NIAID - National Institute of Allergy and Infectious Diseases Grants

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY The goal of this proposal is investigation of the mechanism of ZBP1-mediated response to LPS and protection from bacterial infection that is provided by ZBP1. Our published and preliminary data characterize a novel noncanonical activation fo Caspase 8 in response to LPS, which results in the pyroptotic cell death in macrophages. In further inquiry, we identified that containing CASP8 pro-death complex II that assembles in response to LPS, is not dependent on TNFR1 as was widely accepted so far, but rather on TRIF thus making TRIF a central component of theis activation pathway. To reflect the requirement for TRIF in complex II formation and activation of CASP8, we termed this new pyroptosis-inducing complex the “TRIFosome”. In further mechanistic inquiry, we found that the nucleic acid sensor, ZBP1, which thus far has been implicated only in viral infections, plays a significant role in the formation of the TRIFosome complex by shuttling RIPK1 to TRIF. The reliance of Complex II formation on ZBP1 raised a question whether ZBP1 mediates inflammatory responses to LPS as well. In support of this hypothesis, our preliminary data show that ZBP1 mediates LPS- induced inflammatory responses, thus providing rationale for further in vivo investigations of the role that ZBP1 might play in responses to LPS and Yersinia infection. To address whether ZBP1-mediated response to LPS provides protection from the bacterial infection, we propose 2 aims. In Aim 1, we will investigate ZBP1- mediated in vitro response to LPS using double knockout and gene-silencing approach. We will use ZBP1- specific immunoprecipitation in order to determine the components of ZBP1-interactome. determine the contribution of ZBP1 to LPS-induced immune response, which will include elucidation specific role of ZBP1 in mediating TRIF-dependent and TRIF-independent responses. It will also include delineation of the role of ZBP1 in the RIPK1-specific response to LPS. including understanding the roles of the functional domains of ZBP1 in this pathway, analysis of the recruitment of ZBP1 into the endosomal TRIFosome complex, and characterization of the ZBP1-dependent changes in host response to bacterial infection in vivo. In the second Aim, we will capitalize on our preliminary findings and will further investigate how the kinetics of response to LSP that is conferred by ZBP1 confers sensitivity to LPS-induced tosicity I vivo, and whether this sensitivity provides protection from gram-negative infection in vivo. These studies will help establishing the role of ZBP1 in host response to bacterial infection and will position ZBP1 at the crosstalk of different immune response pathways.

NIAID - National Institute of Allergy and Infectious Diseases

The goal of the proposal is to obtain fundamental functional understanding of human B cell epitopes in food allergy and in response to oral immunotherapies for food allergy. The clinical and serological features of patients who have allergies to different foods suggest that there may be heterogeneity in allergen-specific B cell clones or antibody features for these allergens. This proposal will analyze the epitope targets of allergic patient B cell receptors and antibodies.

NIAID - National Institute of Allergy and Infectious Diseases

This contract will study T cell epitopes in sexually transmitted infection (STI) pathogens: herpes simplex virus types 1 and 2, Treponema pallidum (Tp, syphilis), and Chlamydia trachomatis (Ct). The Deliverables are validated “pairs” of 1) microbial peptide epitopes, and 2) restricting HLA alleles. For HSV, we Offer “triads” that, in addition, also include 3) paired TCRαβ recognizing HSV peptide-HLA complexes. The Approaches enrich STI pathogen-specific T cells from blood or relevant tissues of cohorts of STI pathogen-infected humans.

NIAID - National Institute of Allergy and Infectious Diseases

The offeror’s proposed work plan aims to identify, characterize and optimize non-toxic, low molecular weight agents as adjuvants that a) enhance protein antigen accumulation and release in non-immune and immune cells after intramuscular administration of mRNA vaccine and b) stimulate innate immune pathway-activation in antigen presenting cells.

NIAID - National Institute of Allergy and Infectious Diseases

The contractor will identify and characterize T cell epitopes in bacteria capable of causing pneumonia through person-to-person transmission in the community (Community Acquired Pneumonia = CAP), as such infections cause significant morbidity and mortality worldwide, and T cell responses against these pathogens are understudied. Leveraging results from previous contracts, the contractor will bioinformatically identify peptide candidates that are then synthesized and screened for recognition by T cells to identify bona fide T cell epitopes. The contractor will identify epitopes in currently uninfected, likely exposed individuals and those who have a confirmed diagnosis and will be followed longitudinally. The contractor will characterize epitopes identified from these large-scale screens for their HLA restriction, their ability to bind different HLA molecules, and their recognition in different patient cohorts.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract Prevalent multidrug-resistant bacteria remain a significant threat to human health. About 1 million people, including 214,000 newborn babies, die annually from such infections. Most antibiotics typically target essential cellular components, enacting a high selective pressure that forces bacteria to develop resistance. This factor, among others, led to dire statistical projections citing 10 million annual deaths by 2050, prompting a call-to- action directed at tackling resistance through novel strategies. The most prominent bacterial resistance mechanisms include genetically encoded efflux pumps, structural modification of antibiotics, or modification of their molecular targets. Many target modification events follow well-established mechanisms catalyzed by enzymes. For example, the documented loss of activity by multiple classes of antibiotics that target protein synthesis is attributed to modification of ribosomal RNA (rRNA) through methylation by S-adenosylmethionine (SAM)-dependent methylases. The Chloramphenicol-florfenicol resistance (Cfr) protein is a radical SAM- dependent enzyme that catalyzes the methylation of adenosine 2503 (A2503) of 23S rRNA in the large subunit of bacterial ribosomes, conferring resistance to several classes antibiotics that inhibit translation. The gene encoding Cfr is found on naturally occurring plasmids across multiple pathogenic bacteria including Staphylococcus, Clostridium, Enterococcus, Listeria, and Bacillus species. This proposal focuses on developing compounds that inhibit the activity of Cfr, thereby preventing bacteria from acquiring resistance through rRNA methylation by this enzyme. These inhibitors will act as adjuvants that lack antibacterial activity but can restore the activity of antibiotics affected by this resistance mechanism, when administered in combination. Cfr inhibitors will be identified using a target-based approach involving computer-aided screens to be conducted with virtual libraries of over 120 million commercially available compounds using the Autodock Vina software. Compounds predicted to bind Cfr will be tested for their ability to bind the purified enzyme in vitro using Temperature Related Intensity Change measurements and evaluated for their capacity to inhibit Cfr-mediated methylation of a synthesized rRNA substrate in standard enzyme assays. Promising compounds will then be tested in an E. coli resistance evolution model to assess the inhibition of Cfr activity in bacterial cells by monitoring the antibacterial properties of antibiotics whose activity is abolished by the methylation of A2503. When used in combination, compounds that block the activity of Cfr will result in restored antibiotic activity, killing the bacterial cells. Inhibitors with this property will be co-crystallized with the enzyme to identify their binding sites, and potential mechanism of inhibition of Cfr activity. These structural data will also be used in the design of novel inhibitors with optimized binding affinities and adjuvant properties through fragment-based drug discovery techniques and structure-activity relationship studies. Optimized adjuvants will be tested against clinical isolates of bacterial species that employ this form of resistance mechanism.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Multidrug-resistant organisms (MDROs) remain major causes of morbidity and mortality in hematopoietic cell transplant (HCT) recipients. Because of the substantial use of antibiotics in these patients, their gut microbiome balance is perturbed and becomes dominated by MDROs, vancomycin-resistant enterococci (VRE) in particular. This disturbance is associated with subsequent invasive infections such as bacteremia that can lead to fatal outcome. Restoration of the normal balance of the gut flora and reduction or control of MDRO colonization may curtail these complications and improve outcomes. One innovative approach to restore the microbiome balance of the gut flora and reduce colonization with MDROs in HCT recipients is the administration of bacteriophages (i.e., phages). Phages are ubiquitous and natural entities, present in the environment and in our bodies, and capable of lysing specific pathogens without disturbing the host’s normal flora while averting the collateral damage of antimicrobial usage. My long-term research goal is to understand how phages contribute to host-microbe interactions and their overall impact on the health of HCT recipients. Our preliminary data indicate that VRE colonization can cause inflammation in the gut of germ-free wild-type mice. Additionally, we found that phages are present in high numbers in HCT patients’ stool samples and that VRE phages can be recovered from environmental samples and can lyse a variety of VRE strains in a larva model. The objective of the proposed research is to investigate the interactions between phages, the gut bacterial microbiome, and host responses in VRE-colonized HCT recipients and to identify biomarkers in the gut phage population predisposing patients to complications such as bacterial infections or graft versus host disease. The central hypothesis for this project is that VRE phages can restore balance in the gut microbiota by reducing inflammation and VRE colonization in HCT recipients. My ultimate goal is to generate significant findings and new hypotheses for an R01 application aiming at (1) optimizing the design of a chemotherapy- treated bone marrow-reconstituted mouse model mimicking the condition of HCT patients, (2) testing the efficacy of phages and phages+antibiotic synergy in preventing major MDRO infections in this mouse model, and (3) validating the role of certain phage populations in predicting and preventing poor outcomes. The rationale is that this line of work will provide supportive evidence for future development and evaluation of a phage-based intervention in humans. My long-term career goal is to become a leading investigator with expertise in the design of effective and safe phage-based natural therapeutic products that may restore a healthy gut microbiota and curtail serious complications encountered in HCT recipients (i.e., MDROs), thus improving their overall health outcomes. The proposal will aid in the fight against MDROs by curtailing the incidence of MDRO colonization and infections and by improving survival and quality-of-life of HCT recipients.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Significance: Providing antiretroviral therapy (ART) to pregnant women with HIV (WHIV) is a landmark global public health achievement, preventing millions of perinatal HIV infections. However, there are now >1 million children exposed to antiretrovirals (ARVs) born annually, a number expected to stabilize or increase over the next decade as WHIV and women exposed to HIV during conception and pregnancy are increasingly taking ARVs as treatment or prophylaxis against HIV (PrEP). To date, the effects and safety of ARVs taken in pregnancy are not fully established and prior research is limited by lack of objective measurement of ARV exposure, and data are lacking on the effects of ARVs on the placenta. Thus, there is a critical gap in knowledge about the impact of ARVs, including PrEP, and association with objective drug levels taken in pregnancy on the placenta and fetus, information needed for optimal ARV design and to advise women on the effects of ARVs taken as treatment or prevention during pregnancy to inform risk-benefit discussions. Innovation: We propose one of the first studies to simultaneously measure ARV levels in dried blood spots from pregnant women and their children’s hair to quantify drug exposure to PrEP and ART in utero and relate ARV levels to placental findings and birth weight. Distinct advantages of our proposed research over prior studies include 1) simultaneous collection and comparison of placentas from WHIV taking ART, HIV-uninfected women taking ARVs as PrEP, and HIV- uninfected women taking no ARVs, and 2) prospective enrollment and observation of pregnant women and children from these three groups to minimize bias, enhance rigor and reproducibility, and relate placental and birth outcomes to in utero exposures. Investigator team: PI Bebell has expertise in HIV epidemiology in pregnancy and placental effects. Co-I Ngonzi has expertise with HIV and pregnancy outcomes in Uganda. Biostatistician Correia has expertise in analyzing data from observational maternal-child outcomes studies in HIV-affected populations and mediation analysis. Approach: We will leverage stored dried blood spot and hair samples from the PI’s ongoing NIH-funded (R01HD112302) PACO cohort in Uganda, clinical and placental histopathology data from enrolled women and their children, established laboratory infrastructure at UCSF’s Hair Analytical Laboratory and AHRI’s pharmacology laboratory to elucidate the independent effects of HIV and ARV exposure on the placenta and birth weight through these Specific Aims: 1) Compare histologic placental abnormalities by ARV levels in neonatal hair and maternal DBS, and 2) Determine the effects of ARV exposure on birth weight and whether placental abnormalities mediate these effects. Determining the impact of ARVs in pregnancy on the placenta and birth weight and the possible mediating role of the placenta has great potential to improve child health through optimizing outcomes and inform choices for women accessing ARVs as treatment and prevention during pregnancy. By leveraging already-collected samples and data from an NIH-funded study, this proposal will inform practical strategies to improve ARV-related outcomes.

NIAID - National Institute of Allergy and Infectious Diseases

To develop the HIV-eCaDI device we are developing for our NIAID project R61 AI181052 “Development of a robust HIV-1 diagnostic system (HIV-eCaDI) for at-home testing” we prepare, quantify and validate HIV virions for testing as well as test that our HIV sample inactivation is effective to maintain biosafety during testing. We utilize a combination of chemiluminescent cellular cytopathology assessment for HIV-induced cell killing and absorbance-based ELISAs for p24 antigen quantification and are developing a fluorescence polarization assay for intact virion quantification. The 16-year-old Perkin-Elmer Victor X5 multimode platereader that we use heavily in our BSL-2 laboratory to perform each of these assays recently had a critical control board failure and replacement parts are no longer commercially available, which makes performance of these necessary HIV assessment assays impossible. The objective of this supplement is to correct this limitation by replacing our Victor X5 platereader with an equivalent modern Victor Nivo platereader so we can continue to quantify and validate high-quality HIV samples necessary for quantitative evaluation of the HIV-eCaDI devices.

NIAID - National Institute of Allergy and Infectious Diseases

Abstract Support is requested for a Keystone Symposia conference entitled “B and T Cell Collaboration in Lymphoid and Nonlymphoid Microenvironments,” organized by Drs. Stephanie C. Eisenbarth, Jason G. Cyster and Ziv Shulman, with scientific programming input from Keystone Symposia. The meeting will take place March 16–18, 2026 at the Keystone Resort in Keystone, Colorado, USA. Protective antibody-mediated immune responses typically depend on the generation of high-affinity antibodies capable of neutralizing pathogen activity and triggering effector functions of innate immune cells. However, antibody functions can be harmful in autoimmune diseases and allergic reactions. Therefore, understanding how antibodies are generated is fundamental for designing vaccination strategies and manipulating B cell responses in these pathological conditions. The generation of long-lasting antibodies is critical for infection defense and depends on collaboration between cognate T cells and B cells. The interaction and signaling that occurs between these related cells promote B cell clonal expansion and differentiation into antibody-secreting cells to fight infection, germinal center B cells to improve the quality of the antibodies, and memory B cells to increase immune response. This Keystone Symposia meeting aims to highlight advances in our understanding of basic immune mechanisms of B cell and T cell interactions in humoral immunity by focusing on emerging science obtained from pre-clinical models and translational science. The meeting will emphasize the cellular dynamics of B-T cell interactions and the underlying molecular mechanisms that promote B cell differentiation and will address similar events occurring in non-lymphoid organs. Additionally, T-B collaborations that drive pathological conditions, such as autoimmunity and allergy, as well as their positive functions in cancer, will be discussed. The conference program will provide valuable insight into immunological mechanisms relevant to allergic and autoimmune diseases, with an aim to prevent and expand potential treatments for these diseases. This meeting will bring together a diverse group of immunology investigators from across multiple research areas to present the latest research on how productive antibody responses are mounted, their role in combating infectious diseases and their dysfunction in allergy and autoimmunity. Accordingly, this conference is paired with the Keystone Symposia conference, “B Cells and Plasma Cells: Fundamental and Translational Biology,” to advance collaborative science.

NIAID - National Institute of Allergy and Infectious Diseases

Abstract Support is requested for a Keystone Symposia conference entitled “B Cells and Plasma Cells: Fundamental and Translational Biology,” organized by Drs. Kim Good-Jacobson, Deepta Bhattacharya and Taras Kreslavsky, with scientific programming input from Keystone Symposia. The meeting will take place March 16–18, 2026 at Keystone Resort in Keystone, Colorado, USA. B cells play a fundamental role in human health and longevity, and are essential for creating long-lasting immunity, with plasma cells and memory B cells providing protection against reinfection. However, when B cells malfunction during chronic infection, autoimmunity, and lymphomas, they can drive immunopathogenesis and disease. This Keystone Symposia conference will discuss recent advances in understanding what makes B cell responses last longer and work better. The meeting will also explore how these discoveries can be used to specifically target B cells for therapeutic intervention and utilize antibodies for diagnostics and immunotherapies. Understanding these mechanisms has become even more timely, given newly emerging pathogens and their variants, the expanding portfolio of vaccine platforms, and the need to engineer the B cell response for more effective therapeutics. The program has been designed to serve as a guide for building effective B cell responses and will feature interdisciplinary talks on B cell roles in vaccine design, mechanisms for promoting long-lasting immune memory, understanding harmful antibody production, and new therapeutic strategies to treat immunologic diseases and develop effective therapeutics to improve public health. This Keystone Symposia meeting will bring together global experts in the biology of plasma cells and memory B cells to present the latest research on how productive antibody responses are mounted, their role in combating infectious diseases, and their dysfunction in allergy and autoimmunity. Accordingly, this conference will be held jointly with the Keystone Symposia conference, “B and T Cell Collaboration in Lymphoid and Nonlymphoid Microenvironments,” enabling cross-disciplinary insights and encouraging innovative collaborations towards identifying novel therapeutic targets.

NIAID - National Institute of Allergy and Infectious Diseases

Abstract Support is requested for a Keystone Symposia conference entitled “Myeloid Cells: Functional Heterogeneity with Therapeutic Promise,” organized by Drs. Charlotte L. Scott, Shalin H. Naik and Thomas Fabre, with scientific programming input from Keystone Symposia. The meeting will take place February 23–26, 2026 at the Keystone Resort in Keystone, Colorado, USA. Myeloid cells play crucial roles in the innate immune system, responding to infections and maintaining tissue homeostasis. Despite their significant therapeutic promise, the potential of myeloid cells is yet to be fully realized. This Keystone Symposia meeting aims to bring together key leaders in academia and industry to discuss recent insights regarding myeloid cell functional heterogeneity and how to target these cells for therapeutic interventions. This conference will highlight recent advances in our understanding of the role of myeloid cells in different disease settings, including cancer, infection and other immune-mediated disorders, which will enable new translational perspectives for understanding, treating, and preventing infectious and immunologic diseases. The meeting program will provide opportunities for attendees to gain a deeper understanding of unique and conserved myeloid cell populations across tissues and diseases and explore how these might be leveraged therapeutically. Through rigorous discussions, this meeting aims to outline key questions for future research that will harness the power of myeloid cells and showcase current and emerging technologies. A key feature of this meeting is that it will be co-located with another Keystone Symposia conference, “Hematopoiesis.” This partnership will provide valuable insights into the interconnected roles of hematopoietic stem cells and myeloid lineages in both health and disease. Inclusive poster sessions, panel discussions, shared meals and social activities will promote networking, encourage the sharing of cross-disciplinary insights and provide broader scientific perspectives important for future research collaborations towards the development of successful therapeutic strategies.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Hookworm infection is a leading cause of malnutrition and growth delay in poor countries, especially in sub- Saharan Africa where millions of people are infected with Necator americanus. Data from human studies suggest chronic hookworm infection also impairs routine vaccine efficacy and exacerbates other globally important, co-endemic infectious diseases. Current strategies to control hookworm rely primarily on Mass Drug Administration of standard anthelminthic drugs, although recent evidence calls into question the long-term effectiveness of this approach to control and eliminate hookworm in endemic populations. Since 2007, Yale University and the Noguchi Memorial Institute for Medical Research at the University of Ghana have collaborated to characterize the epidemiology of hookworm infection in endemic communities. The longitudinal field study proposed in Aim 1 will further probe the epidemiology of hookworm by defining risk factors for infection, response to deworming, and reinfection following treatment in the Bono East Region, Ghana. Experiments outlined in Aim 2 will be focused on characterizing changes in the frequency of resistance associated mutations in the N. americanus β-tubulin gene using Next Generation Sequencing methods, as well as the impact of drug pressure on genetic diversity and the population genetics of human hookworms in Beposo. Critical to the detailed study of hookworm pathogenesis is the availability of a facile animal model that is both reproducible and accurately reflects the major clinical features of human disease. Little is known about N. americanus strains originating from populations in Africa, resulting in a significant gap in our understanding of hookworm biology, genomics and evolution. Building on experience in maintaining the laboratory model of Ancylostoma ceylanicum hookworms, field isolates of N. americanus cultured from study subjects in Ghana in 2019 have been used to establish patent infections in hamsters. In the experimental studies outlined in Aim 3, clinical parameters and the kinetics of primary infection with the Ghana strain of N. americanus will be fully characterized in the hamster model. Cellular, humoral and mucosal antibody responses to primary infection, reinfection and vaccination with hookworm proteins will be defined. In addition, novel proteomic methods will be applied to define human antibody profiles that correlate with infection status, intensity and risk of reinfection. The overarching goals of the research outlined in this proposal are (1) to identify factors associated with hookworm infection among people living in Beposo, Ghana, (2) to characterize the impact of deworming pressure on drug resistance markers and genetic diversity of hookworms in Ghana and (3) to characterize the first laboratory adapted African strain of N. americanus and optimize its utility for the study of human hookworm epidemiology, pathogenesis and vaccine development. Results from these innovative studies will enhance our understanding of hookworm pathogenesis in Africa and inform future development of public health tools to reduce the global burden of this neglected tropical disease.

NIAID - National Institute of Allergy and Infectious Diseases

With no effective therapy to date, the ongoing Type 1 diabetes (T1D) epidemic continues to be a major health problem. While immune therapeutics hold great promise for the treatment of T1D, their inadequacy, serious toxicity, side effects, and morbidity have limited research efforts in the lifelong immunosuppression approach. This shortcoming has prompted investigators to search for alternative approaches. Targeted nanomedicine using polymeric nanoparticles (NPs) holds particular promise to enhance the delivery of immune therapeutics to treat T1D. This strategy can minimize the undesirable side effects of immune therapeutics by delivering them to diseased tissues, where they can undergo sustained release. In this multidisciplinary project, we aim to develop an innovative, targeted nanodelivery method for immune therapeutics for T1D. Although progress has been made in developing new formulations, a method of targeted delivery of NPs to specific tissue sites following systemic administration remains to be developed. The priming and activation of autoreactive T cells occurs in the pancreatic lymph nodes (PLNs), where naive T cells enter through lymph node (LN)-restricted vasculature known as high endothelial venules (HEVs) and encounter autoantigens from the pancreas presented by dendritic cells. Activated T cells traffic subsequently to the pancreas, causing insulitis and autoimmune diabetes. Notably, we have found that HEVs are also formed in the pancreas during the onset of diabetes in NOD mice. Here, for the first time, we have developed a nanodelivery of therapeutics to PLN and Pancreata of NOD mice targeting HEV with intra venous injection. We have generated a novel mAb and scFV against the peripheral node addressin (PNAd), a glycoprotein family expressed only by endothelial cells of the HEV. We also provide human data that supports the clinical applicability of our delivery platform. Moreover, our preliminary data shows that delivery of anti-CD3 antibody using our HEV targeted unprecedently increases the efficacy of anti CD3 in suppressing autoimmune diabetes in NOD mice. Our main hypothesis is that targeted delivery of anti-CD3 to the pancreatic lymph nodes (PLNs) and pancreata will increase its efficacy and decrease toxicity by reducing systemic dosing significantly. In Aim 1, we will examine and optimize the stability, binding efficacy, and biodistribution of anti HEV mAb-conjugated NPs in NOD mice. In Aim 2, we will assess the clinical efficacy and the mechanisms by which the delivery of anti-CD3 using anti HEV mAb- conjugated NPs reverse autoimmune diabetes in NOD mice. In Aim 3, we plan to test the binding capacity to the PLNs and pancreata of human T1D patients of our optimized anti HEV mAb-conjugated NPs. This multidisciplinary, collaborative approach will lay the groundwork for the introduction of an innovative, targeted delivery method of immune therapeutics for T1D.

NIAID - National Institute of Allergy and Infectious Diseases

Cold Spring Harbor Laboratory Conference GENE EXPRESSION AND SIGNALING IN THE IMMUNE SYSTEM March 3-7,2026 ABSTRACT The proposed meeting on Gene Expression and Signaling in the Immune System, to be held in March, 2026, will focus on the most recent advances in this rapidly moving field. The meeting will be open, with attendance limited only by the facilities available to a maximum of ~425 participants. Oral presentations will be delivered by both invited speakers and those selected from submitted abstracts. This ensures the participation of junior and senior leaders in the field and the presentation of the most exciting results emerging at the time of the meeting. A particular emphasis will be made to ensure that a substantial number of speakers will be advanced trainees or junior PIs. The oral presentations will be complemented by poster presentations in two sessions, also selected from submitted abstracts. The areas to be covered in the 2026 meeting include 1) Regulation of gene expression; 2) Differentiation; 3) Signaling at the membrane; 4) Intracellular signaling; 5) Intercellular communication; 6) Host:microbe interactions; 7) Immune responses; and 8) Tissue-immune communication (immunophysiology). Rather than focusing on one particular type of immune cell or disease process, the meeting will highlight mechanistic approaches that aim to rigorously advance our knowledge of how the processes of signal transduction and gene regulation operate within the immune system at different scales. Ample opportunity is provided for the presentation of important, late-breaking findings. The meeting format ensures and encourages highly productive discussions, particularly during meals and in poster sessions. The meeting will foster interactions among immunologists working in related areas and provide a forum for the development of new ideas and approaches for current and future investigations of regulation of signaling and gene expression in the immune system.

NIAID - National Institute of Allergy and Infectious Diseases

Summary The transformative advancements in cell and gene therapy have significantly enhanced our understanding and treatment of congenital diseases and regenerative medicine. As we approach the 10th annual Center for Definitive and Curative Medicine (CDCM) symposium, scheduled for March 30-31, 2026, at Stanford University's Li Ka Shing Learning and Knowledge Center, we seek financial support to facilitate this pivotal event. This symposium will serve as a platform for scientific discourse on the latest discoveries and developments in the field, inviting participation from experts and trainees across academia, non-profits, government, and industry. The two-day event will focus on the theme “Past, Present, and Future of Cell and Gene Therapy,” addressing critical challenges in translating laboratory discoveries into clinical applications. Day 1 will feature a Clinical Trial Bootcamp, workshops on relevant topics, a poster session for early- stage investigators, and an evening networking event. Day 2 will showcase luminary speakers discussing breakthroughs in lentiviral and AAV gene therapy, CAR-T, gene editing, regenerative medicine, and hematopoietic stem cell transplantation. Specific aims of the symposium include: (1) elucidating the bench-to-bedside journey through real-world case studies presented by the Stanford CIRM-funded Alpha Clinic; (2) providing a platform for graduate students and early-career researchers to present their findings; (3) facilitating workshops that address community engagement in clinical trials, the role of Artificial Intelligence in healthcare, and career opportunities in health sciences; and (4) fostering collaboration through platform sessions that expose participants to emerging research areas. This symposium has been a cornerstone of the Cell and Gene Therapy Community for the past nine years, celebrating past achievements while catalyzing future innovations. The 2026 meeting promises to be a significant milestone, driving forward the dialogue and collaboration necessary to tackle the complexities of cell and gene therapy and improve patient outcomes.

NIAID - National Institute of Allergy and Infectious Diseases

Summary for the 2026 GRC Immunoengineering Immunoengineering integrates immunology, bioengineering, and computational sciences to advance treatments for cancer, infectious diseases, autoimmune disorders, and transplantation. Key innovations like CAR T-cell therapies, bispecific antibodies, and mRNA vaccines address global health threats. Advances in nanotechnology, biomaterials, AI-driven biomarker discovery, and computational modeling enhance immune modulation and drug delivery. The field bridges synthetic biology, materials science, and data science to accelerate bench-to-bedside translation, impacting diverse medical applications. Growing investment from federal agencies (NIH, NIAID, NCI, NIBIB) and universities supports immunoengineering research and training. Despite increasing interest, existing conferences limit collaboration. The Gordon Research Conference (GRC) on Immunoengineering, first held in 2022, is the only dedicated international meeting advancing interdisciplinary exchange and clinical applications. The goal of the “2026 Immunoengineering GRC: Cells, Proteins, and Biomaterials in Translational Medicine” is to share advances across all subfields simultaneously, to catalyze new ideas and collaborations, and thus serve as the national and international conference “home” for the immunoengineering community. The 2026 Immunoengineering GRC will balance immunology, translational science, biomaterials, and nanotechnology, shaping immunotherapy, vaccine development, and immune modulation strategies. The conference prioritizes academic-industry dialogue, featuring structured mentoring, poster sessions, and career development for trainees and junior investigators. GRC’s established format will ensure productive scientific exchange in a supportive environment. We will fulfill the following specific aims: Aim 1: Advance progress in immunoengineering at two levels – by promoting collaborations and relationships across scientific disciplines (fundamental and translational science) and by fostering interactions between academia and industry. Aim 2: Advance the careers of new investigators and trainees in the field of immunoengineering by showcasing their work and facilitating networking with senior investigators and peer mentors.

NIAID - National Institute of Allergy and Infectious Diseases

Abstract We intend to request funds to help support the 2026 Gordon Research Conference (GRC) on Cell Death to be held May 17-22, 2026 and its associated Gordon Research Seminar (GRS) to be held in May 16-17, 2026 at the Les Diablerets Conference Center, Switzerland . The Cell Death GRC is among the most highly regarded international conferences in the cell death community. Participants will give oral presentations, lead discussions or present their work in poster format. In keeping with the intimate spirit of the Gordon Conference, attendance will be limited, and presentations will feature unpublished work at the leading edge of this field. The overall goal of this conference is to expedite progress in cell death research and to use research findings for the development of new anti-inflammatory and anti-cancer therapies. A secondary goal is to facilitate collaborations among cell death researchers and investigators in complementary basic, translational and clinical fields. The “Power Hour” during the GRC will provide a platform to address challenges trainees at all levels encounter. The GRS target audience are students and postdoctoral trainees. The GRS provides trainees with the opportunity to present their work in a more peer-to-peer setting. The GRS will also have a few established faculties from industry and academia who will provide career counseling and advice to the trainees. We believe the GRS will provide the platform to help trainees launch their own independent research career. The aims of this conference are to: 1) gather established experts, junior scientists and researchers new to this field in a setting that supports structured and casual interactions. 2) promote exchange of cutting edge, innovative and unpublished science relevant to the roles of cell death in healthy and pathologic contexts. 3) expedite discoveries that advance mechanistic knowledge on cell death and facilitate clinical opportunities for the treatment and diagnosis of diseases caused by the dysregulation of this process. The major themes of the meeting will focus on: 1) macromolecular assemblies in cell death, 2) role of cell death in tissue homeostasis, 3) fundamental mechanisms in cell death, 4) cell death in host pathogen interactions, 5) oxidative forms of cell death, 6) applications of cell death in the clinics and 7) role of cell death in tumor immunity. The meeting will facilitate the alignment of recent breakthrough discoveries with the development of new therapies for infections, immunological disorders, and cancers.

NIAID - National Institute of Allergy and Infectious Diseases

Sepsis is a leading cause of death worldwide, with most patient mortality stemming from lingering immune dysfunction in sepsis survivors. A key feature of sepsis-associated immune dysregulation is monocyte exhaustion, a phenotype of paradoxical pro-inflammatory and immunosuppressive gene expression, impaired differentiation, and reduced antigen presentation. Monocyte exhaustion can persist for years after sepsis onset, a result of long-term immune memory. However, the mechanisms controlling such long-term memory remain to be elucidated. Whereas previous research has conceptualized innate immune memory through diametrically opposed mechanisms that either promote (train) or restrict (tolerize) monocyte responses, my preliminary data suggests that exhaustion represents a distinct memory state characterized by unique immune, transcriptional, and epigenetic features. Therefore, in contrast to the two-state model for innate memory, I hypothesize that innate memory represents a continuum of states driven by distinct epigenetic patterning, with prolonged, high- intensity immune stimulation leading to monocyte exhaustion in septic individuals. In Aim 1 of my proposed study, I will profile the unique transcriptional and epigenetic features defining monocyte exhaustion, as well as employ integrative modeling to determine how immune stressor strength, duration, and timing influence the establishment of distinct innate memory states. In Aim 2, given preliminary data showing genome-wide DNA hypermethylation in exhausted monocytes, I will test the hypothesis that inhibition of DNA demethylation enzyme TET2 is upstream of these epigenetic changes, and that treatment with TET agonists is a tractable therapeutic strategy to restore healthy epigenetic memory. Finally, in Aim 3, based on my recent identification of a novel DNMT3L isoform expressed in septic monocytes, I will test the altered chromatin affinity and regulatory activity of this isoform and establish its contribution to DNA methylation reprogramming during monocyte exhaustion. Completion of these proposed Aims will allow me to develop skills in new experimental techniques, including single-cell RNA sequencing, reduced representation bisulfite sequencing, in vivo mouse sepsis modeling, and cytometric arrays. Aims 1 and 3 will be pursued during the K99 mentored research phase at Virginia Tech in the laboratory of Dr. Liwu Li, an expert in the fields of monocyte biology and innate immune memory. Whereas my previous graduate studies focused on epigenetics and mammalian development, Dr. Li will provide valuable instruction as I expand into the topics of immunology and hematology. I will also pursue coursework at Virginia Tech in computational modeling of biological systems while engaging with professional development workshops covering such topics as scientific communication, mentorship, and R-series proposal development. The goal of this project is ultimately to pursue a career as an independent biomedical investigator in academic research; these studies will serve as a foundation for my own research program aimed at identifying the major molecular players responsible for establishing and maintaining innate immune memory.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Women in sub-Saharan Africa face an unacceptably high risk of HIV acquisition during pregnancy and breastfeeding. Daily oral pre-exposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) is effective in reducing HIV acquisition and is recommended in pregnancy. At standard FTC/TDF doses, however, tenofovir drug concentrations are 23-58% lower during pregnancy, raising concerns about reduced efficacy. In this study, we seek to identify and evaluate the optimal dose of FTC/TDF for daily oral PrEP in pregnancy, focusing on pharmacokinetic (PK) and safety outcomes. To accomplish our aims, we plan several key activities. Dose identification (Stage 1): We will randomize 45 pregnant women at 14-24 weeks gestation to three different FTC/TDF doses—standard dose (200mg/300mg), 150% standard dose (300mg/450mg), and 200% standard dose (400mg/600mg). Each participant will undergo three “cycles” comprising 14 days of daily oral PrEP, followed by intensive PK sampling over 24 hours. The first two cycles will occur in the second and third trimesters of pregnancy at the assigned FTC/TDF dose; the third will take place at 12 weeks postpartum and use only standard FTC/TDF. We will compare tenofovir diphosphate in peripheral blood mononuclear cells (PBMCs) in each pregnancy trimester to the postpartum control condition, using defined boundaries for bioequivalence. Preliminary safety data will also be obtained. Independent review: Findings from this initial stage will be independently reviewed by an expert, multidisciplinary Study Monitoring Committee, which will recommend an increased FTC/TDF dose (150% vs. 200% standard dose) for further study. Extended safety assessment (Stage 2): We will randomize 112 pregnant women at 14-24 weeks gestation to receive either standard vs. increased FTC/TDF doses on a daily basis, under direct observation, until time of delivery. Safety monitoring will continue through pregnancy, delivery, and the first six months postpartum. We will compare renal function, adverse events, bone mineral density, weight change/growth in women and infants, and pregnancy outcomes. We will evaluate FTC and TFV (and their metabolites) in plasma, PBMCs, red blood cells, urine, and cervicovaginal fluid. PK modeling: Using empiric study data, we will develop a PK model that estimates concentrations of FTC and TDF across multiple compartments during pregnancy. Our model will consider key factors that may influence drug concentrations (e.g., body weight, gestational age, renal function) to predict safety outcomes for lengthier exposures in pregnancy. This study will be led by an experienced team of researchers, with extensive expertise in HIV, clinical trials, pharmacology, and obstetrics. Our proposal leverages the strengths of its partnering institutions, including the robust research infrastructure at the University of Zimbabwe. Over the course of this award, we will provide key insights into the PK and safety of FTC/TDF in pregnancy. Importantly, these findings will help to optimize PrEP regimens for an important but often overlooked population: pregnant women in sub-Saharan Africa.

NIAID - National Institute of Allergy and Infectious Diseases

Abstract Discoid lupus is a form of cutaneous lupus erythematosus (CCLE) that primarily affects the skin, as well as the oral and nasal mucosa. It is a rare condition, with an estimated prevalence of 3-7 cases per 100,000 people in the United States. Lupus erythematosus, including its cutaneous variants, is characterized by the presence of autoantibodies targeting various self-antigens. While autoantibodies that bind to oral epithelial cells have been identified in lupus, their relevance to mucosal discoid lesions and the specific autoantigens involved remain unclear. This proposal responds to the NIH funding announcement PAR25-122, which supports pilot projects investigating understudied proteins associated with rare diseases like discoid lupus. Among the genes high- lighted in this announcement is ZNF688, a transcription factor belonging to the Krüppel-associated box (KRAB)- zinc finger proteins (KZNFs). KZNFs are primarily known to act as transcriptional repressors, regulating critical cellular processes such as proliferation, differentiation, apoptosis, and genome stability. ZNF688 is particularly intriguing for this funding opportunity due to its underexplored nature, with only four publications on the topic available in PubMed. Notably, two of these studies suggest that ZNF688 is a target of autoantibodies in both lupus and another immune-mediated disease, sarcoidosis. Preliminary data have shown high expression levels of ZNF688 in oral epithelial cells, leading to the central hypothesis of this proposal: ZNF688 may regulate oral epithelial cell function, and autoantibodies targeting ZNF688 could contribute to the pathogenesis of oral lesions in discoid lupus. The proposed studies will investigate whether antibodies against ZNF688 affect the differentia- tion or survival of oral epithelial cells. Additionally, the research will identify target genes and pathways regulated by ZNF688, providing insight into how autoantibodies binding this protein may disrupt oral epithelial cell func- tions. The significance of these studies lies in their potential to: (1) Determine whether antibodies targeting ZNF688 influence cell survival or proliferation. (2) Uncover the target genes and pathways regulated by this understudied transcription factor. (3) Shed light on the potential roles of ZNF688 in the pathophysiology of discoid lupus, a rare disease.

NIAID - National Institute of Allergy and Infectious Diseases

Epidemics of vaccine-preventable zoonotic diseases are ongoing in major urban centers in the US and worldwide. Mass vaccination campaigns can prevent and control epidemics of infectious diseases among humans and animals. The realities of mass vaccination efforts, however, often fall short of their promise. In place of high and even vaccination coverage, many campaigns leave spatial "pockets" of under-vaccinated individuals. Pathogens, taking advantage of these under-vaccinated areas, can persist, diversify, and re-emerge. Modern computational approaches can mitigate geographic imbalances through the careful placement of vaccination sites. The main hypothesis of our study is that participation in mass vaccination campaigns can be significantly increased through spatially responsive vaccination strategies. These strategies have the potential to maximize coverage, minimize waiting time at vaccination sites, and increase immunization in high-risk populations. We test our methods in the context of an ongoing canine rabies epidemic in the city of Arequipa, Peru. This foreign component is scientifically indispensable and cannot be replicated domestically; while US urban zoonoses (such as raccoon rabies) rely on oral baiting or wildlife trapping, Arequipa presents a high-density parenteral vaccination system, where people must attend vaccination sites to immunize their animals. This setting allows us to uniquely integrate human movement, and queueing theory at active, high-throughput centralized vaccination sites under real-world epidemic stress. Importantly, in Arequipa, these mass dog vaccination campaigns are conducted annually, allowing us to implement an efficient stepped-wedge cluster randomized trial to achieve our aims. In the first aim we test spatially optimized mass vaccination sites. In the second test precision mop-up vaccination campaigns. In the third aim we assess the acceptability, scalability, and transferability of spatially responsive vaccination strategies for local, regional, and national stakeholders. Crucially, this research directly benefits the health of US populations by providing a scalable framework for rapid-response mass vaccination logistics and improving strategies to control vaccine-preventable diseases. These optimized strategies can be directly translated to US public health systems to counter localized outbreaks of emerging zoonoses, mitigate border health threats, and optimize domestic immunization delivery during public health emergencies.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary/Abstract The SLC4A2 (or Anion Exchanger2, AE2) is a ubiquitous membrane transporter that mediates the sodium (Na+)- independent and electroneutral exchange of chloride (Cl−) and bicarbonate (HCO3−) ions, and participates in the regulation of intracellular pH (pHi). AE2-deficiency in humans has been linked with the development of Primary Biliary Cholangitis (PBC), which is a chronic cholestatic liver disease associated with autoimmune phenomena. Supporting these findings, mice with whole-body deletion of SLC4A2 develop a spontaneous and progressive autoimmune cholangitis that resembles the human PBC. However, the cell intrinsic requirement of SLC4A2 in immune cells and/or biliary epithelial cells and the mechanisms underlying the loss of tolerance against biliary epithelial cells in the absence of SLC4A2 are unknown. Here, we aim to dissect the role of SLC4A2 in the development of liver inflammation and autoimmune cholangitis using SLC4A2 conditional knockout (cKO) mice. To this end, we have generated tissue-specific SLC4A2-cKO in the liver (i.e., Slc4a2fl/flAlbCre+ mice) as well as in T cells (i.e., Slc4a2fl/flCd4Cre+ mice) to study the requirement of this membrane transporter in immune tolerance in the liver. We aim to: 1) characterize the immune cell composition in the liver and lymphoid organs of Slc4a2fl/flCd4Cre+, Slc4a2fl/flAlbCre+ mice and their control littermates, and ii) study the alterations that occur in T cells and liver cells in the absence of SLC4A2. Investigating the mechanisms underlying the autoimmune cholangitis and liver inflammation caused by SLC4A2 deficiency in mice will be an important step forward to better understand the etiopathogenesis of PBC and to the development of future therapeutic approaches to treat these patients.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY SARS-CoV-2 transmission was expected to have a devastating impact in sub-Saharan African countries. Instead, morbidity and mortality rates in nearly the whole region are an order of magnitude lower than in Europe and the Americas. To identify what is different requires a better understanding of the underlying immunological substrate of the population, and how these factors affect susceptibility to infection, progression of symptoms, transmission, and responses to SARS-CoV-2 vaccination. These populations are assaulted by many infectious diseases, including malaria. Exposure to these pathogens can produce long-lasting changes in the innate immune system, which may confer decreased susceptibility to heterologous infections. By generating rapid responses to the virus, the innate immune system can decrease the susceptibility to SARS-CoV-2 infection and the risk of progression from infection to disease. On the other hand, malaria infections and helminthiasis can impair the acquisition and longevity of antibody (Ab)- induced immunity through several mechanisms, including tolerogenic innate immune responses. In addition to malaria, other co-morbidities, e.g., anemia and chronic undernutrition, are likely to affect Ab-mediated immunity. We hypothesize that malaria and helminthiasis affect morbidity of SARS-CoV-2 in sub-Saharan Africa. Compared to Western populations, both uninfected and infected-but-asymptomatic subjects will have enhanced innate immune phenotypes. Most infections will be asymptomatic. Once infected, though, malaria, infections with intestinal parasites, anemia, and mild undernutrition will decrease the acquisition and longevity of Ab responses, increasing the risk of re-infection. These comorbidities will also reduce longevity of Ab responses elicited by the Astrazeneca vaccine. To test these hypotheses, we will enroll 200 symptomatic individuals (index cases), their household contacts, and 300 vaccinees. We will assess the specific innate immune phenotypes that differentiate uninfected Malawians from Western controls and whether those responses are protecting Malawians from infection and/or progression of disease. We will follow infected participants and vaccinees for 1.5 years to assess acquisition and longevity of Ab responses and memory B cells. The work will be supported by a platform established on the basis of long-term collaborations with the Ministry of Health and the University of Malawi. As global vaccination campaigns launch, data to optimize vaccination in sub-Saharan countries are urgently needed. Identifying groups at high risk of infection and disease and understanding the susceptibility of the local population will help to define optimal vaccination policies to control transmission. Identifying “hypo- responders” and those whose Ab responses wane more quickly will help to optimize vaccination regimen. In summary, data generated by this study will improve our general understanding of SARS-CoV-2 transmission and pathogenesis and will allow regional vaccination programs to be designed for maximum effectiveness.