Selected Grantee Publications
- Clear All
- 14 results found
- Infectious Diseases
- Imaging
- 2024
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.
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.
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.
Characterization of Collaborative Cross Mouse Founder Strain CAST/EiJ as a Novel Model for Lethal COVID-19
Baker et al., Scientific Reports. 2024.
https://www.nature.com/articles/s41598-024-77087-1
Researchers characterized the Collaborative Cross (CC) mouse model founder strain CAST/EiJ as a novel model for severe COVID-19, exhibiting high viral loads and mortality. By leveraging genetically diverse CC strains, this study identified variations in susceptibility and survival against SARS-CoV-2 variants. CAST/EiJ mice developed lung pathology and mortality despite antiviral defenses, making them a valuable tool for understanding host–pathogen interactions. The findings emphasize the utility of diverse animal models in uncovering genetic and immunological factors that influence disease outcomes, facilitating the development of targeted therapies against COVID-19 to mitigate future pandemics. Supported by ORIP (P40OD011102).
Gene Editing of Pigs to Control Influenza A Virus Infections
Kwon et al., Emerging Microbes & Infections. 2024.
https://pubmed.ncbi.nlm.nih.gov/39083026/
A reduction in the efficacy of vaccines and antiviral drugs for combating infectious diseases in agricultural animals has been observed. Generating genetically modified livestock species to minimize susceptibility to infectious diseases is of interest as an alternative approach. The researchers developed a homozygous transmembrane serine protease 2 (TMPRSS2) knockout (KO) porcine model to investigate resistance to two influenza A virus (IAV) subtypes, H1N1 and H3N2. TMPRSS2 KO pigs demonstrated diminished nasal cavity viral shedding, lower viral burden, and reduced microscopic lung pathology compared with wild-type (WT) pigs. In vitro culturing of primary bronchial epithelial cells (PBECs) demonstrated delayed viral replication in TMPRSS2 KO pigs compared with WT pigs. This study demonstrates the potential use of genetically modified pigs to mitigate IAV infections in pigs and limit transmission to humans. Supported by ORIP (U42OD011140), NHLBI, NIAID, and NIGMS.
Enterohemorrhagic Escherichia coli (EHEC) Disrupts Intestinal Barrier Integrity in Translational Canine Stem Cell-Derived Monolayers
Nagao et al., Microbiology Spectrum. 2024.
https://pubmed.ncbi.nlm.nih.gov/39162490/
EHEC produces Shiga toxin, which causes acute colitis with symptoms such as hemolytic uremic syndrome and bloody diarrhea. The researchers developed a colonoid-derived monolayer model to understand EHEC’s impact on canine gut health. Colonoid-derived monolayers co-cultured with EHEC demonstrated key differences compared with the control and nonpathogenic E. coli co-cultures. Scanning electron microscopy displayed EHEC aggregated and attached to the microvilli. EHEC-infected monolayers demonstrated significantly weakened membrane integrity and increased inflammatory cytokine production, specifically TNFα. The researchers developed a novel in vitro model that offers an additional platform for understanding the mechanisms of EHEC pathogenicity, developing therapeutics for EHEC, and studying additional enteric pathogens. Supported by ORIP (K01OD030515, R21OD031903).
Cytomegalovirus Vaccine Vector-Induced Effector Memory CD4+ T cells Protect Cynomolgus Macaques From Lethal Aerosolized Heterologous Avian Influenza Challenge
Malouli et al., Nature Communications. 2024.
Development of a universal influenza vaccine that protects against seasonal strains and future pandemic influenza viruses is a necessity because of the limited efficacy of current influenza vaccines. Researchers developed a cynomolgus macaque β-herpesvirus cytomegalovirus (CyCMV) vaccine that targets the highly conserved proteins in influenza viruses. Male and female Mauritian-origin cynomolgus macaques (MCM) were vaccinated and boosted with the CyCMV vaccine prior to being challenged with small-particle aerosols containing highly pathogenic avian influenza (HPAI). MCMs receiving the CyCMV vaccine still presented with fever and pulmonary infiltration but demonstrated significant protection against HPAI-induced mortality. Unvaccinated MCMs challenged with HPAI did not survive. Survival was correlated with the magnitude of influenza-specific CD4+ T cells prior to infection. These results demonstrate the efficacy of a novel vaccine that protects against HPAI through a CD4 T cell–mediated response. Supported by ORIP (P51OD010425, P51OD011092) and NIAID.
Administration of Anti-HIV-1 Broadly Neutralizing Monoclonal Antibodies With Increased Affinity to Fcγ Receptors During Acute SHIV AD8-EO Infection
Dias et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-51848-y
Anti-HIV broadly neutralizing antibodies (bNAbs) mediate virus neutralization and antiviral effector functions through Fab and Fc domains, respectively. This study investigated the efficacy of wild-type (WT) bNAbs and modified bNAbs with enhanced affinity for Fcγ receptors (S239D/I332E/A330L [DEL]) after acute simian-HIVAD8-EO (SHIVAD8-EO) infection in male and female rhesus macaques. The emergence of the virus in the plasma and lymph nodes occurred earlier in macaques given DEL bNAbs than in those given WT bNAbs. Overall, the administration of DEL bNAbs revealed higher levels of immune responses. The results suggest that bNAbs with an enhanced Fcγ receptor affinity offer a potential therapeutic strategy by targeting HIV more effectively during early infection stages. Supported by ORIP (P40OD028116), NCI, and NIAID.
Comparison of the Immunogenicity of mRNA-Encoded and Protein HIV-1 Env-ferritin Nanoparticle Designs
Mu et al., Journal of Virology. 2024.
https://journals.asm.org/doi/10.1128/jvi.00137-24
Inducing broadly neutralizing antibodies (bNAbs) against HIV-1 remains a challenge because of immune system limitations. This study compared the immunogenicity of mRNA-encoded membrane-bound envelope (Env) gp160 to HIV-1 Env-ferritin nanoparticle (NP) technology in inducing anti-HIV-1 bNAbs. Membrane-bound mRNA encoding gp160 was more immunogenic than the Env-ferritin NP design in DH270 UCA KI mice, but at lower doses. These results suggest further analysis of mRNA design expression and low-dose immunogenicity studies are necessary for anti-HIV-1 bNAbs. Supported by ORIP (P40OD012217, U42OD021458) and NIAID.