative attachment protein (G), small hydrophobic (SH) pentameric ion channel, and the fusion glycoprotein (F) responsible for mediating viral entry are the only three RSV surface-exposed proteins, and typically considered the major antigenic targets for RSV vaccine development. There are two major RSV subtypes, A and B, defined largely by genetic variation in the G glycoprotein. Recent advances in defining the structure of F-specific NT-sensitive epitopes and the structure of the prefusion (pre-F) and postfusion (post-F) conformations of F have led to a better understanding of the mechanisms of NT, the serological responses to natural RSV infection and vaccination, pathogenesis of disease, mechanisms of viral inactivation, and the importance of targeting pre-F surfaces with the vaccine antigen. The talk will review the structure and function of F, and describe the design, antigenicity, immunogenicity, and clinical development plans for a candidate RSV vaccine based on a stabilized version of prefusion RSV F.  In addition, the antigen design strategies for RSV have been leveraged for influenza, coronavirus, HIV, and other paramyxovirus vaccine development programs.

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03/23/17

Robert F. Garry, Ph. D.

Tulane University School of Medicine

Department of Microbiology & Immunology

"An Outbreak of Ebola in the Lassa Fever Zone"

Abstract: The public health impact of Lassa fever in endemic areas of West Africa is immense. Recently, both the World Health Organization and the Coalition for Epidemic Preparedness Innovations (including the Gates and Wellcome Foundations and other partners) ranked Lassa fever among the highest priority pathogens. These rankings are based on the potential for further geographic expansion of the rodent reservoirs, the ease of procurement and weaponization of the virus, the frequent importation to North America and Europe, and the recent emergence of novel strains in and near densely populated Nigeria. There are as yet no approved Lassa fever vaccines or therapeutics for human use. Our team has established research programs in Sierra Leone and Nigeria that provide unique clinical and laboratory resources for viral hemorrhagic fever research, and acquired new information regarding the natural history of Lassa fever. We have made significant progress in developing diagnostic assays, vaccines and immunotherapeutics. For example, we have identified human monoclonal antibodies that provide 100% protection against Lassa virus challenge in Cynomolgus macaques. The West African Ebola outbreak originated in a region of forested Guinea located only about a three-hour drive from our research site in Kenema Sierra Leone. Challenges for a region now threatened with two severe hemorrhagic fever viruses will be discussed.

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03/30/17

Diane Mathis, Ph. D.

Harvard Medical School

Immunology, Department of Immunobiology and Microbiology

"Aire, New Tricks From an Old Dog"

Abstract: Aire is a transcriptional regulator that controls immunological tolerance. Its primary modus operandi is the induction – specifically in thymic medullary epithelial cells – of a battery of transcripts encoding proteins characteristic of terminally differentiated peripheral cell-types, and consequently negative selection of T cells that recognize these proteins. After briefly reviewing the classical findings, this presentation will focus on more recently discovered facets of Aire function, including positive selection of a perinatal population of regulatory T cells, inhibition of the generation of IL-17-producing “early-responder” γ:δ T cell populations, and activation of MEC superenhancers.

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04/06/17

Donna Farber, Ph. D.

Columbia University Medical Center

Department of Microbiology and Immunology 

"Tissue Compartmentalization of T-cell Responses"

Abstract: Dr. Farber’s research for the past 20 years is focused on immunological memory and recently, on how the immune response is compartmentalized in tissue sites in mouse infection models and in humans. In mouse models of influenza infection, Dr. Farber’s group identified a subset of tissue-resident memory T cell that were retained in the lung and mediated optimal protection to influenza infection. For human studies, Dr. Farber set up a unique resource to obtain multiple tissues from organ donors, enabling novel investigation of human immunity throughout the body over age and genetic diversity. Dr. Farber’s group also identified human TRM cells in multiple sites through phenotype, functional and transcriptome profiling, and is carrying out studies to define TRM lineages in humans. In mouse models, Her laboratory is defining mechanisms for how TRM are established and mediate protection in the lung, and how vaccine responses can promote tissue immunity during early life.

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04/13/17

George M. Shaw, M.D., Ph.D.

Perelman School of Medicine, University of Pennsylvania 

"New SHIV Models of bNAb Elicitation and Env-Ab Coevolution: A Molecular Guide to HIV-1 Vaccine Development"

Abstract: Novel SHIVs with primary HIV-1 Envs containing substitutions at residue 375 reflect native primary (T/F) HIV-1 Envs in their antigenicity, neutralization sensitivity and cell entry kinetics. SHIVs with Env 375 substitutions are transmitted efficiently by mucosal routes, exhibit highly reproducible acute and early replication kinetics indistinguishable from HIV-1, and elicit autologous (tier 2) Nab responses indistinguishable from HIV-1. In some cases, these responses lead to neutralization breadth in rhesus macaques. Molecular patterns of SHIV Env-Ab coevolution in rhesus macaques recapitulate molecular patterns of HIV-1 Env-Ab coevolution in humans. Examples include CH505, CH848 and BG505. Characterization of NAb/bNAb elicitation in SHIV infected macaques may help guide the selection of particular HIV-1 Envs (and evolved Env variants) for development as immunogens in diverse vaccine platforms. Such analyses may also assist in the identification of unmutated common ancestor and intermediate stage bNAb lineage rhesus B cell receptors. SHIVs bearing T/F HIV-1 Envs that correspond to candidate vaccine immunogens currently under development (e.g., CH505, CH848, BG505 and B41), can serve as clinically relevant autologous and heterologous challenge viruses in preclinical protection trials. 

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04/20/17

Nancy L. Haigwood, Ph. D.

Oregon Health & Science University 

Oregon National Primate Research Center

"Antibodies as New Therapies for HIV"

Abstract: Preventing infection remains the ultimate goal for HIV vaccination. In nonhuman primate models, there has been progress with two modalities – protective vaccine strategies and vaccines that promote tight viral control, each currently achieving ~50% success. Data from the RV144 trial identified antibodies directed to HIV Envelope as the critical component in reducing the risk of infection, an immune correlate that has encouraged researchers to identify or design Envelope antigens that can generate protective antibodies. Primate models continue to serve as indispensible partners in the development of HIV vaccines, and passive antibody studies in primate models offer a means of determining which antibodies or antibody cocktails are protective. Encouraging data have shown that infection can be blocked with the newer and more potent human neutralizing monoclonals (NmAbs) at concentrations possible for reasonable use in humans when given pre-exposure. However, NmAb treatment during chronic infection has yielded variable and transient reductions in viremia. We have observed that treatment with a cocktail of powerful human NmAbs 24-48 hours after mucosal exposure cleared SHIV infectious centers that were releasing virions into the blood, resulting in apparent sterilization after the infection was underway. Surprisingly, even as late as 48 hours after oral virus exposure, combinations of NmAbs permanently altered the course of disease in newborn macaques. These data support the development of human NmAbs as adjunctive therapy. They also suggest that vaccines that induce protective Abs may do so not only by neutralizing virus, but also by contributing to viral containment within the first several days of virus exposure, yielding powerful effects beyond blocking infection. We are currently investigating the mechanisms responsible for viral containment or elimination by passive antibody treatment.

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04/27/17

Marco Colonna, Ph. D.

Washington University School of Medicine

Department of Pathology and Immunology

"Innate Lymphoid Cells in Immunity"

Abstract: TBA

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05/11/17

Mary Estes, Ph. D.

CANCELLED

Baylor College of Medicine

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05/18/17

Sara Sawyer, Ph. D.

University of Colorado Boulder

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06/15/17

sponsors 2017