All Publications

  • Development of ACE2-tropic-betacoronavirus therapeutics for future pandemic preparedness. Nature communications Utz, A., Armbrust, M., Nguyen, T. T., Morris, M. K., Matthews, C. O., Kompella, P., Cao, Z., Ha, J. W., Violette, A., Brewer, R. C., Lanz, T. V., Robinson, W. H., Xu, D., Hanson, C., Hugenmatter, A., Kim, P. S. 2025

    Abstract

    A major challenge during viral pandemics is the ability to develop therapeutics whose efficacy can withstand viral genetic evolution. During the COVID-19 pandemic, five SARS-CoV-2 monoclonal antibody (mAb) therapeutics were rendered ineffective within a period of 2 years, leading to the U.S. FDA revoking their emergency use authorization. Here, we describe ReconnAb-multimers, a new therapeutic design that broadly and potently neutralize all tested betacoronaviruses that use host ACE2 as their receptor to enter cells. These ReconnAb-multimers have potent neutralization efficacy via avidity, enhanced breadth via a new pan-betacoronavirus-binding antibody that targets a highly conserved epitope on SARS-CoV-2 spike protein, and the potential for clinical development by using a catalytically inactive ACE2 component. We demonstrate that ReconnAb-multimers neutralize all SARS-CoV-2 pseudoviruses and authentic viral variants of concern (VOC) tested, with similar or higher potency than mAbs previously approved by the FDA; neutralize related pandemic-potential betacoronaviruses, including SARS-CoV, WIV1-CoV, PRD-0038, and merbecovirus HKU5-CoV-2; and despite a short half-life, protect female mice against authentic viral challenge with Omicron variant XBB.1.5. Our results highlight ReconnAb-multimers as a broad and highly potent therapeutic that could potentially withstand viral escape against current and future betacoronaviruses that require host ACE2 as a receptor.

    View details for DOI 10.1038/s41467-025-66805-6

    View details for PubMedID 41318533

  • Genome-scale resources in the infant gut symbiont Bifidobacterium breve reveal genetic determinants of colonization and host-microbe interactions. Cell Shiver, A. L., Sun, J., Culver, R., Violette, A., Wynter, C., Nieckarz, M., Mattiello, S. P., Sekhon, P. K., Bottacini, F., Friess, L., Carlson, H. K., Wong, D. P., Higginbottom, S., Weglarz, M., Wang, W., Knapp, B. D., Guiberson, E., Sanchez, J., Huang, P. H., Garcia, P. A., Buie, C. R., Good, B. H., DeFelice, B., Cava, F., Scaria, J., Sonnenburg, J. L., Van Sinderen, D., Deutschbauer, A. M., Huang, K. C. 2025

    Abstract

    Bifidobacteria represent a dominant constituent of human gut microbiomes during infancy, influencing nutrition, immune development, and resistance to infection. Despite interest in bifidobacteria as a live biotic therapy, our understanding of colonization, host-microbe interactions, and the health-promoting effects of bifidobacteria is limited. To address these major knowledge gaps, we used a large-scale genetic approach to create a mutant fitness compendium in Bifidobacterium breve. First, we generated a high-density randomly barcoded transposon insertion pool and used it to determine fitness requirements during colonization of germ-free mice and chickens with multiple diets and in response to hundreds of in vitro perturbations. Second, to enable mechanistic investigation, we constructed an ordered collection of insertion strains covering 1,462 genes. We leveraged these tools to reveal community- and diet-specific requirements for colonization and to connect the production of immunomodulatory molecules to growth benefits. These resources will catalyze future investigations of this important beneficial microbe.

    View details for DOI 10.1016/j.cell.2025.02.010

    View details for PubMedID 40068681

  • Improved mouse models of the small intestine microbiota using region-specific sampling from humans. bioRxiv : the preprint server for biology Culver, R. N., Spencer, S. P., Violette, A., Lemus Silva, E. G., Takeuchi, T., Nafarzadegan, C., Higginbottom, S. K., Shalon, D., Sonnenburg, J., Huang, K. C. 2024

    Abstract

    Our understanding of region-specific microbial function within the gut is limited due to reliance on stool. Using a recently developed capsule device, we exploit regional sampling from the human intestines to develop models for interrogating small intestine (SI) microbiota composition and function. In vitro culturing of human intestinal contents produced stable, representative communities that robustly colonize the SI of germ-free mice. During mouse colonization, the combination of SI and stool microbes altered gut microbiota composition, functional capacity, and response to diet, resulting in increased diversity and reproducibility of SI colonization relative to stool microbes alone. Using a diverse strain library representative of the human SI microbiota, we constructed defined communities with taxa that largely exhibited the expected regional preferences. Response to a fiber-deficient diet was region-specific and reflected strain-specific fiber-processing and host mucus-degrading capabilities, suggesting that dietary fiber is critical for maintaining SI microbiota homeostasis. These tools should advance mechanistic modeling of the human SI microbiota and its role in disease and dietary responses.

    View details for DOI 10.1101/2024.04.24.590999

    View details for PubMedID 38712253

  • A mutant fitness compendium in Bifidobacteria reveals molecular determinants of colonization and host-microbe interactions. bioRxiv : the preprint server for biology Shiver, A. L., Sun, J., Culver, R., Violette, A., Wynter, C., Nieckarz, M., Mattiello, S. P., Sekhon, P. K., Friess, L., Carlson, H. K., Wong, D., Higginbottom, S., Weglarz, M., Wang, W., Knapp, B. D., Guiberson, E., Sanchez, J., Huang, P. H., Garcia, P. A., Buie, C. R., Good, B., DeFelice, B., Cava, F., Scaria, J., Sonnenburg, J., Sinderen, D. V., Deutschbauer, A. M., Huang, K. C. 2023

    Abstract

    Bifidobacteria commonly represent a dominant constituent of human gut microbiomes during infancy, influencing nutrition, immune development, and resistance to infection. Despite interest as a probiotic therapy, predicting the nutritional requirements and health-promoting effects of Bifidobacteria is challenging due to major knowledge gaps. To overcome these deficiencies, we used large-scale genetics to create a compendium of mutant fitness in Bifidobacterium breve (Bb). We generated a high density, randomly barcoded transposon insertion pool in Bb, and used this pool to determine Bb fitness requirements during colonization of germ-free mice and chickens with multiple diets and in response to hundreds of in vitro perturbations. To enable mechanistic investigation, we constructed an ordered collection of insertion strains covering 1462 genes. We leveraged these tools to improve models of metabolic pathways, reveal unexpected host- and diet-specific requirements for colonization, and connect the production of immunomodulatory molecules to growth benefits. These resources will greatly reduce the barrier to future investigations of this important beneficial microbe.

    View details for DOI 10.1101/2023.08.29.555234

    View details for PubMedID 37693407

    View details for PubMedCentralID PMC10491234

https://orcid.org/0009-0004-9561-8926