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Novel point-of-care liquid biopsy for early detection of sepsis-associated organ damage

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National Institute of Allergy and Infectious Diseases (NIAID)

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Sepsis, defined as a dysregulated immune response to infection leading to end-organ damage, is a critical problem that imposes considerable burdens on health care systems globally. However, despite its importance, sepsis is notoriously challenging to diagnose with precision, since neither infection nor organ dysfunction may be evident upon initial clinical assessment. Our overall objective in this application is to develop a novel circulating cellular biomarker for the early detection and assessment of sepsis-induced organ damage. Our team pioneered the “liquid biopsy” approach to cancer detection and monitoring, and we have recently extended this approach to systemic infection, detecting circulating lung epithelial cells in severe COVID-19, and cardiomyocytes in children with cardiac manifestations of multisystem inflammatory syndrome (MIS-C), providing proof of concept for extending our approach to infectious diseases. Our central hypothesis is that the detection of tissue-derived circulating rare cells (tCRCs, e.g. cells originating from the lungs, kidney, etc.) in the peripheral blood of sepsis patients will serve as a measurement of early organ/tissue damage to enable early diagnosis and monitoring of patients. The ability to noninvasively sample tissues affected by sepsis, COVID-19 and hyperinflammatory sequelae such as MIS-C, and ultimately other systemic infectious or inflammatory syndromes may both (1) clarify diagnosis of these syndromes that often lack specific diagnostic criteria or tests and (2) provide important insights into disease mechanisms, tropisms, and treatment response. To minimize one source of heterogeneity (anatomical source of infection) in this pilot study of a notoriously heterogeneous clinical syndrome, we will limit enrollment to sepsis of suspected pulmonary source.  We propose two specific aims: In Aim 1, we propose to optimize a microfluidic enrichment and droplet- based digital PCR (ddPCR) assay to detect tCRCs first in spike-in samples, then in a series of 60 patients with pneumonia at risk for sepsis (n = 30 adjudicated to have sepsis, and 30 without). In Aim 2, we will identify tCRC transcriptional signatures for early detection of sepsis-induced organ damage via bulk (n = 60) and single-cell (n = 15) RNA-Seq. We will use patient enrollment criteria that we have successfully used in prior studies of sepsis.  The proposed research is innovative because our approach has the potential to fill the significant gaps in (1) diagnosis and monitoring of disease progression and treatment response via non-invasive methods (i.e., liquid biopsy) with high sensitivity and specificity, and (2) early, non-invasive pathophysiological characterization of sepsis and potentially other inflammatory conditions. The project is significant because it has the potential to provide a blood-based cellular biomarker for a common and critical illness, via an approach that can potentially extend to other systemic diseases. Ultimately, building upon this pilot proposal, we anticipate in the longer term that this novel approach can offer a novel diagnostic tool to non-invasively sample end-organs affected by systemic infection, just as circulating tumor cell detection has revolutionized the detection of cancer metastasis.

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Multisystem Inflammatory Syndrome in Children

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2025 Biomaterials and Tissue Engineering Gordon Research Conference and Seminar

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National Institute of Biomedical Imaging and Bioengineering (NIBIB)

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Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. SUMMARY Significance, timeliness and rationale. NIBIB’s mission is to transform through engineering the understanding of disease and its prevention, detection, diagnosis, and treatment. Life would not be possible without liquid crystalline (LC) order. The most celebrated example is the unique combination of flexibility and confining ability of cell membranes which is possible because lipids cooperatively aggregate into a lamellar LC phase in water. Many viruses, e.g., SARS-CoV-2, are enveloped in a lipid membrane and they may employ LC order for packing their nucleic acid cargo. Non-biological LCs have turned out to be sensitive in detecting and reporting on the presence of pathogens and toxins, making them highly interesting for autonomous bio-/chemosensors. LC formation is thus an integral component of what keeps us healthy, and they are emerging as a powerful tool for detecting disease agents. Although this connection is long known, it has until now been researched only marginally, constituting an under-explored opportunity in addressing societal needs. Today, the international LC research community is undergoing a rebirth, fully embracing these aspects. Interdisciplinary crossovers where LC science meets biological, life and pharmaceutical sciences, and engineering and materials science, play a groundbreaking role in leveraging the opportunities. Additional impact on the core fields of the NIH-NIBIB mission comes from, e.g., the exploration of LC elastomers in soft actuators or implants in the human body. Objective. Gordon Research Conference (GRC) and Gordon Research Seminar (GRS) in Liquid Crystals, 2025: “Uniting disciplines for global challenges: Liquid crystals as active and learning materials” to take place July 6-11th 2025 (GRS July 5-6, 2025) at the Southern New Hampshire University, Manchester, NH, US. The joint meetings will bring together US and international researchers at the forefront of today’s vibrant LC science, spanning its full breadth and connecting academia, industry and military labs, early career and established researchers, and harnessing every opportunity to promote scientific discussions and encourage collaboration between speakers, discussing leaders and participants. Approach. 23 prominent speakers have confirmed our invitations to present unpublished cutting-edge research. Our goal is to promote the participation of students, postdocs, and scholars at an early stage of their careers. We seek to promote scientific discussion among all participants who will fuel the future of Liquid Crystal Science in biomedical and biotechnology applications. Academic speakers are complemented by 2 industry and 2 military research lab speakers. Additionally, 5 speaker slots will be given to outstanding scientists selected from submitted poster abstracts. To further strengthen the voice of young researchers, the GRC is preceded by the GRS, catering only to students and post-docs and providing mentoring and career advice. During the GRC, young scientists will be given priority in all scientific discussions.

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National Institute of Biomedical Imaging and Bioengineering

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United States National Institutes of Health

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RANKL regulation of human B cell responses

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National Institute of Allergy and Infectious Diseases (NIAID)

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Improved understanding of B cell biology may uncover therapies that will restore immune tolerance in autoimmune disease with minimal safety risk. Tumor necrosis factor (TNF) superfamily members are key regulators of B cell biology, and blockade of several of these pathways has shown significant clinical benefit in autoimmunity with minimal infectious risk. For example, B cell activating factor (BAFF)-blockade provides benefit in lupus, a proliferation-inducing ligand (APRIL)-blockade provides benefit in IgA nephropathy, CD40L-blockade shows promise in Sjogren’s disease, and all these therapies are well-tolerated. TNF superfamily member receptor activator of NF-κB (RANK), and its ligand RANKL, are highly expressed by memory B cell subsets. Human genetic variation in RANK is associated with the autoantibody-mediated disease myasthenia gravis. In mice, transient blockade of RANKL increases the quantity of antigen-specific vaccine titers. Yet, the impact of RANKL on human humoral immunity remains unknown. Understanding RANK-RANKL B cell control in humans may identify a new pathway to augment antibody responses to vaccination or dampen autoantibody responses in autoimmunity with limited safety risk. To address this gap in knowledge, I captured the in vivo human experiment by collecting plasma and peripheral blood mononuclear cells from individuals receiving denosumab, an FDA approved RANKL-blocking antibody commonly used in the treatment of osteoporosis, and matched controls following Covid-19 booster vaccination. I observed a significant increase in Covid-specific IgG responses, total IgG1, and autoantibody formation to numerous self-antigens in individuals receiving RANKL- blockade. As RANK signaling can induce FAS in osteoclasts and FAS expression in B cells is a critical negative regulator of T cell-dependent B cell responses, I hypothesize that blockade of RANKL broadly increases human B cell responses to vaccination and self-antigen by impairing B cell FAS-mediated apoptosis. This hypothesis will be tested through the following 3 aims: 1) Determine the impact of RANKL-blockade on humoral and cellular immunity to recent Covid and influenza vaccination versus remote tetanus vaccination, 2) Define the site of impaired B cell tolerance and the pattern of autoantibodies following RANKL-blockade, and 3) Test the impact of RANKL-blockade on FAS-mediated B cell survival in vitro and in vivo. Collectively, these studies will address the existing knowledge gap of RANKL control of human B cell responses and may provide the foundation to target RANK-RANKL to tune human humoral immunity.

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Notch regulation of airway epithelial-immune cell cross-talk in SARS-CoV-2 infection

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National Institute of Allergy and Infectious Diseases (NIAID)

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19. Infection with SARS-CoV-2 begins in epithelial cells of the upper airways, which triggers multiple antiviral responses that activate myeloid immune cells, coordinate the early innate immune response, and limit viral spread. Notably, our understanding of the cell signaling mechanisms that regulate early epithelial-immune cell interactions and induction of tissue pathology during SARS-CoV-2 infection of the human airway remains limited. To investigate these processes, we have developed a novel in vitro all human 3D model of the upper airways (HUA) composed of layers of primary differentiated airway epithelial cells expressing ACE2, lung fibroblasts in a collagen matrix, and pulmonary endothelial cells, with myeloid cells present in each layer. SARS-CoV-2 infection of the HUA model results in virus replication and induction of an immune response reminiscent of in vivo infection, and the presence of myeloid cells limits viral replication. Therefore, we will use the HUA model to perform kinetic studies of the mechanisms by which human airway cells interact to regulate virus-host interactions, inflammation, and tissue pathology associated with SARS-CoV-2. We will focus on the Notch pathway, which acts via direct cell- to-cell signaling to regulate airway epithelial cell fate decisions as well as myeloid cell maintenance, Toll-like receptor signaling, pro-inflammatory polarization, and antiviral functions. However, the mechanisms by which Notch signaling regulates airway epithelial-myeloid cell interactions during SARS-CoV-2 infection remain unknown. Our preliminary analyses showed that airway epithelial cells and myeloid cells express multiple Notch ligands and receptors in uninfected HUA models, suggesting that the Notch pathway will mediate bidirectional crosstalk during the airway response to infection. We will test the central hypothesis that Notch receptor signaling in myeloid cells regulates their pro-inflammatory phenotype, thereby promoting the host innate antiviral immune response and contributing to airway epithelial cell damage and remodeling during SARS-CoV-2 infection. Using lentivirus vectors and inducible expression systems, we will attenuate expression of individual Notch ligands and receptors in a cell-type specific and temporal manner. Following SARS-CoV-2 infection, we will quantify the impact of reducing Notch signaling activity on virus replication, myeloid cell phenotypes, the host immune response, and airway epithelial remodeling. The data collected in this study will advance our understanding of the mechanisms that regulate airway epithelial-immune cell interactions during SARS-CoV-2 infection and may identify candidate therapeutic targets in the Notch pathway to enhance antiviral immunity and reduce epithelial injury and remodeling in the upper airway.

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Deciphering the Transcriptomic Basis of Chemo Fog

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CANDIDATE: My long-term career objective is to lead an independent research program dedicated to improving the efficacy of cancer treatments and the post-treatment experiences of cancer survivors. This proposed research represents a convergence of my research experiences: to elucidate the transcriptional mechanisms underpinning cognitive impairment induced by cancer therapies, a critical issue affecting cancer survivors. In preparation for this transition to independence, I have curated a training plan encompassing four key objectives: (1) acquiring essential skills, (2) forging strategic scientific collaborations, (3) honing professional development, and (4) ensuring a seamless transition to independence. This proposal serves as a blueprint for my future research career in the field of cancer biology. RESEARCH: Chemotherapy, despite its life-saving potential, often leads to debilitating side effects such as cognitive impairment, significantly diminishing the quality of life for cancer survivors. Multiple studies have identified disturbances in brain cell homeostasis upon chemotherapy treatment, including neuronal death, disrupted myelination, and activated microglia. However, the transcriptional regulation governing these changes remains largely unclear. My early postdoctoral research revealed substantial transcriptional overlaps shared among various forms of cognitive impairment, including aging, Alzheimer's disease, and severe COVID-19. Yet, whether this transcriptional overlap, and more crucially, its regulatory mechanisms, extend to chemotherapy-induced cognitive impairment (CICI) remains unknown. Through comparative analysis of brain transcriptomic profiles of mice upon systemic chemotherapy treatment and other forms of cognitive impairment, I have identified candidate transcription factor drivers of CICI. This proposal will test the hypothesis that transcriptomic states (Aim 1) and key underlying transcription factor regulators (Aim 2) can be manipulated to modify CICI behaviors in mice (Aim 3). These investigations will illuminate the transcriptional underpinnings of cognitive impairment induced by chemotherapy, offering new insights into potential therapeutic strategies to ameliorate or reverse this debilitating side effect. ENVIRONMENT: The Harvard Medical School community provides an optimal setting for me to achieve my training and research objectives while successfully transitioning to an independent faculty position. My mentors, Dr. Frank Slack and Dr. Clifford Woolf, are global leaders in RNA biology and neuroscience, respectively. Additionally, I have assembled an advisory committee comprising three established scientists—Drs. Rosalind Segal, Winston Hide, and Marcia Haigis—with pertinent expertise and strong commitment to mentorship. Their support will be invaluable in guiding my research endeavors and facilitating my path toward independence. Combined with the intellectually rich and resource-abundant communities of BIDMC and BCH, this mentorship team will foster an ideal environment, enabling me to effectively execute the proposed research and transition to independence.

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United States National Institutes of Health

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Develop novel iNOS/NO inhibitors for mitigating inflammatory cell death, ARDS, and MODS

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National Institute of Allergy and Infectious Diseases (NIAID)

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Many causes can trigger excessive production of inflammatory cytokines (i.e., cytokine storm). Elevated circulating cytokines induce extensive cell death (i.e., inflammatory cell death) that causes severe organ injuries, eventually leading to acute respiratory distress syndrome (ARDS) and multi-organ dysfunction (MODS). Patients with ARDS and MODS have extremely high mortality (~46%). There is an unmet clinical need for novel therapeutics capable of inhibiting inflammatory cell death to mitigate ARDS and MODS. Recent studies find that the excessive expression of inducible Nitric Oxide Synthase (iNOS) and over-production of nitric oxide (NO) play a critical role in inflammatory cell death. Therefore, inhibiting iNOS/NO represents a promising therapeutic approach. Hydrogen sulfide (H2S), a gaseous signaling molecule in our body, is known for its capability to inhibit iNOS and quench NO. However, due to its gaseous nature, its therapeutic application is limited by the challenge of administering a precise dose into the target cells sustainably. Preliminary studies developed five polymeric micelles containing H2S donating-anethole dithiolethione (ADT) groups to overcome the problem. The micelles enter cells via endocytosis and release H2S upon oxidation by reactive oxygens species (ROS) inside cells. The release rate can be controlled by changing the polymer design. The micelles have no significant cytotoxicity. In a proof-of-concept study, the micelles effectively inhibited cytokine-induced cell death. In short, the data show that the micelles are promising drug candidates. This project proposes systematically evaluating their therapeutic potential using vitro and mouse models, with the goal of gathering robust evidence to support their advancement into full drug development. The hypothesis is that the micelles can effectively mitigate iNOS/NO, inflammatory cell death, ARDS, and MODS. Aim 1 will test the hypothesis that micelles can mitigate iNOS/NO activity and inflammatory cell death in vitro. Aim 2 will test the hypothesis that micelles can mitigate cytokine storm, inflammatory cell death, organ injury, and mortality in mouse models. This project will collect essential efficacy/potency data, identify the most promising candidates, and provide valuable insights into polymer structure-property relationships to optimize these candidates further. The work is significant, as it has the potential to lead to novel therapeutics for managing ARDS and MODS, conditions responsible for ~11 million deaths annually. In terms of innovation, this is the first to investigate H₂S as an iNOS/NO inhibitor to reduce inflammatory cell death, cytokine storms, ARDS, and MODS. The micelle design is also highly innovative, enabling sustained, targeted, and ROS-responsive intracellular delivery of H₂S - a combination of features currently unmatched by any existing technology.

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Long-lived highly differentiated monocyte-derived cells (LDMs) activate lung-resident CD8+ T cell memory

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National Institute of Allergy and Infectious Diseases (NIAID)

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The lung, as it is constantly challenged, has a unique immune system, much of which is still underappreciated. Respiratory viral infection, including influenza and SARS-CoV-2, is among the worst burdens of disease worldwide and in the US, and especially viral pneumonia is one of the leading causes for irreversible tissue damage and death. Importantly, immune responses of the lung to the viral infection determine the outcome of these viral illnesses, so better understanding of the lung immunology is warranted. CD8+ T cells are the most important immune effector against viral infection of the respiratory organs because they significantly reduce virus burden and spread by eliminating infected cells. But T cell immunity is not an autonomous system and innate immune cells are required for the T cells to be functional. In the lung, dendritic cells (DCs) and macrophages play such regulatory roles in general. I had previously demonstrated that tissue- infiltrated monocytes are also important for efficient T cell immune responses during influenza infection of the lung and trachea, adding to the knowledge of innate immune regulation of T cell responses. Now I have strong evidence that the monocytes infiltrating into the lung during influenza virus infection further differentiate into a novel myeloid cell type, long-lived highly differentiated monocyte-derived cell (LDM), and the LDM cells persist in the lung for many months since recovery from the infection. I also obtained preliminary, but significant, data indicating that those LDM cells are a key regulator of lung-resident memory T cell (TRM). TRM is an effective cytolytic immune effector to protect hosts from recurrent infection, however current understanding of regulatory mechanisms for lung-resident T cell memory remains insufficient. We will address an unsolved issue in this field–how lung TRM is regulated by innate immunity. In Aim 1, it will be tested if LDM, not conventional DCs, activates lung TRM upon recurrent influenza infection using a LDM depletion mouse model that I newly developed. In Aim 2, I will investigate the mechanism(s) by which the LDM activates TRM. Through rechallenge of virus-immune mice with viral antigens, reconstituted in vitro cell assays and reporter assays that distinguish cytokine signals and TCR activation signal, it will be determined if the LDM is a lung-resident antigen presenting cell (APC) type for TRM activation. In Aim 3, to corroborate evidence that the LDM promotes TRM activation, interaction, migration and tissue localization of LDM and TRM in the lung will be investigated using cutting-edge lung imaging technologies.

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A synthetic miR-7702: a potential therapeutic approach for SARS-CoV-2 infection

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National Institute of Allergy and Infectious Diseases (NIAID)

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Coronavirus disease 2019 (COVID-19) is caused by the newly identified coronavirus termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus has caused over 775 million infections and more than 7 million deaths worldwide. There is an urgent need to identify host factors that restrict SARS-CoV-2 infection and thus aid in developing novel therapeutics to combat this disease. The long-term goal of this project is to understand the molecular mechanisms of the host factors that regulate SARS-CoV-2 infection and to develop antiviral drugs targeting these host factors. Among host factors, microRNAs (miRNAs) are small noncoding RNAs that control the expression of most genes at the posttranscriptional level. miRNAs have been implicated in diverse biological processes and diseases, including viral infections. Our understanding of the role of host cellular miRNAs in SARS-CoV-2 replication is very limited. We found that miR-7702 was the most potent miRNA in inhibiting SARS-CoV-2 infection by targeting a viral RNA. Our overall objective of the current application is to develop a synthetic miR-7702 as a therapeutic for SARS-CoV-2 infection. We hypothesize that miR-7702 attenuates SARS-CoV-2 infection by targeting a viral RNA. Aim I will delineate the mechanism of action by which miR-7702 exerts its anti-SARS-CoV-2 activity. Aim II will evaluate the in vivo toxicity, biodistribution and therapeutic efficacy of a synthetic miR-7702 mimic against SARS-CoV-2 infection in a preclinic mouse model. We expect to establish a previously unrecognized role for host miR-7702 in the repression of SARS-CoV-2 replication and provide preclinical data for miR-7702 as a therapeutic for SARS- CoV-2 infection.

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Middle East Respiratory Syndrome Coronavirus

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Development of siRNA-peptide libraries for delivery screening

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National Institute of Allergy and Infectious Diseases (NIAID)

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Viral infections pose a major public health concern, affecting millions and contributing significantly to global mortality, as evidenced by the COVID-19 pandemic, which cut short over 7 million lives worldwide. The success of mRNA vaccines during this pandemic showcased the power of nucleic acid therapeutics in combating emerging viral threats. However, vaccines rely on the adaptive immune response, requiring time to mount protection and unable to treat ongoing infections. Small interfering RNAs (siRNAs) represent a promising class of nucleic acid therapeutics with the potential to overcome these limitations. siRNAs induce gene silencing by directly degrading targeted RNAs, offering rapid action and adaptability to emerging viral strains. These properties make siRNAs attractive for treating viral infections, with positive indications in models for many viruses on NIAID’s priority list, including Dengue Fever, Ebola, Hepatitis, Herpes, Human Papillomavirus, Influenza, Respiratory Syncytial Virus (RSV), Smallpox, West Nile Virus, and Zika Virus. Despite demonstrated efficacy in tissue culture and model systems, clinical translation of siRNAs is hampered by challenges in efficient delivery to target tissues. While the development of GalNAc-siRNA conjugates has led to FDA-approved liver-targeted therapies, scalable methods for screening siRNA delivery strategies in tissues beyond the liver are lacking. This proposal aims to address these limitations by developing high-throughput technologies for generating and screening siRNA-peptide conjugates—a novel approach to improving delivery efficiency and overcoming key bottlenecks of cellular uptake, endosomal escape, and siRNA activation. In Aim 1, we will adapt mRNA display, an established method for creating diverse mRNA-protein libraries, to synthesize compact siRNA-peptide conjugates. By encoding each peptide's amino acid sequence within its conjugated siRNA nucleotide sequence, we will create libraries with millions of variants, enabling high-throughput functional screening. In Aim 2, we will evaluate the functionality of these siRNA-peptide conjugates using biochemistry and small RNA sequencing (sRNA-seq) to identify those that successfully load into Argonaute 2 (Ago2), the enzyme that mediates silencing directed by siRNAs. This method allows for a direct, highly sensitive assessment of delivery efficiency and quantitative identification of the most promising siRNA conjugates for further development. Completion of this project will establish new technologies for high-throughput siRNA conjugate screening, facilitating the discovery of efficient delivery strategies for siRNA-based antiviral therapeutics across diverse biological contexts. This will significantly impact the treatment of viral infections, providing a pathway toward developing siRNA therapies that can rapidly respond to emerging viral threats, treat chronic infections, and protect vulnerable populations such as immunocompromised individuals. This work aligns with NIAID’s mission to combat infectious diseases through innovative therapeutics and the development of broadly applicable antiviral treatments.

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National Institute of Allergy and Infectious Disease

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Modeling and validating dynamic accessibility to healthcare with system science approach

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National Institute of Allergy and Infectious Diseases (NIAID)

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In public health sciences, people’s accessibility to healthcare determines how easily they can reach and utilize health services. For researchers and policy makers, modeling and measuring accessibility to healthcare is key to narrowing disparities and achieving health equality. Each year, a plethora of research efforts aim to model, estimate, and map geographic disparities in healthcare accessibility, informing targeted interventions in underserved areas. These studies have predominantly adopted either a travel cost-based approach or supply- demand approach to measure accessibility. Both approaches are population-based and temporally static, assuming uniformity among individuals and disregarding temporal factors. The derived accessibility measures fail to account for temporal variations, as well as heterogenous individuals and their interactions. To address these limitations, I will propose new conceptual frameworks to model and validate accessibility to healthcare using a system science approach. This two-year small project will study people’s access to healthcare in a dynamic and social system that involves complex interactions among individuals, as well as interactions between individuals and the environment (e.g., transportation network and health facilities). I will pioneer two models in system science, namely the system dynamics model and the agent-based model, to represent this system. I will implement these two types of models in the state of Florida in the context of recent ‘triplepidemic’ (flu, RSV and COVID) during 2022-23 season, and attempt to validate the model results. This study will contribute to the literature by adding a time dimension, individuals’ heterogeneity, and their social networks to the models of healthcare accessibility. Additionally, this study will investigate a novel method to validate healthcare accessibility models, addressing a persistent gap in existing research. Researchers and policy makers can use the newly developed tools to better monitor dynamics of healthcare accessibility and to mitigate health disparities more precisely with spatio-temporally dependent intervention.