Biology subjects

Miller, H. A.

Publications and source records attributed to Miller, H. A..

5 recordsLinked to original sources

bioRxiv2026

Comprehensive Profiling of Monkeypox Virus Antigens Identifies Potent Targets for Next-Generation mRNA Vaccine Development

The 2022 Monkeypox virus (MPXV) outbreak renewed interest in vaccines for orthopoxviruses. Initial development efforts focused on well-established antigen targets, especially A35, B6, and M1. However, orthopoxvirus surfaces are complex, displaying many antigens across two infectious forms, mature virions (MV) and extracellular virions (EV) and targets relevant to protection remain to be comprehensively defined. We leveraged advances in orthopoxvirus protein biology and mRNA vaccine technology to compare immunity to all feasible targets. Mice were immunized with mRNAs encoding each antigen, or antigen complex, and neutralizing antibody responses were measured prior to heterologous challenge with vaccinia virus. Among MV antigens, A28 induced potent complement-mediated neutralizing antibodies, and the A17:G10 complex induced neutralizing antibodies and protected from challenge. For EV antigens, A36 induced neutralizing antibodies and protected from challenge. Our results affirm the consensus strategy focusing on key antigens while highlighting additional targets that could enhance updated MPXV mRNA vaccines. SIGNIFICANCEMonkeypox virus, a member of the Orthopoxvirus genus along with variola virus, has been associated with two recent outbreaks of mpox disease leading to a renewed focus on orthopoxvirus vaccine development. We report an agnostic screen of all monkeypox virus surface antigens where we combined recent advances in structural biology and mRNA technology to evaluate these potential new vaccine targets. We confirmed that historically prioritized antigens M1, A35 and B6 were protective but also discovered new antigens of interest including A28, the A17:G10 complex and A36 that can be the targets of protective immune responses. These findings are critical to inform next-generation vaccine designs should novel orthopoxviruses emerge as human pathogens.

microbiology↗

bioRxiv2026

Multi-dimensional optimization of a lysin towards a ribolysin against life-threatening S. aureus infections: Fc-LysM-CHAP and its strong synergy with standard of care antibiotics

Bacterial lysins are promising novel antimicrobials but are limited by poor pharmacokinetics and challenging manufacturability. We developed a lysin discovery platform tailored for lysin delivery via mRNA: staphylococcal LysM-CHAP (cysteine, histidine-dependent amidohydrolases/peptidase) autolysin was selected and its serum half-life extended via Immunoglobulin G1-Fc-fusion. The Fc-induced drop in lysin potency was rescued by the concerted optimization of linkers, binding kinetics and catalytic activity, using a combination of rational and AI-guided approaches. The engineered Fc-LysM-CHAP was active against planktonic bacteria (minimum inhibitory concentration of 1 - 2 {micro}g/mL) and simulated endocardial vegetations and synergized strongly (Fractional eradication concentration index FECI = 0.06) with cell wall active antibiotics in vitro. In mouse models of Staphylococcus aureus sepsis, the recombinant Fc-LysM-CHAP - antibiotic combination was superior to single agent treatments and mRNA-delivered Fc-LysM-CHAP showed single agent activity at a mRNA-lipid nanoparticle dose as low as 0.2 mg/kg.

microbiology↗

bioRxiv2025

The hypoxic response extends lifespan through a bioaminergic and peptidergic neural circuit.

A coordinated response to stress is crucial for promoting the short- and long-term health of an organism. The perception of stress, frequently through the nervous system, can lead to physiological changes that are fundamental to maintaining homeostasis. Activating the response to low oxygen, or hypoxia, extends healthspan and lifespan in C. elegans. However, despite some positive impacts, negative effects of the hypoxic response in specific tissues prevent translation of their benefits in mammals. Thus, it is imperative to identify which components of this response promote longevity. Here, we interrogate the cell-nonautonomous signaling pathway downstream of genetic activation of the hypoxic response. We find that HIF-1-mediated signaling in ADF serotonergic neurons is both necessary and sufficient for lifespan extension. Signaling through the serotonin receptor SER-7 in the GABAergic RIS interneurons is necessary in this process. Our findings also highlight the involvement of additional neural signaling molecules, including the neurotransmitters tyramine and GABA, and the neuropeptide NLP-17, in mediating longevity effects. Finally, we demonstrate that oxygen- and carbon-dioxide-sensing neurons act downstream of HIF-1 in this circuit. Together, these insights develop a circuit for how genetic induction of the hypoxic response cell-nonautonomously modulates aging and suggests valuable targets for modulating aging in mammals.

physiology↗

bioRxiv2021

FMO rewires metabolism to promote longevity throughtryptophan and one carbon metabolism

Flavin containing monooxygenases (FMOs) are promiscuous enzymes known for metabolizing a wide range of exogenous compounds. In C. elegans, fmo-2 expression increases lifespan and healthspan downstream of multiple longevity-promoting pathways through an unknown mechanism. Here, we report that, contrary to its classification as a xenobiotic enzyme, fmo-2 expression leads to rewiring of endogenous metabolism principally through changes in one carbon metabolism (OCM). Using computer modeling, we identify decreased methylation as the major OCM flux modified by FMO-2 that is sufficient to recapitulate its longevity benefits. We further find that tryptophan is decreased in multiple mammalian FMO overexpression models and is a validated substrate for FMO enzymes. Our resulting model connects a single enzyme to two previously unconnected key metabolic pathways and provides a framework for the metabolic interconnectivity of longevity-promoting pathways such as dietary restriction. FMOs are well-conserved enzymes that are also induced by lifespan-extending interventions in mice, supporting a conserved and critical role in promoting health and longevity through metabolic remodeling.

molecular biology↗

bioRxiv2021

Serotonin and dopamine modulate aging in response to food perception and availability

An organisms ability to perceive and respond to changes in its environment is crucial for its health and survival. Here we reveal how the most well-studied longevity intervention, dietary restriction (DR), acts in-part through a cell non-autonomous signaling pathway that is inhibited by the perception of attractive smells. Using an intestinal reporter for a key gene induced by DR but suppressed by attractive smells, we identify three compounds that block food perception in C. elegans, thereby increasing longevity as DR mimetics. These compounds clearly implicate serotonin and dopamine in limiting lifespan in response to food perception. We further identify an enteric neuron in this pathway that signals through the serotonin receptor 5-HT1A/ser-4 and dopamine receptor DRD2/dop-3. Aspects of this pathway are conserved in D. melanogaster and mammalian cells. Thus, blocking food perception through antagonism of serotonin or dopamine receptors is a plausible approach to mimic the benefits of dietary restriction.

molecular biology↗