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Tract Pathogen-Mediated Inflammation Through Development of Multimodal Treatment Regimen and Its Impact on SIV Acquisition in Rhesus Macaques
Bochart et al., PLOS Pathogens. 2021.
https://doi.org/10.1371/journal.ppat.1009565
In addition to being premier HIV models, rhesus macaques are models for other infectious diseases and colitis, where background colon health and inflammation may confound results. Starting with the standard specific-pathogen-free (SPF) model, researchers established a gastrointestinal pathogen-free (GPF) colony via multimodal therapy (enrofloxacin, azithromycin, fenbendazole, and paromomycin) to eliminate common endemic pathogens (EPs). This treatment combined with continued pathogen exclusion eliminated common EPs, improved mucosal barriers, and reduced mucosal and systemic inflammation without microbiota disruption. GPF animals challenged with SIV intrarectally demonstrated a more controlled and consistent rate of SIV acquisition, suggesting the value of this model for HIV studies. Supported by ORIP (U42OD023038, P51OD011092), NCI, and NIAID.
Psychosocial Stress Alters the Immune Response and Results in Higher Viral Load During Acute SIV Infection in a Pigtailed Macaque Model of HIV
Guerrero-Martin et al., Journal of Infectious Diseases. 2021.
https://doi.org/10.1093/infdis/jiab252
Social distancing is an important countermeasure for a pandemic, but social isolation may also have adverse health outcomes in the context of infectious diseases, such as HIV. Researchers compared commonly measured parameters of HIV progression between singly and socially housed simian immunodeficiency virus (SIV)-infected pigtailed macaques. Throughout acute SIV infection, singly housed pigtailed macaques had a higher viral load in the plasma and cerebrospinal fluid and demonstrated greater CD4+ T cell declines and more CD4+ and CD8+ T cell activation compared to socially housed macaques. These findings suggest that psychosocial stress could augment the progression of HIV infection. Supported by ORIP (U42OD013117, P40OD013117, K01OD018244), NIAID, NINDS, and NIMH.
Postpubertal Spermatogonial Stem Cell Transplantation Restores Functional Sperm Production in Rhesus Monkeys Irradiated Before and After Puberty
Shetty et al., Andrology. 2021.
https://onlinelibrary.wiley.com/doi/10.1111/andr.13033
Cancer treatment of prepubertal patients impacts future fertility due to the abolition of spermatogonial stem cells (SSCs). Prepubertal rhesus monkeys (n=6) were unilaterally castrated, and the remaining testes irradiated twice to insure loss of SSCs; the animals were treated with a vehicle or GnRH antagonist for 8 weeks (n=3/treatment). The cryopreserved prepubertal testicular tissue was allergenically transplanted into the intact testes of the monkeys after puberty. Recovery of viable donor epididymal sperm was observed in half the monkeys. These results illustrate that sperm production can be restored in primates by transplantation of testicular cells from cryopreserved untreated prepubertal testes into seminiferous tubules of the remaining testes. Supported by ORIP (P51OD011092), NICHD, and NCI.
Combining In Vivo Corneal Confocal Microscopy With Deep Learning-Based Analysis Reveals Sensory Nerve Fiber Loss in Acute Simian Immunodeficiency Virus Infection
McCarron et al., Cornea. 2021.
https://doi.org/10.1097/ICO.0000000000002661
Researchers characterized corneal subbasal nerve plexus features of normal and simian immunodeficiency virus (SIV)-infected pigtail and rhesus macaques using in vivo confocal microscopy and a deep learning approach for automated assessments. Corneal nerve fiber length and fractal dimension measurements did not differ between species, but pigtail macaques had significantly higher baseline corneal nerve fiber tortuosity than rhesus macaques. Acute SIV infection induced decreased corneal nerve fiber length and fractal dimension in the pigtail macaque model for HIV. Adapting deep learning analyses to clinical corneal nerve assessments will improve monitoring of small sensory nerve fiber damage in numerous clinical contexts, including HIV. Supported by ORIP (U42OD013117) and NINDS.
MRI Characteristics of Japanese Macaque Encephalomyelitis (JME): Comparison to Human Diseases
Tagge et al., Journal of Neuroimaging. 2021.
https://onlinelibrary.wiley.com/doi/10.1111/jon.12868
Magnetic resonance imaging data (MRI) were obtained from 114 Japanese macaques, including 30 animals of both sexes that presented with neurological signs of Japanese macaque encephalomyelitis (JME). Quantitative estimates of blood-brain barrier permeability to gadolinium-based-contrast agent (GBCA) were obtained in acute, GBCA-enhancing lesions, and longitudinal imaging data were acquired for 15 JME animals. Intense, focal neuroinflammation was a key MRI finding in JME. Several features of JME compare directly to human inflammatory demyelinating diseases. The development and validation of noninvasive imaging biomarkers in JME provides the potential to improve diagnostic specificity and contribute to the understanding of human demyelinating diseases. Supported by ORIP (P51OD011092, S10OD018224), NINDS, and NIBIB.
Modulation of MHC-E Transport by Viral Decoy Ligands Is Required for RhCMV/SIV Vaccine Efficacy
Verweij et al., Science. 2021.
https://doi.org/10.1126/science.abe9233
Rhesus cytomegalovirus (RhCMV) strain 68-1-vectored simian immunodeficiency virus (SIV) vaccines elicit strong CD8+ T cell responses that can clear SIV infections. Peptides targeted by these T cells are presented on major histocompatibility complex (MHC) II and MHC-E rather than MHC-Ia. Researchers showed that VL9 drives intracellular transport of MHC-E and recognition of RhCMV-infected targets by MHC-E-restricted CD8+ T cells. Specific-pathogen-free (SPF) rhesus macaques vaccinated with a mutant 68-1 RhCMV lacking VL9 showed no priming of MHC-E-restricted CD8+ T cells and no protection against SIV, suggesting that future effective CMV-based HIV vaccines will require MHC-E-restricted CD8+ T cell priming. Supported by ORIP (U42OD023038, P51OD011092), NIAID, and NCI.
Functional Convergence of a Germline-Encoded Neutralizing Antibody Response in Rhesus Macaques Immunized with HCV Envelope Glycoproteins
Chen et al., Immunity. 2021.
https://doi.org/10.1016/j.immuni.2021.02.013
Immunoglobulin heavy chain variable gene IGHV1-69-encoded broadly neutralizing antibodies (bnAbs) targeting the hepatitis C virus (HCV) envelope glycoprotein (Env) E2 are important for protection against HCV infection in humans. An IGHV1-69 ortholog, VH1.36, is preferentially used for bnAbs isolated from rhesus macaques immunized against HCV Env. Researchers investigated the genetic, structural, and functional properties of VH1.36-encoded bnAbs generated by HCV Env vaccination of macaques and compared their findings to IGHV1-69-encoded bnAbs from HCV patients. The investigators found that macaque VH1.36- and human IGHV1-69-encoded bnAbs share many common features, which provides an excellent framework for rational HCV vaccine design and testing. Supported by ORIP (P51OD011133, U42OD010442), NIAID, NCI, and NIGMS.
Best Practices for Correctly Identifying Coronavirus by Transmission Electron Microscopy
Bullock et al., Kidney International. 2021.
https://pubmed.ncbi.nlm.nih.gov/33493525/
This paper provides strategies for identifying coronaviruses by transmission electron microscopy in ultrathin sections of tissues or tissue cultures. As illustrated by results in the literature, organ damage may be incorrectly attributed to the presence of virus, since images of coronavirus may resemble subcellular organelles. The paper also references numerous biochemical and imaging techniques to aid an investigator in avoiding pseudo positive identifications. Supported by ORIP (S10OD026776) and others.
Cytomegaloviral Determinants of CD8+ T Cell Programming and RhCMV/SIV Vaccine Efficacy
Malouli et al., Science Immunology. 2021.
https://www.science.org/doi/10.1126/sciimmunol.abg5413
Cytomegalovirus (CMV)-based vaccine vectors were developed to leverage the ability of CMVs to elicit sustained CD4+ and CD8+ T cell responses with broad tissue distribution. The 68-1 rhesus cytomegalovirus (RhCMV) vectors that express simian immunodeficiency virus (SIV) inserts induce major histocompatibility complex E (MHC-E)- and MHC-II-restricted, SIV-specific CD8+T cell responses. The contribution of this unconventional MHC restriction to RhCMV/SIV vaccine efficacy are poorly understood. Researchers demonstrated that these responses result from genetic rearrangements in 68-1 RhCMV that disrupt the function of eight immunomodulatory proteins encoded by the virus. Repair of each of these genes with either RhCMV or human CMV counterparts shifted responses to MHC-Ia-restricted, or MHC-Ia- and MHC-II-restricted, CD8 T cell responses, but repairing the RhCMV genes did not protect against SIV. These findings suggest that MHC-E-restricted CD8+ T cell responses may be critical to protection against SIV. Supported by ORIP (U42OD023038, P51OD011092).
The SARS-CoV-2 Receptor and Other Key Components of the Renin-Angiotensin-Aldosterone System Related to COVID-19 are Expressed in Enterocytes in Larval Zebrafish
Postlethwait et al., Biology Open. 2021.
https://bio.biologists.org/content/10/3/bio058172.article-info
Hypertension and respiratory inflammation are exacerbated by the Renin-Angiotensin-Aldosterone System (RAAS), which normally protects from dropping blood pressure via Angiotensin II (Ang II) produced by the enzyme Ace. The Ace paralog Ace2 degrades Ang II and serves as the SARS-CoV-2 receptor. To exploit zebrafish to understand the relationship of RAAS to COVID-19, the group conducted genomic and phylogenetic analyses. Results identified a type of enterocyte as the expression site of zebrafish orthologs of key RAAS components, including the SARS-CoV-2 co-receptor. Results identified vascular cell subtypes expressing Ang II receptors and identified cell types to exploit zebrafish as a model for understanding COVID-19 mechanisms. Supported by ORIP (R24OD026591, R01OD011116), NIGMS, NICHD.