Selected Grantee Publications
Engineered Bacteria That Self-Assemble Bioglass Polysilicate Coatings Display Enhanced Light Focusing
Sidor et al., PNAS. 2024.
https://pubmed.ncbi.nlm.nih.gov/39656206
Organisms in nature have evolved to create multifunctional structures with advanced optical properties that can be used to design new optical materials. Researchers created constructs containing the enzyme silicatein, derived from sea sponges, and the outer membrane protein A (OmpA) to engineer Escherichia coli bacteria to express surface-level silicatein enzymes. Using Rhodamine123 staining and transmission electron microscopy, results showed that engineered E. coli expressing OmpA-silicatein displayed polysilicate encapsulation with smooth, nonruffled cell borders compared with wild-type E. coli. Light-scattering analysis demonstrated that engineered E. coli create photonic nanojets that are brighter than wild-type E. coli. This study serves as proof of concept that cells can be engineered for potential utilization as tunable photonic components. Supported by ORIP (S10OD030296) and NIGMS.
Indoleamine-2,3-Dioxygenase Inhibition Improves Immunity and Is Safe for Concurrent Use with cART During Mtb/SIV Coinfection
Singh et al., JCI Insight. 2024.
https://pubmed.ncbi.nlm.nih.gov/39114981/
HIV and tuberculosis (TB) coinfection can lead to TB reactivation that is caused by chronic immune system activation. Researchers explored indoleamine-2,3-dioxygenase (IDO) inhibition as a host-directed therapy (HDT) to mitigate immune suppression and TB reactivation in a rhesus macaque Mycobacterium tuberculosis (Mtb)/simian immunodeficiency virus (SIV) model. The IDO inhibitor D-1-methyl tryptophan improved T-cell immunity, reduced tissue damage, and controlled TB-related inflammation without interfering with the efficacy of combinatorial antiretroviral therapy (cART). These findings support IDO inhibition as a potential HDT in HIV/TB coinfection, providing a strategy to balance immune control while preventing TB reactivation in cART-treated patients. Supported by ORIP (S10OD028732, U42OD010442, S10OD028653) and NIAID.
Immune Restoration by TIGIT Blockade is Insufficient to Control Chronic SIV Infection
Webb et al., Journal of Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38775481/
T-cell exhaustion from prolonged upregulation of immune checkpoint receptors (ICR) contributes to immune dysfunction and viral persistence of both human and simian immunodeficiency virus (HIV/SIV) infection. Previous in vitro research has demonstrated the potential use of ICR blockade as a therapeutic. Researchers used a monoclonal antibody targeting humanized T cell immunoreceptor with Ig and ITIM domain (TIGIT) in male and female cynomolgus macaque and female rhesus macaque SIV models, 4–14 years of age. TIGIT blockade was well tolerated, with moderately increased proliferation of T cells and natural killer cells, but a reduction in plasma viral load was not observed. Future research to eliminate SIV should combine ICR blockades with other immunotherapies. Supported by ORIP (P51OD011092), NIAID, and NIMH.
A Switch from Glial to Neuronal Gene Expression Alterations in the Spinal Cord of SIV-Infected Macaques on Antiretroviral Therapy
Mulka et al., Journal of Neuroimmune Pharmacology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38862787/
Up to one-third of patients with HIV experience HIV-associated peripheral neuropathy, affecting sensory pathways in the spinal cord. Spinal cord sampling is limited in people with HIV. Researchers examined gene expression alterations in the spinal cords of simian immunodeficiency virus (SIV)-infected male pigtail macaques with and without antiretroviral therapy (ART), using RNA sequencing at key time points throughout infection. Results indicate a shift from glial cell-associated pathways to neuronal pathways in SIV-infected animals receiving ART. These findings suggest that neurons, rather than glia, are predominantly involved in ART-related neurotoxicity and offer new insights into therapeutic strategies for maintaining synaptic homeostasis. Supported by ORIP (U42OD013117, T32OD011089) and NINDS.
Elevated Inflammation Associated With Markers of Neutrophil Function and Gastrointestinal Disruption in Pilot Study of Plasmodium fragile Co-Infection of ART-Treated SIVmac239+ Rhesus Macaques
Nemphos et al., Viruses. 2024.
https://pubmed.ncbi.nlm.nih.gov/39066199/
Because of geographic overlap, a high potential exists for co-infection with HIV and malaria caused by Plasmodium fragile. Meta-analysis of data collected from 1991 to 2018 demonstrated co-incidence of these two infections to be 43%. Researchers used a male rhesus macaque (RM) model, 6–12 years of age, coinfected with P. fragile and antiretroviral (ART)-treated simian immunodeficiency virus (SIV) to mimic HIV/malaria co-infection observed in patients. ART-treated co-infected RMs demonstrated increased levels of inflammatory cytokines, shifts in neutrophil function, and gastrointestinal mucosal dysfunction. This model may be used to study molecular mechanisms of disease pathology and novel therapies, such as neutrophil-targeted interventions, for patients experiencing co-infection. Supported by ORIP (U42OD010568, U42OD024282, P51OD011104, R21OD031435) and NIGMS.
Transiently Boosting Vγ9+Vδ2+ γδ T Cells Early in Mtb Coinfection of SIV-Infected Juvenile Macaques Does Not Improve Mtb Host Resistance
Larson et al., Infection and Immunity. 2024.
https://pubmed.ncbi.nlm.nih.gov/39475292/
Children with HIV have a higher risk of developing tuberculosis (TB), which is caused by the bacterium Mycobacterium tuberculosis (Mtb). This study utilized juvenile Mauritian cynomolgus macaques to investigate whether enhancing Vγ9+Vδ2+ γδ T cells with zoledronate treatment could improve TB resistance in HIV–TB coinfection. Researchers found that although boosting these immune cells temporarily increased their presence, it did not enhance the macaques’ ability to fight Mtb infection. These findings suggest that solely targeting γδ T cells may not be an effective strategy for improving TB immunity in immunocompromised individuals. These insights are crucial for developing better treatments for HIV–TB coinfections. Supported by ORIP (K01OD033539, P51OD011106) and NIAID.
The Buoyancy of Cryptococcal Cells and Its Implications for Transport and Persistence of Cryptococcus in Aqueous Environments
Jimenez et al., mSphere. 2024.
https://pubmed.ncbi.nlm.nih.gov/39601568/
Cryptococcosis is a major fungal pathogen that causes life-threatening infections. Researchers discovered that Cryptococcus has unique buoyancy properties that help with its survival and spread through water transport. This study explores how these fungal cells remain suspended in liquid, potentially enhancing their ability to survive in their surroundings and infect new hosts. Understanding the role of cellular buoyancy in Cryptococcus transport could improve strategies to prevent spread in aqueous settings, offering new insights into fungal infection risks. Supported by ORIP (T32OD011089), NIAID, and NHLBI.
Three Novel Neoplasms in Nancy Ma's Owl Monkeys (Aotus nancymaae)
Bacon et al., Veterinary Pathology. 2024.
https://pubmed.ncbi.nlm.nih.gov/39692093/
Researchers have identified three previously unreported tumor types in male and female Nancy Ma’s owl monkeys (Aotus nancymaae), a nonhuman primate species that is rarely associated with tumors. Although past cases in owl monkeys were mostly linked to Herpesvirus saimiri–induced lymphoma, this research expands the understanding of tumor development in this species. These findings highlight potential new disease patterns and could inform veterinary care and biomedical research involving owl monkeys. Continued monitoring and investigation of tumors in New World primates are crucial for ensuring animal welfare and research integrity. Supported by ORIP (T32OD011083).
Transcriptomic and Genetic Profiling in a Spontaneous Non-Human Primate Model of Hypertrophic Cardiomyopathy and Sudden Cardiac Death
Rivas et al., Scientific Reports. 2024.
https://pubmed.ncbi.nlm.nih.gov/39733099/
Approximately 1 in 500 individuals are affected by hypertrophic cardiomyopathy (HCM). HCM is characterized by increased left ventricular wall thickness, diastolic dysfunction, and myocardial fibrosis. Outcomes of HCM range from arrhythmias and thromboembolic complications to sudden cardiac death. A current knowledge gap is in understanding the genetic cause of HCM. Researchers compared a nonhuman primate rhesus macaque HCM model to an adult human cohort data set and found that they shared 215 upregulated differentially expressed genes (DEGs); 40 downregulated DEGs; and enriched gene ontology terms, including cardiac muscle cell contraction and heart contraction. The molecular similarity in transcriptomic signatures could be used to develop novel drug therapies to treat HCM in patients. Supported by ORIP (P51OD011107, T32OD011147), NCATS, and NHLBI.
Aberrant Activation of Wound-Healing Programs within the Metastatic Niche Facilitates Lung Colonization by Osteosarcoma Cells
Reinecke et al., Clinical Cancer Research. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11739783/
The leading cause of deaths in the pediatric osteosarcoma is due to lung metastasis. A current clinical need is the development of therapies that disrupt the later stages of metastasis. Researchers used 6- to 8-week-old female C57BL/6 and CB17-SCID mice to understand how tumor cells disrupt the lung microenvironment to promote tumor growth. Single-cell RNA sequencing and spatial transcriptomics demonstrated osteosarcoma–epithelial cell interactions in a chronic state of wound healing in the lung. Nintedanib administration significantly disrupted metastatic progression compared with the vehicle control, demonstrating a potential novel therapeutic for combating osteosarcoma lung metastasis. Supported by ORIP (K01OD031811), NCI, and NCATS.