Biology subjects

Golden, N. A.

Publications and source records attributed to Golden, N. A..

4 recordsLinked to original sources

bioRxiv2026

Metabolic reprogramming by caloric restriction enhances acute phase virological control and reduces chronic inflammation in SIV-infected rhesus macaques

Nutrient metabolism influences HIV-1 replication, antiviral immunity, and chronic inflammation, yet is difficult to leverage for therapeutic gain. We sought to modulate metabolism in the non-human primate model of HIV-1 by caloric restriction (CR), a modality canonically known for its antiaging benefits. Four months of 30% CR was safe and resulted in broad and systemic metabolic reprogramming in healthy adult male and female rhesus macaques. Relative to that of ad libitum-fed animals, CR lowered the frequencies of target CCR5+ CD4 T cells in the gut mucosa. Upon infection with SIV, CR reduced acute phase viremia, dampened type I interferon signaling, and overall permitted a more vigorous cycling of CD8+ T cells in lymphoid tissues. CR-induced protection from SIV was associated with a robust up-regulation of glycolysis, which supported an early reduction in viremia that ultimately waned over time. During virologic suppression with antiretroviral therapy (ART), CR significantly limited gastrointestinal (GI) immune activation, improved tricarboxylic acid cycle flux, and lowered concentrations of soluble CD14 and several TNF-related molecules in plasma. Blood SIV DNA levels however were unchanged by CR, suggesting that residual GI dysfunction and inflammation can be decoupled from viral persistence. Our findings highlight that a dietary modality can limit pathology in a primate lentiviral infection. They also reveal the robust but temporally constrained nature of glycolysis in supporting an acute antiviral response. SIGNIFICANCECaloric restriction (CR) is a safe dietary intervention known to confer anti-aging and health benefits across diverse animal models. However, its application in the context of infectious diseases has yielded mixed outcomes and has largely been limited to murine systems. In this study, we therefore employed CR to examine the impact of dietary modulation on SIV infection outcomes. Our findings demonstrate that CR reduced acute-phase viremia and attenuated markers of chronic inflammation following ART, effects that were associated with distinct metabolic signatures. Collectively, these findings underscore the importance of diet and nutrition in shaping chronic viral infection outcomes, such as SIV, within a clinically relevant non-human primate model.

immunology↗

bioRxiv2025

Therapeutic remodeling of the tuberculosis granuloma with 1-methyl-D-tryptophan enhances CD8+ T cell-macrophage interactions

Granulomas, the hallmark of tuberculosis (TB) disease, can both restrict Mycobacterium tuberculosis (Mtb) dissemination and impede its clearance. Recent studies indicate that indoleamine 2,3-dioxygenase (IDO1), an immunosuppressive metabolic enzyme, limits infiltration of activated T cells and can contribute to TB disease progression. Treatment with 1-methyl-D-tryptophan (D-1MT), a small molecule inhibitor that restores mTOR signaling, has been shown to improve immune responses Mtb-infected rhesus macaques. Here, we investigated the impact of D-1MT treatment on TB granuloma architecture using 30-plex high-dimensional issue imaging in rhesus macaques. By spatially mapping 13 distinct cell populations, we found D-1MT treatment corresponded with significantly increased infiltration CD8+ T cells into granulomas compared to untreated controls. Notably, these CD8+ T cells expressed markers of cell proliferation and cytotoxicity. D-1MT enhanced CD8+ T cell infiltration throughout the granuloma, with particularly pronounced effects in the myeloid core, where we observed significantly enhanced spatial interactions between macrophages and CD8+, but not CD4+ T cells. Our results demonstrate that: (i) effective intra-granulomatous Mtb control is associated with the close spatial proximity between CD8+ T cells and macrophages, a feature less abundant in uncontrolled pulmonary TB; (ii) IDO1 induction blocks CD8+ T cell infiltration and reduces T cell activation and proliferation; and (iii) therapeutic strategies, including D-1MT, that improve intra-granulomatous killing hold strong translational potential. Significance statementOur understanding of immune mechanisms within the TB granuloma has advanced greatly with the advent of high-resolution single cell multiplexed imaging. Using such imaging, we show that TB granulomas in rhesus macaques, a highly translational model of human TB pathology, are characterized by IDO1-mediated immunoregulation. Early pharmacologic restoration of mTOR signaling via D-1MT treatment can reduce IDO1 enzymatic activity and facilitate the recruitment and function of CD8+ T cells within the granulomas. These findings reveal specific mechanisms exploited by Mtb to maintain intra-granuloma persistence and underscore immune responses. Future vaccine and therapeutic design should consider these immunoregulatory features to achieve better control of Mtb infection.

immunology↗

bioRxiv2021

An Orally Available Cathepsin L Inhibitor Protects Lungs Against SARS-CoV-2-Induced Diffuse Alveolar Damage in African Green Monkeys

The COVID-19 pandemic resulted from global infection by the SARS-CoV-2 coronavirus and rapidly emerged as an urgent health issue requiring effective treatments. To initiate infection, the Spike protein of SARS-CoV-2 requires proteolytic processing mediated by host proteases. Among the host proteases proposed to carry out this activation is the cysteine protease cathepsin L. Inhibiting cathepsin L has been proposed as a therapeutic strategy for treating COVID-19. SLV213 (K777) is an orally administered small molecule protease inhibitor that exhibits in vitro activity against a range of viruses, including SARS-CoV-2. To confirm efficacy in vivo, K777 was evaluated in an African green monkey (AGM) model of COVID-19. A pilot experiment was designed to test K777 in a prophylactic setting, animals were pre-treated with 100mg/kg K777 (N=4) or vehicle (N=2) before inoculation with SARS-CoV-2. Initial data demonstrated that K777 treatment reduced pulmonary pathology compared to vehicle-treated animals. A second study was designed to test activity in a therapeutic setting, with K777 treatment (33 mg/kg or 100 mg/kg) initiated 8 hours after exposure to the virus. In both experiments, animals received K777 daily via oral gavage for 7 days. Vehicle-treated animals exhibited higher lung weights, pleuritis, and diffuse alveolar damage. In contrast, lung pathology was reduced in K777-treated monkeys, and histopathological analyses confirmed the lack of diffuse alveolar damage. Antiviral effects were further demonstrated by quantitative reductions in viral load of samples collected from upper and lower airways. These preclinical data support the potential for early SLV213 treatment in COVID-19 patients to prevent severe lung pathology and disease progression.

immunology↗

bioRxiv2021

Particle Dynamics and Bioaerosol Viability of Aerosolized BCG Vaccine Using Jet and Vibrating Mesh Clinical Nebulizers

BackgroundBacillus Calmette-Guerin (BCG) is a vaccine used to protect against tuberculosis primarily in infants to stop early infection in areas of the world where the disease is endemic. Normally administered as a percutaneous injection, BCG is a live, significantly attenuated bacteria that is now being investigated for its potential within an inhalable vaccine formulation. This work investigates the feasibility and performance of four jet and ultrasonic nebulizers aerosolizing BCG and the resulting particle characteristics and residual viability of the bacteria post-aerosolization. MethodsA jet nebulizer (Collison) outfitted either with a 3- or 6-jet head, was compared to two clinical nebulizers, the vibrating mesh Omron MicroAir and Aerogen Solo devices. Particle characteristics, including aerodynamic particle sizing, was performed on all devices within a common aerosol chamber configuration and comparable BCG innocula concentrations. Integrated aerosol samples were collected for each generator and assayed for bacterial viability using conventional microbiological technique. Results and ConclusionsA batch lot of BCG (Danish) was grown to titer and used in all generator assessments. Aerosol particles within the respirable range were generated from all nebulizers at four different concentrations of BCG. The jet nebulizers produced a uniformly smaller particle size than the ultrasonic devices, although particle concentrations by mass were similar across all devices tested with the exception of the Aerogen Solo, which resulted in a very low concentration of BCG aerosols. The resulting measured viable BCG aerosol concentration fraction produced by each device approximated one another; however, a measurable decrease of efficiency and overall viability reduction in the jet nebulizer was observed in higher BCG inoculum starting concentrations, whereas the vibrating mesh nebulizer returned a remarkably stable viable aerosol fraction irrespective of inoculum concentration.

biophysics↗