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Rapid Body-Wide Transcriptomic Turnover During Rhesus Macaque Perinatal Development.

ABSTRACT: An hourglass cup-shape pattern of regulation at the molecular level was detected during the development of the primate brain. Specifically, a peak of temporally differentially expressed genes around the time of birth has been observed in the human brain. However, to what extend this peak of regulation exists among species has not been investigated in great detail. Here, by integrating multiple large-scale transcriptome data from rhesus macaques, we confirmed that a similar differential expression peak exists during the development of the macaque brain. We also found that a similar peak exists during the development of other organs, such as liver, testis, kidney and heart. Furthermore, we found that distinct pathways are regulated in the peak period of those organs. Our results highlight the importance of co-evolution of diverse organs during critical periods of perinatal development in primates.

SUBMITTER: Zhang W

PROVIDER: S-EPMC8223001 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Rapid Body-Wide Transcriptomic Turnover During Rhesus Macaque Perinatal Development.

Zhang Wenqian W Wang Wei W Zhao Manman M Turck Christoph W CW Zhu Ying Y Wang Guang-Zhong GZ

Frontiers in physiology 20210610

An hourglass cup-shape pattern of regulation at the molecular level was detected during the development of the primate brain. Specifically, a peak of temporally differentially expressed genes around the time of birth has been observed in the human brain. However, to what extend this peak of regulation exists among species has not been investigated in great detail. Here, by integrating multiple large-scale transcriptome data from rhesus macaques, we confirmed that a similar differential expressio ...[more]

PMID: 34177627

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Project description:Background: Clinical measurements commonly used to evaluate overall health of laboratory animals including complete blood count, serum chemistry, weight, and immunophenotyping, differ with respect to age, development, and environment. This report provides comprehensive clinical and immunological reference ranges for pediatric rhesus macaques over the first year of life. Methods: We collected and analyzed blood samples from 151 healthy rhesus macaques, aged 0-55 weeks, and compared mother-reared infants to two categories of nursery-reared infants; those on an active research protocol and those under derivation for the expanded specific-pathogen-free breeding colony. Hematology was performed on EDTA-anticoagulated blood using a Sysmex XT2000i, and serum clinical chemistry was performed using the Beckman AU480 chemistry analyzer. Immunophenotyping of whole blood was performed with immunofluorescence staining and subsequent flow cytometric analysis on a BD LSRFortessa. Plasma cytokine analysis was performed using a Millipore multiplex Luminex assay. Results: For hematological and chemistry measurements, pediatric reference ranges deviate largely from adults. Comparison of mother-reared and nursery-reared animals revealed that large differences depend on rearing conditions and diet. Significant differences found between two nursery-reared cohorts (research and colony animals) indicate large influences of experimental factors and anesthetic events on these parameters. Immune cells and cytokine responses presented with distinct patterns for infants depending on age, birth location, and rearing conditions. Conclusions: Our results illustrate how the immune system changed over time and that there was variability among pediatric age groups. Reference ranges of results reported here will support interpretations for how infection and treatment may skew common immune correlates used for assessment of pathology or protection in research studies as well as help veterinarians in the clinical care of infant non-human primates. We highlighted the importance of using age-specific reference comparisons for pediatric studies and reiterated the utility of rhesus macaques as a model for human studies. Given the rapid transformation that occurs in multiple tissue compartments after birth and cumulative exposures to antigens as individuals grow, a better understanding of immunological development and how this relates to timing of infection or vaccination will support optimal experimental designs for developing vaccines and treatment interventions.

Project description:Infection with yellow fever virus (YFV), an explosively replicating flavivirus, results in viral hemorrhagic disease characterized by cardiovascular shock and multi-organ failure. Unvaccinated populations experience 20 to 50% fatality. Few studies have examined the pathophysiological changes that occur in humans during YFV infection due to the sporadic nature and remote locations of outbreaks. Rhesus macaques are highly susceptible to YFV infection, providing a robust animal model to investigate host-pathogen interactions. In this study, we characterized disease progression as well as alterations in immune system homeostasis, cytokine production and gene expression in rhesus macaques infected with the virulent YFV strain DakH1279 (YFV-DakH1279). Following infection, YFV-DakH1279 replicated to high titers resulting in viscerotropic disease with ∼72% mortality. Data presented in this manuscript demonstrate for the first time that lethal YFV infection results in profound lymphopenia that precedes the hallmark changes in liver enzymes and that although tissue damage was noted in liver, kidneys, and lymphoid tissues, viral antigen was only detected in the liver. These observations suggest that additional tissue damage could be due to indirect effects of viral replication. Indeed, circulating levels of several cytokines peaked shortly before euthanasia. Our study also includes the first description of YFV-DakH1279-induced changes in gene expression within peripheral blood mononuclear cells 3 days post-infection prior to any clinical signs. These data show that infection with wild type YFV-DakH1279 or live-attenuated vaccine strain YFV-17D, resulted in 765 and 46 differentially expressed genes (DEGs), respectively. DEGs detected after YFV-17D infection were mostly associated with innate immunity, whereas YFV-DakH1279 infection resulted in dysregulation of genes associated with the development of immune response, ion metabolism, and apoptosis. Therefore, WT-YFV infection is associated with significant changes in gene expression that are detectable before the onset of clinical symptoms and may influence disease progression and outcome of infection.

Dataset Information

Rapid Body-Wide Transcriptomic Turnover During Rhesus Macaque Perinatal Development.

Publications

Rapid Body-Wide Transcriptomic Turnover During Rhesus Macaque Perinatal Development.

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