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New Activators and Mechanistic Insights into SARM1 in Neurodegeneration
No full textResearchers have realized a common mechanism in traumatic injury and multiple neurodegenerative diseases: when neuronal metabolism is disrupted, axons undergo an intrinsic programmed degeneration process. In this process, the key executor is SARM1, a TIR domain NADase enzyme that senses the NMN/NAD+ ratio in neurons. When NAD+ level declines or NMN accumulates, SARM1 is activated and leads to axon degeneration. In recent years, this signaling pathway has been recognized as a key mediator of axon degeneration in various neurodegenerative diseases. During my Ph.D., I investigated how SARM1 activation is triggered by environmental toxins and DNA damage-induced cell death, broadening our understanding of SARM1’s role beyond classical axonal injury. In my first study, I found some neurotoxins can be converted into potent SARM1 activators in cells. Specifically, we found the Nam analog 3-AP, can be converted into 3-APMN in neurons, which binds to the allosteric NMN-binding site and activates SARM1. This process leads to NAD+ depletion, cADPR generation, axon degeneration and neuronal death. We have validated the molecular mechanism and confirmed corresponding phenotypes in both in vitro neuronal cultures and in mouse models. These results demonstrate that exogenous neurotoxins can mimic the role of NMN to activate SARM1, therefore causing pathological axon degeneration. In my second study, I further demonstrated that SARM1 is a crucial component of neuronal Parthanatos and excitotoxic neuronal death. Parthanatos is a type of programmed cell death characterized by excessive PARP1 activation after DNA damage. My research revealed that, once PARP1 is activates, SARM1 is subsequently activated, leading to mitochondrial depolarization, AIF translocation and neuronal death. Importantly, inhibiting SARM1 can effectively prevent the progression of neuronal death and rescue neuropathological phenotypes. Overall, my studies elucidate the nexus role of SARM1 in pathological axon degeneration and neuronal death. SARM1 activation can be triggered by disruption of the NMN/NAD+ ratio, which can come from the accumulation of NMN analogs, or substantial NAD+ declines caused by other NADase enzymes like PARP1. In addition, SARM1 plays an essential role in executing neuronal Parthanatos and excitotoxic cell death. Besides revealing novel biological mechanisms, my research provides some important therapeutic insights. Firstly, 3-AP or other pyridine-based neurotoxins can be used as potential neurolytic agents to selectively degenerate axonal terminals. Moreover, targeting SARM1 provides promising strategies for treatment in DNA damage-associated ALS, Parkinson’s disease, and stroke. Together, my work broadens the biological understanding of SARM1-mediated neurodegeneration and highlights its therapeutic potential for pain treatment and neurodegenerative diseases
Humoral Immune Responses following Immunization with SARS-CoV-2 Variant Vaccines
No full textViruses are infectious agents that depend on host cells for replication and can cause diseases ranging from mild illness to severe outcomes, including cancer and death. In the 21st century, several major viral outbreaks have occurred, including the 2002 severe acute respiratory syndrome coronavirus (SARS), the 2009 H1N1 influenza pandemic, the 2012 Middle East respiratory syndrome (MERS), the 2014 Ebola virus outbreak, and most recently, the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 2019. SARS-CoV-2 is a positive-sense, single-stranded RNA virus of the Betacoronavirus genus in the Coronaviridae family. First identified in Wuhan, China, the virus quickly spread worldwide and was announced as a pandemic by the World Health Organization (WHO) in 2020. Coronavirus disease 2019 (COVID-19) manifests with signs and symptoms ranging from mild, flu-like illness to acute respiratory distress, severe pneumonia, and death. The development of mRNA vaccines targeting the viral spike protein, a crucial mediator for viral entry, contributed to early pandemic control. However, as SARS-CoV-2 evolved, mutations in the spike protein reduced the neutralizing capacity of antibodies elicited by the initial vaccines, leading to the design and deployment of variant-matched vaccines including Wuhan-1/Omicron bivalent formulations and more recent monovalent Omicron XBB.1.5 and KP.2 vaccines. Although the goal of variant-matched vaccines is to enhance immunogenicity and protection against the variant strain, it is not clear whether variant-specific immunity is induced, or if such responses are limited by immune imprinting, in which prior exposure to ancestral antigens biases subsequent immune responses. During an initial encounter with SARS-CoV-2, naïve B cells recognizing spike proteins are activated and differentiate into antibody-secreting cells (ASCs) for rapid production of antibodies or differentiate into germinal center (GC) B cells that ultimately give rise to memory B cells (MBCs) and long-lived plasma cells (LLPCs). Upon secondary antigen exposures, MBCs are rapidly activated and initiate a recall response. In imprinted individuals, cross-reactive MBCs that recognize epitopes shared between the original and the secondary antigen are thought to outcompete and limit the activation of naïve B cells targeting epitopes unique to the secondary antigen. Multiple studies have suggested that SARS-CoV-2 infections and vaccinations result in imprinting effects on subsequent responses to variant strains. However, as these studies examined either the serum response as a whole or the specificity of MBCs, a key question remains as to whether variant-matched booster vaccines induce serum antibody responses that are cross-reactive or variant-specific, and how much each of these contribute to neutralization of the variant strain. In this study, we designed an antibody-depletion assay to isolate type-specific from cross-reactive antibodies. Using the assay, we characterized immune responses in mice and humans primed with the Wuhan-1-based mRNA-1273 vaccine and subsequently boosted with variant-matched vaccines. In mice, two priming doses of mRNA-1273 imprinted serum responses such that Omicron BA.1 boosters induced minimal variant-specific antibodies. However, imprinting was alleviated by a second dose of BA.1 booster. In humans who received two Omicron-matched boosters following two or more doses of mRNA-1273, strong imprinting was observed, with antibody responses largely cross-reactive to the Wuhan-1 strain. These cross-reactive antibodies neutralized Omicron variants and even distantly related sarbecoviruses, suggesting a potentially beneficial effect of imprinting in increasing the breadth of protection. Given the continued emergence of variant strains that evade neutralization provided by Wuhan-1-based vaccines, the induction of variant-specific immunity may be increasingly important. Thus, we also evaluated strategies to enhance variant-specific responses in mice imprinted by Wuhan-1-based vaccines and then boosted with variant-matched vaccines targeting XBB.1.5. Whereas extending the boosting interval or altering the intramuscular injection site did not noticeably improve variant-specific serum antibody responses, increasing booster antigen doses, administering repeated variant boosters, and delivering variant booster vaccines intranasally enhanced XBB.1.5-specific responses. Intranasal boosting with a chimpanzee adenoviral-vectored vaccine encoding the XBB.1.5 spike protein (ChAd-XBB.1.5) elicited stronger XBB.1.5-specific responses in serum, bronchoalveolar lavage fluid, and draining lymph nodes than intramuscular boosting with the same vaccine. Notably, and in contrast to earlier SARS-CoV-2 variants, neutralization of XBB.1.5 was mediated predominantly by XBB.1.5 spike-specific antibodies rather than those cross-reactive to Wuhan-1. These findings highlight the potential of intranasal or repeated variant-matched boosting to mitigate imprinting and improve protective immunity. Overall, this work provides new insights into how immune imprinting shapes humoral responses to variant vaccines and identifies strategies to enhance variant-specific immunity. These findings have important implications for the design of future vaccination regimens capable of achieving protection against current and emerging viral variants
A Computational Algorithm for Dead Time Correction in Fluorescence Lifetime Imaging Microscopy (FLIM)
No full textThis project aims to develop and implement a computational algorithm for dead time correction in fluorescence lifetime imaging microscopy (FLIM). In photon counting applications, dead time is the time after one photon is counted that another photon cannot be counted due to the limited bandwidth of the electronics that perform the photon counting. Existing dead time correction methods from Light Detection and Ranging (LiDAR) will be adapted to address the challenges in photon counting applications within FLIM. Specifically, an algorithm that compensates for the loss of photon data during the system\u27s dead time will be developed, leveraging statistical models of photon arrival. The project involves extensive computational work, including algorithm development, simulation, and evaluation using FLIM datasets. The ultimate goal is to enhance the accuracy of FLIM measurements
On Appreciating Evidence
Get PDFThe topic of this dissertation is the kind of understanding or grasping necessary for successfully using something as evidence. I call this kind of grasp “appreciation”. Take the case of a fossil. Intuitively, you can only successfully use a fossil as evidence for the existence of dinosaurs if you appreciate the epistemic link between the fossil and dinosaurs. If you fail to grasp the relevance of the fossil and you think it is just a rock with a funny pattern, you would not be justified to form the belief that dinosaurs once existed based on that fossil. However, what it takes to appreciate the relevance of evidence is unclear and no account exists of it in the literature on evidence or reasons. After developing an account of appreciation, I proceed to apply that account to mental states. It is often assumed that some mental states, like beliefs and perceptual experiences, can be used as evidence. For instance, seeing a dog in the park, or believing that there is a dog in the park, can be used as evidence that there are animals in the park. I investigate how we can appreciate the import of our own mental states for specific conclusions such that they can be used as evidence and argue that this is not as easy nor automatic as is often presumed
Induced CD8a Identifies Enhanced Human NK cell IL-15-induced Proliferation and Metabolism and Modulates NK cell Activation
Get PDFNatural Killer (NK) cells are cytotoxic innate lymphoid cells that play an important role in the surveillance and elimination of virally-infected and malignantly-transformed cells. These primary effector functions are achieved by producing cytokines and chemokines which activate and recruit additional immune effectors, as well as direct cytotoxic killing via perforin and granzymes. NK cell function is tightly regulated by a balance of germ-line encoded activating, inhibitory, co-stimulatory, and cytokine receptors expressed at the cell surface. Through these activating and inhibitory receptors, NK cells recognize and kill targets without prior sensitization through the loss of self-identifying molecules such as major histocompatibility complex (MHC) class I that bind to inhibitory receptors on NK cells (detection of ‘missing self’) or through the upregulation of ligands recognized by activating receptors on NK cells that can overcome inhibitory signals. The ability of NK cells to eliminate malignant cells has been established in the hematopoietic cell transplantation (HCT) setting, where a ‘graft vs leukemia’ effect can be exploited clinically through allogenic HCT and through adoptive NK cell therapy to treat hematologic malignancies such as acute myeloid leukemia (AML). NK cells briefly stimulated with the pro-inflammatory cytokines IL-12/15/18 become long-lived, memory-like (ML) NK cells with the ability to respond robustly upon reactivation with cytokines, activating receptors, or tumor target engagement, and further clinical trials have demonstrated their safety and efficacy as cellular therapy for AML. However, many of the factors that affect response versus treatment failure after ML NK cell therapy remain unknown. Unexpectedly, multidimensional immune correlatives revealed a novel, direct correlation between CD8α expression on donor ML NK cells and treatment failure. However, the impact of CD8α on human NK cell subsets, phenotype, and function are poorly understood. While CD8αβ has been extensively characterized on human and mouse T cells as a co-receptor for the T cell receptor (TCR), CD8α is not expressed on murine NK cells. Approximately 40% of human NK cells express a homodimeric CD8αα chain, and a much smaller fraction of NK cells (1-2%) express CD8αα. CD8αα contains an extracellular region that can bind to the conserved α3 region of HLA class I, a transmembrane domain, and a short cytoplasmic tail that interacts with the Src tyrosine kinase Lck. There are few and conflicting reports on the function of CD8α on the biology of human NK cells. Given the paucity of data on CD8α and human NK cells, and the striking negative association between CD8α expression and treatment response in our recent data, my thesis aimed to comprehensively elucidate the functional role of CD8α on conventional NK cells. Here, we show that CD8α marks a spectrum of functionality on human NK cells, and plays a functional, inhibitory role. We demonstrated that sorted CD8α- NK cells had superior tumor control of K562-engrafted NSG mice, and that this was likely mediated by an enhanced capacity for proliferation and survival of CD8α- NK cells. We observed that CD8α expression was dynamic and induced by IL-15, likely mediated by the transcription factor RUNX3. A subset of sorted CD8α- NK cells induced CD8α expression (‘induced’ or ‘iCD8α+’), while the remainder persisted as CD8α- (‘persistent CD8α- ‘), and those sorted CD8α+ sustained CD8α expression (‘sustained CD8α+’). Notably, NK cells with induced CD8α expression were the most proliferative in vitro and in vivo in NSG models. Mechanistically, we found that iCD8α NK cells had greater expression of IL-15Rb and gc components, which resulted in a greater induction of downstream signaling following IL-15 stimulation. Interestingly, we found that the differences in IL-15R expression were due to a preferential expansion and upregulation of CD8α in cells with greater pre-existing IL-15Rb expression. We demonstrated that these enhanced IL-15 signals corresponded to greater expression of nutrient receptors, glucose uptake, and overall metabolic activity. Further, we showed that this also translated to enhanced responses to tumor and cytokine stimulation in iCD8α+ NK cells, and this hyperfunctionality persisted even after three weeks in vivo. We also interrogated the functional role of CD8α using CRISPR-Cas9 deletion of CD8A in primary human NK cells, and did not identify a role in proliferation, survival, or responses to IL-15 signaling. However, we found that CD8 KO led to greater cytokine production and degranulation following activating receptor ligation, particularly through NKp30. This was likely mediated by CD8α enhancing the inhibitory function of KIR3DL1, rather than by abrogating activating receptor signaling. In summary, this thesis highlights a role for induced CD8α expression in marking a time-dependent functional capacity, in addition to identifying a novel role for CD8α in inhibiting NK activation. These findings highlight the importance of interrogating the dynamics of NK cell marker acquisition as they relate to functionality, particularly in the context of understanding NK cell biology and improving cellular therapies
Biophysical insights into immunoglobulin interactions with influenza viral proteins
No full textInfluenza viruses cause a significant burden across the globe leading to thousands of mortalities annually. It remains challenging to acquire long-lasting immunity against influenza viruses due to the rapid rate of mutation within circulating strains and limited protection provided by seasonal flu vaccines. While the generation of influenza-specific antibodies provides a major source of protection against viral infection, our understanding of how biophysical properties of antibody-antigen interaction influence antibody protection against influenza viruses remains elusive. To address these challenges, we first developed imaging-based approaches in combination with computational models to elucidate the extent and mechanism of antibody inhibition of influenza virus assembly and release. We found that, depending on the binding orientation and target location of the antibodies, multivalent antibodies could adopt two “crosslinking” modes to achieve inhibition of viral shedding. Additionally, by establishing an in vitro system to mimic the competition between soluble antibodies and B cell receptors, we identified physical constraints that could limit effective B cell responses during repeated exposures to influenza viral antigens. Particularly, we found that membrane-proximal viral epitopes are at an inherent disadvantage for B cell recognition, due to steric hindrance by both directly and non-directly competing antibodies. Together, these insights call attention to the multi-faceted roles of antibodies in generation of long-lasting protection against influenza viral infection, highlighting the importance of optimizing epitope accessibility in current vaccine design strategies
Advancing Predictive Modeling with Deep Representation Learning on Diverse Clinical Data
Get PDFElectronic health records (EHRs) provide a wealth of information crucial for enhancing clinical decisions, patient outcomes, and healthcare efficiency. However, leveraging EHR data for predictive modeling involves significant challenges, including managing imbalanced and incomplete data, effectively integrating heterogeneous data types, efficiently capturing temporal and hierarchical structures, and ensuring the interpretability and clinical reliability of predictive outcomes. This dissertation addresses these critical challenges by proposing novel deep representation learning frameworks specifically designed for clinical predictive modeling from diverse EHR data. By integrating sophisticated deep learning techniques, this research demonstrates innovative deep learning modeling approaches and delivers tangible improvements in clinical predictive performance. The dissertation applies these novel frameworks to address three significant, real-world clinical problems: intraoperative hypoxemia prediction, physician burnout prediction, and antimicrobial resistance (AMR) prediction in sepsis patients. For intraoperative hypoxemia prediction, it introduces a Hybrid Inference Network (HiNet), a memory-augmented model designed to robustly predict rare but critical events like hypoxemia, significantly outperforming existing predictive approaches and enhancing clinical decision-making during surgery. For physician burnout prediction, it proposes the Hierarchical Physician Activity Logs (HiPAL) framework, which leverages hierarchical temporal sequence modeling and unsupervised clinical activity embeddings to deliver end-to-end burnout predictions based on raw EHR activity logs, enabling targeted clinical interventions to improve physician well-being and healthcare quality. Finally, to address AMR prediction in sepsis care, the Multimodal Contrastive Clinical Representation Learning (MOCCA) framework is developed, which effectively integrates structured EHR data, clinical notes, and physiological signals through a reliable cross-modal contrastive learning mechanism. The proposed framework shows promise in guiding effective antimicrobial therapies for sepsis patients and improving care quality. Overall, this dissertation contributes to the fields of applied machine learning and healthcare analytics by advancing reliable and clinically impactful predictive models that effectively harness diverse EHR data
Rotavirus Pathogenesis and Broad-Spectrum Antiviral Exploration: Insights from Molecular and Cellular Studies
No full textRotavirus (RV) is a non-enveloped, double-stranded RNA virus that infects mature intestinal epithelial cells (IECs) and induces diarrhea and gastroenteritis in young mammals, including humans. Meanwhile, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, is mostly regarded as a respiratory virus but also infects IECs, which might explain the gastrointestinal symptoms observed in COVID-19 patients. In the first study, we conducted a small-molecule inhibitor screen of about 200 molecules against SARS-CoV-2 and discovered the broad antiviral activities of JIB-04, a molecule formerly known as an anti-tumor agent, which also inhibits the infection of other viruses including RV and enteric coronaviruses. Additionally, we established how RV induces diarrhea in the absence of viral replication in neonatal mice, showing that sensing of double-stranded RNA in IECs triggers a type III interferon response and water malabsorption. Lastly, we explored the potential RV antagonism of gasdermin D, which is the final effector of the inflammasome pathway and plays an important role in the host innate immune response against RV. Overall, this dissertation covers enteric viral pathogenesis in both fundamental and translational aspects, highlighting host and viral factors that could be targeted for further therapeutic development
Afflicted Epistemology: Knowledge, Illness, and New Media After “Truth”
Get PDFThis study examines how people living with complex, medically underdetermined chronic illnesses make sense of their experiences through self-experimentation mediated by online forums and self-help groups in a cultural context characterized by significant controversy surrounding the status of science, expertise, and conventionally authoritative knowledge-producing institutions. Using virtual and conventional ethnography and critical media studies methods, it finds that the fragmentary and decentralized nature of the U.S. healthcare system intensified the interpretive challenges associated with complex chronic illnesses: information was extremely abundant, but deciphering its accuracy, reliability, and relevance proved difficult. In this context, participants relied on experiential knowledge to filter, mediate, and make sense of knowledge from other sources. Placing these findings in the historical context of ubiquitous medical pluralism in the U.S. and globally, I argue that what is unique about medical science in the present is not its coexistence with other modalities of healing, but its imbrication in an inherently fragmentary information technology ecosystem. Drawing on medical anthropology and postcolonial science and technology studies, I argue that medical pluralism itself is not inherently threatening to or incompatible with biomedicine or biomedical public health goals. Further, the ethnographic data strongly suggest that, for this population, it is not alternative epistemologies or anti-science ideology that drive people away from biomedicine, but lack of access to quality care. Information infrastructures that support discernment and improved biomedical care are more likely to result in increased trust in and uptake of biomedicine, regardless of whether or not patients also engage other modalities of healing
Biophysical insights into emerging virus-host interactions
No full textLarge-scale viral outbreaks present significant threats to human health and the stability of our healthcare systems. Such outbreaks are exacerbated by the rapidity with which diseases can spread, facilitated by modern domestic and international travel. In the wake of the recent pandemic, it is likely that the next major viral challenge will be caused by a pathogen with which we have some, albeit limited, familiarity. It is crucial to investigate the biophysical and structural interactions between viruses and their hosts to develop effective therapeutics and vaccines, thereby protecting our most vulnerable populations. We have identified several viruses, monkeypox virus and human astrovirus, that have demonstrated their potential for large-scale circulation but have been historically understudied. Cases of monkeypox virus have been on the rise worldwide since late 2021, and there are currently no vaccines or antiviral against human astroviruses. In this context, I examine the immune evasion mechanisms of the monkeypox virus and the virus-receptor interactions of classical human astroviruses (HAstVs). Poxviruses are double-stranded DNA viruses that cause sores and blisters on infected individuals and are considered contagious among their respective hosts. These viruses have extremely large genomes, averaging 200 open reading frames (ORFs), with the majority of ORFs important for replication and assembly of the virus concentrated in the middle of the genome. The ORFs located at the terminal regions of the genome encode for a broad array of proteins that serve to evade the host immune system. The Fremont lab previously identified a structural scaffold in unrelated poxviral proteins that bore no structural relation to any eukaryotic or prokaryotic protein. Although these proteins share a conserved β-sandwich fold, they appear to offer a diverse range of functions and ligands, all under the umbrella of incapacitating the host immune defenses. This scaffold is called the poxvirus immune evasion (PIE) domain. Monkeypox virus (MPXV) is the causative agent of the smallpox-related disease mpox in humans and has been the cause of recent 2022-2023 and 2024 outbreaks in both endemic and non-endemic countries, including the USA. The smallpox vaccine, which has not been regularly administered since 1980, provided cross-protection against other poxviruses, including MPXV. As such, the majority of people do not have immunity against MPXV, allowing its spread from human-to-human transmission. MPXV’s immune evasion strategies are not well-studied, and the virus encodes for several PIE proteins. One of these is an ortholog for vCCI, one of the most extensively studied PIE proteins, well-known for its ability to bind to chemokines, which are an important part of anti-viral defense. Here, we characterize the chemokine binding of several PIE proteins from MPXV. We assessed six PIE proteins from MPXV: vCCI, A41, CrmB, M2, Scp-1, and Scp-3. The chemokine binding of these PIEs against 46 chemokines revealed three PIEs capable of forming kinetically stable, long-lasting complexes with multiple chemokines: vCCI, A41, and CrmB. Scp-1 and Scp-3 had no specific interaction with any chemokines, while M2 appeared to have a weak signal with two chemokines. We determined that MPXV-encoded vCCI binds its own distinct set of chemokines with nanomolar affinities and long half-lives, while A41 and CrmB had more overlap among the chemokines they bind with a wide range of kinetics. Interestingly, the chemokines that A41/CrmB had the highest affinities for were the same ones that vCCI had the lowest affinities for. However, the varying degree of chemokine binding observed for A41 and CrmB suggests that this might be a vestigial function, and that their primary immunological function is yet to be identified. Still, these results show that MPXV selectively targets different elements of host chemokine networks during its pathogenesis and paves the way to better understand how PIE proteins are important for MPXV vaccine efforts and can even act as immunomodulatory therapeutics. In addition to these studies, we investigated the host receptor(s) for human astroviruses (HAstVs), which has gone unidentified for almost 50 years. Human astroviruses are major causes of gastroenteritis worldwide, especially in children and the elderly. They were initially identified in 1975 in the fecal matter of ill children. They can be broadly divided into two categories: classical (HAstV1-8) and nonclassical (MLB1-3/VA1-5). Seroprevalence studies show that the majority of adults have been infected with at least one HAstV in childhood, although they are extremely likely to be infected with more than one over the course of a lifetime. Additionally, nonclassical HAstVs, which are highly divergent and novel from classical HAstVs, cause neurological complications such as encephalitis and meningitis in immunocompromised individuals. Outbreaks of HAstV happen frequently at daycares, schools, and nursing homes. HAstVs are just one type of astrovirus, and over 20 species can be infected by astroviruses. Additionally, evolutionary analyses suggest that there have been extensive cross-species events of astrovirus between animal species and humans. Very little is known about host factors required for HAstV cellular entry. Members of the Baldridge lab utilized complementary CRISPR-Cas9-based knockout and activation screens to identify neonatal Fc receptor (FcRn) and dipeptidyl-peptidase IV (DPP4) as entry factors for HAstV1 and HAstV8 infection of human intestinal epithelial cell lines. Disruption of FcRn or DPP4 using single-guide RNAs reduced HAstV infection in permissive cells. Reciprocally, overexpression of these factors in HEK293, which were previously non-permissive, was sufficient to promote infection. We investigated direct binding between HAstV virions with both entry factors but found that only FcRn had a significant binding signal. We saw this same trend again using purified spike protein against both FcRn and DPP4, and found no binding between HAstV1/8 spike and DPP4. This suggests that FcRn is a receptor for HAstVs while DPP4’s role remains unclear. Finally, inhibitors for DPP4 and FcRn currently in clinical use prevented HAstV1 and HAstV8 infection in cell lines and human enteroids. Thus, our results reveal mechanisms of HAstV entry as well as druggable targets to limit HAstV infection. We biophysically assessed FcRn against spike proteins from classical and nonclassical HAstVs. All spike proteins from classical HAstVs bound to FcRn in a specific and saturable manner, while the nonclassical spikes had little to no interaction with FcRn, suggesting that they may utilize different host factors. Furthermore, there is a ~3-fold increase is binding affinity between HAstV1 and FcRn at pH 5.5, which is the pH of late-endosomal compartments. Lastly, we structurally characterized the interaction between FcRn and mature HAstV1 using cryo-EM reconstructions of HAstV1 alone and in complex with FcRn. We determined a 2.77 Å resolution cryo-EM reconstruction of the capsid protein assembled as a trimer. 60 of these trimers organize with T=3 icosahedral symmetry, and feature positively charged coiled-coil bundles at their N-terminal region that project into the core where they likely interact with viral RNA. We found that there are no structural differences in the capsid shell of HAstV1 with or without FcRn. HAstV1 displays 30 dimeric spikes protruding from the 2-fold axes of the mature virion, with deep clefts between the 3- and 5-fold axes, facilitating the protease-mediated removal of the other 60 spike dimers found on the immature virion. We determined a 5 to 9 Å resolution cryo-EM reconstruction of FcRn in complex with HAstV1, the low resolution likely caused by mobility of the spike due to the linker region connecting it to capsid protein. FcRn engages with HAstV1 spikes in a 2:2 stoichiometry, sitting to the sides of the spike dimer. Through competition and mutational assays, we found that FcRn utilizes the same determinants to interact with both HAstV1 spike and IgG. The interaction of FcRn with both IgG and serum albumin is highly pH-dependent, allowing these proteins to be recycled from early endosomes to the plasma membrane for release. In contrast, FcRn binding to the HAstV1 spike is only mildly pH-dependent, potentially providing a mechanism to protect virions from lysosomal degradation as well as plasma membrane release. In summary, these studies reveal how two different viruses, monkeypox virus and human astrovirus, interact with a human host from two different angles: how one evades the host immune system and how one interacts with its entry receptor, respectively. By employing a biophysical approach to these emergent and re-emergent viruses, we enhance our quantitative understanding of their host interactions, thereby providing a more solid foundation for future therapies and vaccines