Selected Grantee Publications
Whole-Genome Sequences of Six Borrelia recurrentis Strains Obtained via PacBio Sequencing
Gaber et al., Microbiology Resource Announcements. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11895452
The spirochetal bacterium Borrelia recurrentis causes louse-borne relapsing fever (LBRF), which leads to significant morbidity and mortality in several African countries. Previous sequencing studies of B. recurrentis demonstrated discrepancies and did not accurately define the antigenic variation system. In this study, researchers used long-read PacBio technology to conduct whole-genome sequencing of six B. recurrentis strains that had been isolated from LBRF patients earlier. The resulting sequences of each genome included one linear chromosome and five linear plasmids, whose average size was 1,284,895 bp, with the mean GC content being 27.5%. Supported by ORIP (T32OD011083) and NIAID.
Quorum Sensing LuxR Proteins VjbR and BabR Jointly Regulate Brucella abortus Survival During Infection
Caudill et al., Journal of Bacteriology. 2025.
https://pubmed.ncbi.nlm.nih.gov/40013834
Brucella abortus is a zoonotic bacterial pathogen that causes brucellosis, a persistent chronic infection that is globally endemic. B. abortus uses quorum sensing to escape immune clearance attempts, regulate virulence, and cause persistent infection within hosts. B. abortus quorum sensing system comprises two LuxR proteins, VjbR and BabR, as well as two signals, dodecanoyl (C12 AHL) and 3-oxododecanoyl (3-OXO-C12 AHL) homoserine lactone. Using chronic infection 6- to 7-week-old C57Bl/6 and BALB/c male and female mouse models, researchers found that the ΔvjbRΔbabR double-deletion strain was attenuated compared with single mutants. These results demonstrate that both quorum sensing proteins, VjbR and BabR, coordinate to maintain survival. This study helps further characterize the Brucella quorum sensing systems and indicates that further attention should be given to the joint interactions between VjbR and BabR in controlling virulence. Supported by ORIP (T32OD028239) and NIAID.
Dysregulation of mTOR Signalling Is a Converging Mechanism in Lissencephaly
Zhang et al., Nature. 2025.
https://pubmed.ncbi.nlm.nih.gov/39743596
Lissencephaly (smooth brain) is a rare genetic condition, with such symptoms as epilepsy and intellectual disability and a median life expectancy of 10 years. This study reveals that reduced activity of the mTOR pathway may be a common cause of lissencephaly. Researchers used laboratory-grown brain models (organoids) and sequencing and spectrometry techniques to identify decreased mTOR activation in two types of lissencephaly disorders: p53-induced death domain protein 1 and Miller–Dieker lissencephaly syndrome. Pharmacological activation of mTOR signaling with a brain-selective mTORC1 activator molecule, NV-5138, prevented and reversed the morphological and functional defects in organoids. These findings suggest that mTOR dysregulation contributes to the development of lissencephaly spectrum disorders and highlight a potential druggable pathway for therapy. Supported by ORIP (S10OD018034, S10OD019967, S10OD030363), NCATS, NHGRI, NICHD, NIDA, NIGMS, NIMH, and NINDS.
Liver-Specific Transgenic Expression of Human NTCP In Rhesus Macaques Confers HBV Susceptibility on Primary Hepatocytes
Rust et al., PNAS. 2025.
https://pubmed.ncbi.nlm.nih.gov/39937851
This study establishes the first transgenic nonhuman primate model for hepatitis B virus (HBV). Male and female rhesus macaques were engineered to express the human HBV receptor, NTCP (hNTCP), specifically in the liver. Researchers used PiggyBac transposon technology to introduce a liver-specific NTCP transgene into embryos, which were then implanted into surrogate females. The resulting offspring expressed hNTCP in hepatocytes and demonstrated high susceptibility to HBV infection. This model overcomes the species-specific limitations of HBV research, providing a powerful tool for studying HBV biology and evaluating HBV treatments in a clinically relevant model system. Supported by ORIP (P51OD011092), NIDA, and NIAID.
Suppression of Viral Rebound by a Rev-Dependent Lentiviral Particle in SIV-Infected Rhesus Macaques
Hetrick et al., Gene Therapy. 2025.
https://pubmed.ncbi.nlm.nih.gov/39025983/
Viral reservoirs are a current major barrier that prevents an effective cure for patients with HIV. Antiretroviral therapy (ART) effectively suppresses viral replication, but ART cessation leads to viral rebound due to the presence of viral reservoirs. Researchers conducted in vivo testing of simian immunodeficiency virus (SIV) Rev-dependent vectors in SIVmac239-infected male and female Indian rhesus macaques, 3–6 years of age, to target viral reservoirs. Treatment with the SIV Rev-dependent vector reduced viral rebound and produced neutralizing antibodies following ART cessation. These results indicate the potential to self-control plasma viremia through a neutralizing antibody-based mechanism elicited by administration of Rev-dependent vectors. This research could guide future studies focused on investigating multiple vector injections and quantifying cell-mediated immune responses. Supported by ORIP (P51OD011104, P40OD028116), NIAID, and NIMH.
Potent Broadly Neutralizing Antibodies Mediate Efficient Antibody-Dependent Phagocytosis of HIV-Infected Cells
Snow et al., PLOS Pathogens. 2024.
https://pubmed.ncbi.nlm.nih.gov/39466835
This study investigates the role of potent broadly neutralizing antibodies (bNAbs) in mediating antibody-dependent cellular phagocytosis (ADCP) of HIV-infected cells. Researchers developed a novel cell-based approach to assess the ADCP of HIV-infected cells expressing natural conformations of the viral envelope glycoprotein, which allows the virus to infect a host cell. The findings in this study demonstrate that bNAbs facilitate efficient ADCP, highlighting their potential in controlling HIV infection by promoting immune clearance of infected cells. This study provides valuable insights into antibody-mediated immune mechanisms and supports the development of antibody-based therapies and vaccines targeting HIV. Supported by ORIP (P51OD011106) and NIAID.
Phenotypic Characterization of Subtype A and Recombinant AC Transmitted/Founder Viruses From a Rwandan HIV-1 Heterosexual Transmission Cohort
Yue et al., Viruses. 2024.
https://pubmed.ncbi.nlm.nih.gov/39599821
HIV-1 is classified into several phylogenetic groups and subgroups, and to be effective, a vaccine would require broad activity across diverse viral strains. The most widespread group, M, is subdivided into several subgroups (A–D, F–H, J, K, and L). In a previous study, these researchers analyzed cohorts of people with recent or acute HIV infection in Rwanda. Subtype A was the dominant subtype, but a significant number of infections were caused by recombinants of subtypes A and C. This study assessed the characteristics of 16 infectious molecular clones (IMCs) of subtype A or AC recombinant viruses. Viral replication scores varied among the IMCs, and amino acid substitutions in the viral Gag gene were linked to higher replication activity. The sensitivity of different clones to broadly neutralizing antibodies also was assessed. This panel of well-characterized viral IMCs will support studies required to develop an effective HIV-1 vaccine. Supported by ORIP (P51OD011132) and NIAID.
Multimodal Analysis of Dysregulated Heme Metabolism, Hypoxic Signaling, and Stress Erythropoiesis in Down Syndrome
Donovan et al., Cell Reports. 2024.
https://pubmed.ncbi.nlm.nih.gov/39120971
Down syndrome (DS), a genetic condition caused by the presence of an extra copy of chromosome 21, is characterized by intellectual and developmental disability. Infants with DS often suffer from low oxygen saturation, and DS is associated with obstructive sleep apnea. Investigators assessed the role that hypoxia plays in driving health conditions that are comorbid with DS. A multiomic analysis showed that people with DS exhibit elevated heme metabolism and activated stress erythropoiesis, which are indicators of chronic hypoxia; these results were recapitulated in a mouse model for DS. This study identified hypoxia as a possible mechanism underlying several conditions that co-occur with DS, including congenital heart defects, seizure disorders, autoimmune disorders, several leukemias, and Alzheimer's disease. Supported by ORIP (R24OD035579), NCATS, NCI, and NIAID.
Transcriptomic Analysis of Skeletal Muscle Regeneration Across Mouse Lifespan Identifies Altered Stem Cell States
Walter et al., Nature Aging. 2024.
https://pubmed.ncbi.nlm.nih.gov/39578558
Age-related skeletal muscle regeneration dysfunction is poorly understood. Using single-cell transcriptomics and high-resolution spatial transcriptomics, researchers evaluated factors contributing to age-related decline in skeletal muscle regeneration after injury in young, old, and geriatric male and female mice (5, 20, and 26 months old). Eight immune cell types were identified and associated with age-related dynamics and distinct muscle stem cell states specific to old and geriatric tissue. The findings emphasize the role of extrinsic and intrinsic factors, including cellular senescence, in disrupting muscle repair. This study provides a spatial and molecular framework for understanding regenerative decline and cellular heterogeneity in aging skeletal muscle. Supported by ORIP (F30OD032097), NIA, NIAID, NIAMS, NICHD, and NIDA.
Extended Survival of 9- and 10-Gene-Edited Pig Heart Xenografts With Ischemia Minimization and CD154 Costimulation Blockade-Based Immunosuppression
Chaban et al., The Journal of Heart and Lung Transplantation. 2024.
https://pubmed.ncbi.nlm.nih.gov/39097214
Heart transplantations are severely constrained from the shortage of available organs derived from human donors. Xenotransplantation of hearts from gene-edited (GE) pigs is a promising way to address this problem. Researchers evaluated GE pig hearts with varying knockouts and human transgene insertions. Human transgenes are introduced to mitigate important physiological incompatibilities between pig cells and human blood. Using a baboon heterotopic cardiac transplantation model, one female and seven male specific-pathogen-free baboons received either a 3-GE, 9-GE, or 10-GE pig heart with an immunosuppression regimen targeting CD40/CD154. Early cardiac xenograft failure with complement activation and multifocal infarcts were observed with 3-GE pig hearts, whereas 9- and 10-GE pig hearts demonstrated successful graft function and prolonged survival. These findings show that one or more transgenes of the 9- and 10-GE pig hearts with CD154 blockade provide graft protection in this preclinical model. Supported by ORIP (U42OD011140) and NIAID.