Biology subjects

Cho, R. H.

Publications and source records attributed to Cho, R. H..

3 recordsLinked to original sources

bioRxiv2026

Inducible nitric oxide synthase (iNOS) regulates skin eschar lesions, bacterial persistence, and inflammatory resolution in mouse models of scrub typhus

Orientia tsutsugamushi (Ot) is an obligately intracellular bacterium that causes scrub typhus, a potentially severe infectious disease characterized by systemic inflammation and multiorgan dysfunction. We recently reported a protective role for IFN-{gamma} signaling in host defense against Ot infection; however, the underlying mechanisms remain obscure. Inducible nitric oxide synthase (iNOS, encoded by Nos2) is a key antimicrobial effector induced downstream of IFN-{gamma} signaling. Here, we used transgenic mouse models to further investigate the biological functions of iNOS. We first revealed the requirement of iNOS for the restriction of Ot growth in cultured bone marrow-derived macrophages. Using an intradermal mouse model, we found that while tissues of Nos2-/- and wild-type mice exhibited comparable bacterial burdens during acute infection phases, Nos2-/- mice developed eschar-like lesions similar to those observed in Ifngr1-/- mice, indicating a critical role for the IFN-{gamma}/iNOS axis in regulating skin pathology in scrub typhus. Notably, Nos2-/- mice displayed impaired bacterial clearance during the recovery phase (day 42), with persistent bacterial burdens in multiple organs accompanied by sustained immune activation and elevated inflammatory responses. Histopathological and biochemical analyses further revealed increased tissue damage and dysregulated physiological homeostasis in Nos2-/- mice during recovery. Mechanistically, iNOS deficiency resulted in heightened myeloid cell activation and prolonged expression of proinflammatory mediators, suggesting a dual contribution of iNOS in both antimicrobial defense and inflammation resolution. Collectively, these findings provide new insight into IFN-{gamma}-mediated defense mechanisms and imply the distinct roles of iNOS during different stages of scrub typhus. Author summaryScrub typhus is a potentially severe infectious disease caused by the bacterium Orientia tsutsugamushi (Ot), which is transmitted to humans through the bite of infected mites. Despite its global impact and expanding geographic distribution, the immune mechanisms that protect against this infection remain incompletely understood. In this study, we examined the role of inducible nitric oxide synthase (iNOS), an immune effector molecule that helps the host control infection. Using mouse models, we found that iNOS plays dual and stage-specific roles during Ot infection. Mice lacking iNOS developed dysregulated immune homeostasis during acute infection and exhibited skin lesions resembling the eschars observed in some patients with scrub typhus. In addition, these mice showed delayed bacterial clearance, prolonged inflammation, and increased tissue damage during the recovery phase. Our findings indicate that iNOS contributes not only to host antimicrobial defense but also to the control of excessive inflammation following infection. These results provide new insight into host defense mechanisms in scrub typhus and may help inform future therapeutic or preventive strategies.

immunology↗

bioRxiv2026

Next generation protein-corrole bio-assemblies provide effective tumoricidal treatment in a metastatic triple-negative breast cancer model

Assemblies that combine chemotherapeutics with tumor-targeting proteins are promising agents for treating resistant cancers but require full biochemical characterization before therapeutic deployment. We developed and optimized a HER3-targeting capsomere, HPK2.0, which forms stable nanoscale assemblies with cytotoxic corroles via electrostatic neutralization and shape complementarity. These nanocomplexes exhibit durable serum stability, HER3-dependent tumor invasion, and efficient endosomal escape, resulting in potent and selective cytotoxicity in triple-negative breast cancer (TNBC) cells. In an orthotopic metastatic TNBC model, systemic treatment with HPK2.0-corrole assemblies achieved 67-83% tumor regression, near-complete suppression of spontaneous lung metastasis, and a [~]2-fold improvement in survival relative to mock treatment, with minimal off-target toxicity. By integrating tumor specificity with therapeutic potency, this next-generation protein-corrole platform establishes a clinically scalable strategy for treating metastatic HER3-positive TNBC. SignificanceTriple-negative breast cancer (TNBC) is an aggressive disease with high rates of metastasis and mortality, largely because it lacks molecular targets for precision therapy. As a result, patients rely primarily on chemotherapy, which causes systemic toxicity and frequently fails to control metastatic spread. Here, we introduce a targeted therapeutic strategy in which a bioengineered protein selectively recognizes a receptor highly expressed in metastatic TNBC and delivers a potent cytotoxic payload directly into tumor cells. In mouse models, this approach produced robust tumor regression, markedly reduced lung metastases, extended survival, and showed minimal off-target toxicity. These findings establish a versatile platform for targeted treatment of TNBC and highlight a strategy that may be broadly applicable to other HER3-expressing cancers.

cancer biology↗

bioRxiv2025

A Humanized IFN-γ Mouse Model Reveals Skin Eschar Formation, Enhanced Susceptibility and Scrub Typhus Pathogenesis

Scrub typhus, caused by Orientia tsutsugamushi (Ot) bacteria, is a serious acute febrile illness associated with significant mortality. An estimated one million cases occur annually, with more than one billion people at risk. No effective vaccine is currently available, largely due to the complex Ot strain diversity and an incomplete understanding of protective immune mechanisms. To overcome these challenges, there is a critical need for a suitable animal model that mimics human disease through the natural route of infection via mites. Here, we report for the first time that a genetically engineered humanized mouse strain (with triple knockout/knock-in of IFN-{gamma} and its receptors), exhibits increased susceptibility to intradermal Ot infection compared to wild-type (WT) mice. This is evidenced by greater body weight loss, elevated bacterial burden, and reduced expression of interferon-stimulated genes (ISGs). Humanized mice exhibit pronounced biochemical abnormalities and tissue pathology accompanied by dysregulated T cell and neutrophil responses following infection. Notably, these immunocompetent mice develop skin eschar-like lesions resembling those observed in human patients. Overall, our study introduces a promising humanized mouse model to dissect the immunopathogenesis of scrub typhus and evaluate future vaccine candidates. Author SummaryScrub typhus is a serious disease caused by the obligately intracellular bacterium Ot that spreads to humans through the bite of larval mites called chiggers. It affects over a million people each year, primarily in Asia, and can lead to life-threatening complications. Unfortunately, we still lack a clear understanding of how this infection causes disease, partly because there is not a good laboratory model that closely reflects how humans respond to infection. Our recent reports have suggested an important role of IFN-{gamma} in host protection against Ot infection. In this study, we used a new genetically modified mouse strain that carries human IFN-{gamma} signaling in place of its mouse counterpart. We found that these humanized mice are more vulnerable to infection, develop skin eschar lesions like those in patients, and show signs of systemic inflammation and organ damage. Their immune response also resembled what has been observed in human patients. This new mouse model can help scientists better understand the mechanisms as to how this bacterial species causes severe disease outcomes in patients. Once those mechanisms are understood, this mouse model will serve a further purpose as a tool for testing new vaccines and treatments to aid humans at-risk for scrub typhus.

immunology↗