Grantee Publications

Last Updated: March 8, 2021

 

Imbalance of Regulatory and Cytotoxic SARS-CoV-2-Reactive CD4+ T Cells in COVID-19

Meckiff et.al., Cell. 2020 Nov 25;183(5):1340-1353.e16.  

It is not clear why COVID-19 is deadly in some people and mild in others. To understand the underlying mechanism, investigators studied the contribution of CD4+ T cells in immune responses to SARS-CoV-2 infection. They analyzed single-cell transcriptomic data of >100,000 viral antigen-reactive CD4+ T cells from 40 COVID-19 patients. In hospitalized patients compared to non-hospitalized patients, they found increased proportions of cytotoxic follicular helper cells (TFH) and cytotoxic T helper (TH) cells responding to SARS-CoV-2 and reduced proportion of SARS-CoV-2-reactive regulatory T cells (TREG). Importantly, in hospitalized COVID-19 patients, a strong cytotoxic TFH response was observed early in the illness, which correlated negatively with antibody levels to SARS-CoV-2 spike protein. Polyfunctional TH1 and TH17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4+ T cells compared to influenza-reactive CD4+ T cells. Together, these analyses provided insights into the gene expression patterns of SARS-CoV-2-reactive CD4+ T cells in distinct disease severities. Supported by ORIP  (S10RR027366 and S10OD025052), NIAID, NHLBI, NIGMS and other sources.

 

Sequence Diversity Analyses of an Improved Rhesus Macaque Genome Enhance its Biomedical Utility

Warren et al., Science. 18 December 2020: Vol. 370, Issue 6523, eabc6617

https://science.sciencemag.org/content/370/6523/eabc6617

Investigators sequenced and assembled an Indian-origin female rhesus macaque (RM) genome using a multiplatform genomics approach that included long-read sequencing, extensive manual curation, and experimental validation to generate a new comprehensive annotated reference genome. As a result, 99.7% of the gaps in the earlier draft genome are now closed, and more than 99% of the genes are represented. Whole-genome sequencing of 853 RMs of both sexes identified 85.7 million single-nucleotide variants and 10.5 million indel variants, including potentially damaging variants in genes associated with human autism and developmental delay. The improved assembly of segmental duplications, new lineage-specific genes and expanded gene families provide a framework for developing noninvasive NHP models of human disease as well as studies of genetic variation and phenotypic consequences. Supported by ORIP (P51OD011106, P51OD011107, P51OD011132, P51OD011104, U42OD024282, U42OD010568, R24OD011173, R24OD021324, and R24OD010962), NHGRI, NIMH, NHLBI, and NIGMS.

 

Antiretroviral Therapy Does Not Reduce Tuberculosis Reactivation in a Tuberculosis-HIV Coinfection Model

Ganatra, Shashank R. et al., Journal of Clinical Investigation. 2020 October;130(10):5171-5179

https://www.jci.org/articles/view/136502

Despite treatment of HIV with antiretroviral therapy (ART), the risk of tuberculosis (TB) reactivation is higher in HIV-infected than HIV-uninfected persons. Researchers used Mycobacterium tuberculosis/SIV-coinfected rhesus macaques to model the impact of ART on TB reactivation due to HIV-induced immunosuppression. ART significantly reduced viral loads and increased CD4+ T-cell counts in blood, spleen, and bronchoalveolar lavage samples, but it did not reduce the risk of SIV-induced TB reactivation during the early phase of treatment. This study offers a translational model for the investigation of TB/SIV coinfection and the evaluation of treatment regimens to prevent TB reactivation in HIV-infected individuals.

Supported by ORIP (P51OD011133, P51OD011132) and NIAID.

 

Biological Activities of a New Crotamine-like Peptide from Crotalus Oreganus Helleri on C2C12 and CHO Cell Lines, and Ultrastructural Changes on Motor Endplate and Striated Muscle

Salazar et al. Toxicon. 2020 December;188:95-107 (PMC7720416)

https://pubmed.ncbi.nlm.nih.gov/33065200/

Crotamine and crotamine-like peptides are non-enzymatic polypeptides found in high concentration in the Crotalus genus venom. Helleramine was isolated and purified from the venom of the rattlesnake, Crotalus oreganus helleri. Purified helleramine increased intracellular Ca2+ in Chinese Hamster Ovary (CHO) cell line, inhibited cell viability of C2C12 (immortalized skeletal myoblast) and promoted early apoptosis and cell death. Skeletal muscle harvested from mice 24 h after helleramine injection showed contracted myofibrils and profound vacuolization, with loss of plasmatic and basal membrane integrity. The effects of helleramine provide evidence of myotoxic activities of crotamine-like peptides and their possible role in crotalid envenoming.

Supported by ORIP (P40 OD010960).

 

Deploying MMEJ using MENdel in Precision Gene Editing Applications for Gene Therapy and Functional Genomics

Martínez-Gálvez G. et al. Nucleic Acids Research. 2021 January 11;49(1):67-78 (PMC7797032)

https://academic.oup.com/nar/article/49/1/67/6030233

Gene-editing experiments commonly elicit the error-prone non-homologous end joining for DNA double-strand break (DSB) repair. Martinez-Galvez et al. compared three DSB repair prediction algorithms - MENTHU, inDelphi, and Lindel. MENTHU correctly identified 46% of all PreMAs available, a ∼2- and ∼60-fold sensitivity increase compared to inDelphi and Lindel, respectively.  The investigators report the new algorithm MENdel, a combination of MENTHU and Lindel, that achieves the most predictive coverage of homogeneous out-of-frame mutations. They suggest that the use of MENdel helps researchers use MMEJ at scale for reverse genetics screenings to be viable for nearly all loss-of-function based gene editing therapeutic applications.

Supported by ORIP (R24 OD020166), NIGMS.

 

Endogenous Zebrafish Neural Cre Drivers Generated by CRISPR/Cas9 Short Homology Directed Targeted Integration

Almeida, M.P. et al., Scientific Reports 2021 January 18;11(1):1732 (PMC7813866)

https://www.nature.com/articles/s41598-021-81239-y

Almeida et al. previously reported precision targeted integration of reporter DNA in zebrafish using CRISPR/Cas9. Here, they isolated zebrafish Cre recombinase drivers. A 2A-Cre recombinase transgene with 48 bp homology arms was targeted into proneural genes ascl1b, olig2 and neurod1. They observed high rates of germline transmission from 10 to 100% (10% olig2; 20% neurod1; 100% ascl1b). The lines Tg(ascl1b-2A-Cre)is75, Tg(olig2-2A-Cre)is76, and Tg(neurod1-2A-Cre)is77 expressed functional Cre recombinase in the cell populations. Results demonstrate Cre recombinase expression is driven by the native promoter and regulatory elements of targeted genes. This approach is a cost-effective method to generate cell type specific zebrafish Cre and CreERT2 drivers.

Supported by ORIP (R24 OD020166).

 

Trim-Away Mediated Knock Down Uncovers a New Function for Lbh During Gastrulation of Xenopus laevis

Weir, Emma et al. Dev Biol. 2021 Feb; 470:74-83 (PMC7855437)

https://pubmed.ncbi.nlm.nih.gov/33159936/

The protein Lbh was identified as necessary for cranial neural crest cell migration in Xenopus. To investigate its role in embryonic events, the authors employed the technique "Trim-Away" to degrade this maternally deposited protein. Trim-Away utilizes the E3 ubiquitin ligase trim21 to degrade proteins targeted with an antibody. Early knockdown of Lbh in Xenopus results in defects in gastrulation that present with a decrease in fibronectin matrix assembly, an increase in mesodermal cell migration and decrease in endodermal cell cohesion. The technique is also effective on a second abundant maternal Protein Kinase C And Casein Kinase Substrate In Neurons 2.

Supported by ORIP (R24 OD021485), NIDCR

 

A Frog with Three Sex Chromosomes that Co-Mingle Together in Nature: Xenopus tropicalis Has a Degenerate W and a Y that Evolved from a Z Chromosome

Furman, Benjamin L. S., et al. PLoS Genet. 2020 Nov 9; 16(11):e1009121 (PMC7652241)

https://pubmed.ncbi.nlm.nih.gov/33166278/

Genetic systems governing sexual differentiation vary among species. Furman et al. investigated a frog with three sex chromosomes, the Western clawed frog, Xenopus tropicalis. They demonstrate that natural populations from the western and eastern edges of Ghana have a young Y chromosome, and that a male-determining factor on this Y chromosome is in a similar genomic location as a previously known female-determining factor on the W chromosome. Their findings are consistent with theoretical expectations associated with recombination suppression on sex chromosomes and demonstrate that several characteristics of old and established sex chromosomes can arise well before they become cytogenetically distinguished.

Supported by ORIP (P40 OD010997), NICHD

 

3-D Printed Customizable Vitrification Devices for Preservation of Genetic Resources of Aquatic Species

Tiersch, Connor J., et al. Aquac Eng. 2020 Aug; 90:102097 (PMC7434064)

https://www.sciencedirect.com/science/article/pii/S0144860920300406

Sperm vitrification as an alternative approach to conventional cryopreservation allows quick and low-cost sample preservation and is suitable for small-bodied aquatic species with miniscule testis, fieldwork at remote locations, and small-scale freezing for research purposes. Tiersch et al. report the developing of operational prototypes of 3-dimensional (3-D) printed vitrification devices.  This study demonstrated the feasibility of developing standardized low-cost devices fabricated by 3-D printing with functions including vitrification, volume control, labeling, protection, and storage. These prototypes can be further developed to assist development of germplasm repositories to protect the genetic resources of aquatic species by breeders, hatcheries, aquariums, and researchers.

Supported by ORIP (R24 OD010441)

 

Epidemiological and Molecular Characterization of a Novel Adenovirus of Squirrel Monkeys after Fatal Infection during Immunosuppression

Rogers, Donna L. et al. Microb Genom. 2020 Sep; 6(9):mgen000395 (PMC7643968)

https://pubmed.ncbi.nlm.nih.gov/32614763/

Adenoviruses frequently cause upper respiratory tract infections often causing disseminated disease in immunosuppressed patients. A novel adenovirus was identified, squirrel monkey adenovirus 1 (SqMAdV-1), as the cause of a fatal infection in an immunocompromised squirrel monkey (Saimiri boliviensis). A nucleotide polymorphism at the stop codon of the DNA polymerase gene results in a 126 amino acid extension at the carboxy terminus. A single adenovirus variant, SqMAdV-3, has similarity to tufted capuchin (Sapajus apella) adenoviruses. The largest group of adenovirus variants detected, SqMAdV-2.0-2.16, has high similarity (93-99 %) to the TMAdV, suggesting that squirrel monkeys may be the natural host of the TMAdV.

Supported by ORIP (P40 OD010938, R24 OD018553), NIAID

 

Modified Vaccinia Ankara Vector-Based Vaccine Protects Macaques from SARS-CoV-2 Infection, Immune Pathology and Dysfunction in the Lung

Routhu, Nanda Kishore et al., Immunity. 2021 Feb; Epub ahead of print.

https://doi.org/10.1016/j.immuni.2021.02.001

Any SARS-CoV-2 vaccine may have limitations such as need for ultracold storage, poor induction of CD8+ T cell response, or lack of cross-reactivity with emerging strains. Thus, multiple vaccines may be needed to bring COVID-19 under control. Using rhesus macaques, researchers showed that a modified vaccinia Ankara (MVA) vector-based SARS-CoV-2 vaccine expressing prefusion-stabilized spike protein induced strong neutralizing antibody and CD8+ T cell responses. The vaccine protected macaques from SARS-CoV-2 infection as well as infection-induced inflammation and B cell abnormalities in the lung. These results are promising considering the excellent safety and performance of MVA vector-based vaccines for other pathogens.

Supported by ORIP (P51OD011132, S10OD026799) and NIAID

 

Lung Expression of Human Angiotensin-Converting Enzyme 2 Sensitizes the Mouse to SARS-CoV-2 Infection

Han, Kun et al., American Journal of Respiratory Cell and Molecular Biology. 2021 Jan; 64(1):79-88.

https://doi.org/10.1165/rcmb.2020-0354OC

A rapidly deployable mouse model that recapitulates a disease caused by a novel pathogen would be a valuable research tool during a pandemic. Researchers were able to produce C57BL/6J mice with lung expression of human angiotensin-converting enzyme 2 (hACE2), the receptor for SARS-CoV-2. They did so by oropharyngeal delivery of a recombinant human adenovirus type 5 expressing hACE2. The transduced mice were then infected with SARS-CoV-2. Thereafter, the mice developed interstitial pneumonia with perivascular inflammation, exhibited higher viral load in lungs compared to controls, and displayed a gene expression phenotype resembling the clinical response in lungs of humans with COVID-19.

Supported by ORIP (P51OD011104, R21OD024931), NHLBI, and NIGMS

 

Antibody-Mediated Depletion of Viral Reservoirs is Limited in SIV-Infected Macaques Treated Early With Antiretroviral Therapy

Swanstrom, Adrienne E. et al., Journal of Clinical Investigation. 2021 Jan; Epub ahead of print.

https://doi.org/10.1172/JCI142421

Virus-specific strategies to target the latent HIV reservoir in individuals on combination antiretroviral therapy (cART) have been limited by inefficient induction of viral protein expression. Researchers used rhesus macaques to investigate an antibody-mediated reservoir targeting strategy, targeting the CD4 molecule rather than a viral protein, to deplete potential viral target cells irrespective of infection status. Despite profound CD4+ T cell depletion in blood and lymph nodes, time to viral rebound following cART cessation was not delayed in anti-CD4 treated animals compared with controls, likely due to the limited antibody-mediated cell depletion that occurred in rectal tissue and lymphoid follicles.

Supported by ORIP (R24OD010976), NCI, and NIAID

 

Polyfunctional Tier 2–Neutralizing Antibodies Cloned Following HIV-1 Env Macaque Immunization Mirror Native Antibodies in a Human Donor

Spencer, David A. et al., Journal of Immunology. 2021 Mar; 206(5):999-1012.

https://doi.org/10.4049/jimmunol.2001082

HIV vaccine efforts are limited by viral strain diversity and the shielding of neutralization epitopes on the viral envelope, yet isolation of broadly neutralizing antibodies from infected individuals suggests the potential for eliciting protective antibodies through vaccination. Researchers cloned 58 monoclonal antibodies (mAbs) from a rhesus monkey immunized with envelope glycoprotein immunogens from an HIV-1 clade C–infected volunteer. Twenty mAbs exhibited some neutralizing activity. Cloned mAbs targeting the V3 region and CD4 binding site were capable of tier 2 (i.e., moderate) neutralization. This study demonstrates partial recapitulation of the human donor’s humoral immune response through nonhuman primate vaccination.

Supported by ORIP (P51OD011092) and NIAID

 

Lipocalin-2 Is an Anorexigenic Signal in Primates

Petropoulou, Peristera-Ioanna et al., eLife. 2020 Nov; 9:e58949.

https://doi.org/10.7554/eLife.58949

The hormone Lipocalin-2 (LCN2) suppresses food intake in mice. Researchers demonstrated that LCN2 increases after a meal and reduces hunger in people with normal weight or overweight, but not in obese individuals. The researchers also showed that LCN2 crosses the blood-brain barrier and binds to the hypothalamus in vervet monkeys. LCN2 was found to bind to the hypothalamus in human, baboon, and rhesus macaque brain sections. When injected into vervets, LCN2 suppressed food intake and lowered body weight without toxic effects in short-term experiments. These findings lay the groundwork to investigate whether LCN2 might be a useful treatment for obesity.

Supported by ORIP (P40OD010965), NCATS, NIDDK, NIA, NHLBI, and National Institute of Food and Agriculture.

 

SARS-CoV-2 Induces Robust Germinal Center CD4 T Follicular Helper Cell Responses in Rhesus Macaques

Lakshmanappa, Yashavanth Shaan et al., Nature Communications. 22 January 2021, Article 541. https://www.nature.com/articles/s41467-020-20642-x

SARS-CoV-2 infection in both sexes of rhesus macaques, either infused with convalescent plasma, normal plasma, or receiving no infusion, resulted in transient accumulation of pro-inflammatory monocytes and proliferating CD4 T follicular helper (Tfh) cells, which are critical for persistent antibody responses. CD4 helper cell responses skewed predominantly toward a Th1 response in blood, lung, and lymph nodes. This skewing is important to note, as weak interferon responses observed in COVID patients could hamper effective antiviral antibody and CD8 T-cell responses. Collectively, the data show induction of GC responses in a rhesus model of mild COVID-19.

Supported by ORIP (P51OD011107 and P40OD010976) and NIAID

 

Myelin‐specific T Cells in Animals with Japanese Macaque Encephalomyelitis

Govindan, Aparna N. et al., Wiley Online Library, first published 13 January 2021, Vol. 8, Issue 2.

https://onlinelibrary.wiley.com/doi/10.1002/acn3.51303

Investigators characterized the CD4+ and CD8+ T cells in demyelinating Japanese macaque encephalomyelitis (JME) lesions in age‐ and sex‐matched macaques and discovered differences in expression of myelin antigen sequences in the T cell. Mapping myelin epitopes revealed a heterogeneity in T cell responses among JME animals, which are associated with a proinflammatory pathogenic role in multiple sclerosis (MS). These findings draw further parallels between JME and MS and support the hypothesis that JME and possibly MS are triggered by mechanisms involving myelin damage and not myelin epitope mimicry.

Supported by ORIP (P51OD011092) and NINDS

 

Autologous Transplant Therapy Alleviates Motor and Depressive Behaviors in Parkinsonian Monkeys

Tao, Yunlong et al., Nature Medicine, 1 March 2021.

https://www.nature.com/articles/s41591-021-01257-1

Generation of induced pluripotent stem cells (iPSCs) enables standardized of dopamine (DA) neurons for autologous transplantation therapy to improve motor functions in Parkinson disease (PD). Adult male rhesus PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs of PD over a 2-year period without immunosuppressive therapy. Mathematical modeling showed correlations between surviving DA neurons with PET signal intensity and behavior recovery regardless of autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number. The results demonstrate favorable efficacy of the autologous transplant approach to treat PD. Supported by ORIP (P51OD011106) NINDS, and NICHD

 

Immunogenic BNT162b Vaccines Protect Rhesus Macaques from SARS-CoV-2

Vogel et al., Nature. 2021 Feb 1. Online ahead of print

The preclinical development of two BNT162b vaccine candidates, which contain lipid-nanoparticle formulated nucleoside-modified mRNA encoding SARS-CoV-2 spike glycoprotein-derived immunogens, was performed in rhesus macaques at the Southwest National Primate Research Center (SNPRC). BNT162b1 encodes a soluble, secreted, trimerised receptor-binding domain. BNT162b2 encodes the full-length transmembrane spike glycoprotein, locked in its prefusion conformation. Prime/boost vaccination of rhesus macaques with BNT162b candidates elicits SARS-CoV-2 neutralizing antibody titers that are 8.2 to 18.2 times that of a SARS-CoV-2 convalescent human serum panel. The vaccine candidates protected macaques from SARS-CoV-2 challenge, with BNT162b2 protecting the lower respiratory tract from the presence of viral RNA and with no evidence of disease enhancement. The BNT162b2 vaccine recently received emergency use authorization from FDA and is being administered within the United States. The SNPRC is supported by ORIP P51OD011103.

 

A Modular Master Regulator Landscape Controls Cancer Transcriptional Identity

Paul et al., Cell. 2021 Jan 21;184(2):334-351.e20

The mechanisms linking genomic alterations to transcriptional identity of cancer cells remain elusive. Integrative genomic analysis, using a network-based approach, identified 407 master regulator (MR) proteins responsible for canalizing the genetics of individual samples from 20 cohorts in The Cancer Genome Atlas into 112 transcriptionally distinct tumor subtypes. MR proteins could be further organized into 24 pan-cancer, MR block modules (MRBs), each regulating key cancer hallmarks and predictive of patient outcome in multiple cohorts. Of all somatic alterations detected in each individual sample, >50% were predicted to induce aberrant MR activity, yielding insight into mechanisms linking tumor genetics and transcriptional identity and establishing non-oncogene dependencies. Genetic and pharmacological validation assays confirmed the predicted effect of upstream mutations and MR activity on downstream cellular identity and phenotype. Thus, co-analysis of mutational and gene expression profiles identified elusive subtypes and provided testable hypothesis for mechanisms mediating the effect of genetic alterations. Supported by ORIP (S10OD012351 and S10OD021764), NCI, and other sources.

 

Severely Ill COVID-19 Patients Display Impaired Exhaustion Features in SARS-CoV-2-Reactive CD8+ T Cells

Kusnadi1 et al., Sci Immunol. 2021 Jan 21;6(55):eabe4782

How CD8+ T cells respond to SARS-CoV-2 infection is not fully known. Investigators reported on the single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells, obtained using a modified Antigen-Reactive T cell Enrichment assay, from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patient cells were segregated into two groups based on whether the dominant CD8+ T cell response to SARS-CoV-2 was “exhausted” or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed less cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the dominant non-exhausted subset from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival Nuclear Factor κB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8+ T cell memory responses in patients with severe COVID-19 illness. Overall, this single-cell analysis revealed substantial diversity in the nature of CD8+ T cells responding to SARS-CoV-2. Supported by ORIP (S10RR027366 and S10OD025052), NIAID, NHLBI, NIGMS, and other sources.

 

The Immune Landscape in Tuberculosis Reveals Populations Linked to Disease and Latency

Esaulova et al., Cell Host Microbe. 2020 Dec 16;S1931-3128(20)30635-1

Mycobacterium tuberculosis infection of adult rhesus macaques (RMs), predominantly males (81%), recapitulates both latent (LTBI) and active pulmonary TB (PTB) observed in humans. The immune characterization in lungs of RMs with PTB exhibited an influx of plasmacytoid dendritic cells, an interferon-responsive macrophage population, and activated T cell responses. In contrast, a CD27+ natural killer (NK) cell subset accumulated in the lungs of RMs with LTBI. This NK cell population was also detected in the circulation of humans with LTBI. This characterization of lung immune cells enhances our understanding of TB immunopathogenesis and provides potential targets for therapies and vaccines for TB control. Supported by ORIP (P51OD011104 and P51OD011133), NHLBI and NIAID.

 

Increased Proviral DNA in Circulating Cells Correlates with Plasma Viral Rebound in SIV-Infected Rhesus Macaques after Antiretroviral Therapy Interruption

Ziani et al., J Virol. 2021 Jan 6;JVI.02064-20

Investigators longitudinally tracked dynamic decay of cell-associated viral RNA/DNA in systemic and lymphoid tissues in SIV-infected rhesus macaques on prolonged combined antiretroviral therapy (cART) to evaluate predictors of viral rebound after treatment cessation. Suppressive cART substantially reduced plasma SIV RNA, cell-associated unspliced, and multiply spliced SIV RNA to undetectable levels, yet viral DNA remained detectable in systemic tissues and lymphoid compartments throughout cART. A rapid increase of integrated proviral DNA in peripheral mononuclear cells was detected once cART was withdrawn, accompanied by the emergence of detectable plasma viral load. The increase of peripheral proviral DNA post cART interruption correlated with the emergence and degree of viral rebound. These results suggest that measuring total viral DNA in SIV infection may be a relatively simple surrogate marker of reservoir size, and may predict viral rebound after treatment interruption, and inform treatment strategies. Supported by ORIP (P51OD011104), NIAID and NICHD.

 

Thresholds for Post-Rebound SHIV Control after CCR5 Gene-Edited Autologous Hematopoietic Cell Transplantation

Cardozo-Ojeda et al., Elife. 2021 Jan 12;10:e57646

Investigators developed a mathematical model to project the minimum threshold of C-C chemokine receptor type 5 (CCR5) gene-edited cells necessary for a functional cure from HIV. This was based on blood T cell reconstitution and plasma simian-HIV (SHIV) dynamics from SHIV-1157ipd3N4-infected juvenile pig-tailed macaques that underwent autologous transplantation with CCR5 gene editing. The model predicts that viral control can be obtained following analytical treatment interruption (ATI) when: (1) transplanted hematopoietic stem and progenitor cells (HSPCs) are at least fivefold higher than residual endogenous HSPCs after total body irradiation and (2) the fraction of protected HSPCs in the transplant achieves a threshold (76–94%) sufficient to overcome transplantation-dependent loss of SHIV immunity. Under these conditions, if ATI is withheld until transplanted gene-modified cells engraft and reconstitute to a steady state, spontaneous viral control is projected to occur. Supported by ORIP (P51OD010425), NCATS and NIAID.

 

Publications Archive

 

Responses to Acute Infection with SARS-CoV-2 in the Lungs of Rhesus Macaques, Baboons and Marmosets
Singh, Dhiraj K. et al., Nature Microbiology, 18 December 2020 
https://www.nature.com/articles/s41564-020-00841-4
Investigators compared acute SARS-CoV-2 infection in young and old rhesus macaques and baboons. Macaques had clinical signs of viral infection, mild to moderate pneumonitis and extra-pulmonary pathologies; both age groups recovered within two weeks. Baboons had prolonged viral RNA shedding and more lung inflammation compared with macaques; inflammation in bronchoalveolar lavage was increased in old versus young baboons. Macaques developed T-cell memory responses and bystander cytokine production. Old macaques had lower titers of SARS-CoV-2-specific IgG antibody levels compared with young macaques. The results indicate macaques and baboons experience acute respiratory distress that recapitulates the progression of COVID-19 in humans. 
Supported by ORIP (P51OD111033 and U42OD010442) and NIAID.


Germline Transmission of Donor, Maternal and Paternal mtDNA in Primates
Ma, Hong et al, 2020;
https://academic.oup.com/humrep/advance-article/doi/10.1093/humrep/deaa308/6025644#218455297 
Mitochondrial gene mutations contribute to incurable human disorders. The possibility of using mitochondrial replacement therapy (MRT) to prevent transmission of pathogenic mitochondrial (mt)DNA was explored in rhesus macaques. Development of spindle MRT transfer in oocytes in 5 female rhesus macaques resulted in healthy and fertile offspring.  These results demonstrate that MRT is compatible with normal postnatal development including overall health and reproductive fitness in nonhuman primates with no detected adverse effects. Additional research is needed to more fully explore the use of MRT to prevent disorders as this study had a limited number of animals with only one female offspring. 
Supported by ORIP (P51OD0092) and NIA.


Infant Isoflurane Exposure Affects Social Behaviours, but Does Not Impair Specific Cognitive Domains in Juvenile Non-human Primates
Neudecker, Viola et al., British Journal of Anaesthesia 14 November 2020
https://www.sciencedirect.com/science/article/pii/S0007091220308503
Researchers investigated the impact of extended (5 hours) isoflurane anesthetic exposure (1-3 exposures) of rhesus macaque (RM) infants of both sexes on cognitive testing and behavioral assessments. Cognitive function did not differ among groups; however, compared to controls, RMs exposed three times during infancy exhibited less close social behavior. One isoflurane exposure resulted in increased anxiety-related behaviors and more inhibition towards novel objects. These findings are consistent with behavioral alterations observed in social settings of human clinical studies. 
Supported by ORIP (P51OD011092). 


Estrogen Acts Through Estrogen Receptor 2b to Regulate Hepatobiliary Fate During Vertebrate Development
Chaturantabut, Saireudee et al. Hepatology. 2020 Nov;72(5):1786-1799
https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.31184
During liver development, bipotent progenitor cells differentiate into hepatocytes and biliary epithelial cells to ensure a functional liver. The developmental cues controlling the differentiation of committed progenitors into these cell types are not completely understood. These authors report an essential role for estrogenic regulation in vertebrate liver development to affect hepatobiliary fate decisions. The studies identify17β-estradiol (E2), nuclear estrogen receptor 2b (esr2b), and downstream bone morphogenetic protein (BMP) activity as important regulators of hepatobiliary fate decisions during vertebrate liver development. These results have significant implications for liver development in infants exposed to abnormal estrogen levels or estrogenic compounds during pregnancy.
Supported by ORIP (R24 OD017870), NIDDK.

Intra-Strain Genetic Variation of Platyfish (Xiphophorus maculatus) Strains Determines Tumorigenic Trajectory
Lu, Yuan et al., Frontiers in Genetics 2020 Oct 6;11:562594
https://www.frontiersin.org/articles/10.3389/fgene.2020.562594/full
Xiphophorus interspecies hybrids represent a valuable model system to study heritable tumorigenesis. Although the ancestors of the two X. maculatus parental lines, Jp163 A and Jp163 B, were siblings produced by the same mother, backcross interspecies hybrid progeny between X. hellerii and X. maculatus Jp163 A develop spontaneous melanoma initiating at the dorsal fin due to a regulator encoded by the X. maculatus genome; the backcross hybrid progeny with X. hellerii or X. couchianus and Jp163 B exhibit melanoma on their flanks. Comparative genomic analyses revealed genetic differences are associated with pathways highlighting fundamental cellular functions. Disruption of these baselines may give rise to spontaneous or inducible tumorigenesis.
Supported by ORIP (R24 OD-011120), NCI, NIGMS.

Induction and Characterization of Pancreatic Cancer in a Transgenic Pig Model
Boas, F. Edward et al., PLoS One. 2020 Sep 21;15(9):e0239391
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239391
Preclinical testing of new therapies for pancreatic cancer has been challenging due to lack of a suitable large animal model. Pigs, however, have similar physiology and immune response to humans. Boas et al report the development of a porcine model of pancreatic cancer.  H&E and immunohistochemical stains revealed undifferentiated carcinomas, like those of human pancreatobiliary systems. In several pigs, angiographies revealed that the artery supplying the pancreatic tumor could be catheterized using a 2.4 F microcatheter. In summary, pancreatic cancer can be induced in a transgenic pig, and intra-arterial procedures using catheters designed for human interventions were feasible in this model. 
Supported by ORIP (U42 OD011140), NCI.

'21

Last updated: 03-08-2021