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. 2020 Sep 22;117(38):23317-23322.
doi: 10.1073/pnas.1820846116. Epub 2019 Oct 14.

Social history and exposure to pathogen signals modulate social status effects on gene regulation in rhesus macaques

Joaquín Sanz  1   2   3 , Paul L Maurizio  3 , Noah Snyder-Mackler  4   5 , Noah D Simons  4 , Tawni Voyles  4 , Jordan Kohn  6 , Vasiliki Michopoulos  6   7 , Mark Wilson  6   7 , Jenny Tung  8   9   10 , Luis B Barreiro  11   3
Affiliations

Social history and exposure to pathogen signals modulate social status effects on gene regulation in rhesus macaques

Joaquín Sanz et al. Proc Natl Acad Sci U S A. .

Abstract

Social experience is an important predictor of disease susceptibility and survival in humans and other social mammals. Chronic social stress is thought to generate a proinflammatory state characterized by elevated antibacterial defenses and reduced investment in antiviral defense. Here we manipulated long-term social status in female rhesus macaques to show that social subordination alters the gene expression response to ex vivo bacterial and viral challenge. As predicted by current models, bacterial lipopolysaccharide polarizes the immune response such that low status corresponds to higher expression of genes in NF-κB-dependent proinflammatory pathways and lower expression of genes involved in the antiviral response and type I IFN signaling. Counter to predictions, however, low status drives more exaggerated expression of both NF-κB- and IFN-associated genes after cells are exposed to the viral mimic Gardiquimod. Status-driven gene expression patterns are linked not only to social status at the time of sampling, but also to social history (i.e., past social status), especially in unstimulated cells. However, for a subset of genes, we observed interaction effects in which females who fell in rank were more strongly affected by current social status than those who climbed the social hierarchy. Taken together, our results indicate that the effects of social status on immune cell gene expression depend on pathogen exposure, pathogen type, and social history-in support of social experience-mediated biological embedding in adulthood, even in the conventionally memory-less innate immune system.

Keywords: biological embedding; dominance rank; gene expression; immune response; social adversity.

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Conflict of interest statement

The authors declare no competing interest.

Figures

Fig. 1.
Fig. 1.
Social status effects on gene expression within and across conditions. (A) PCA of gene expression data across all 3 conditions. PC1, PC4, and PC5 separate negative controls (NC, blue) from LPS (green) and Gard (yellow)-stimulated samples. (B) Number of rank-associated genes (FDR <5%) that are more highly expressed in high-ranking females (top bars) or low-ranking females (bottom bars), within condition.
Fig. 2.
Fig. 2.
Contrasting effects of dominance rank in cells challenged with a bacterial mimic vs. a viral mimic. (A) Distribution of effect sizes among genes for which the magnitude of the response to LPS (green) and Gard (yellow) depends on dominance rank. After LPS stimulation, but not after Gard stimulation, most genes respond more strongly in low-status females. (B) Polarization of rank effects in the union of the top 10 GO categories, per condition, that were most enriched for up-regulation by LPS/Gard. Darker squares correspond to stronger statistical support for enrichment. Violin plots are colored based on the proportion of rank-associated genes that are more highly expressed in high-ranking individuals, separately by condition. Positive x-axis values: more highly expressed in high-ranking females; negative x-axis values: more highly expressed in low-ranking females. The gray-shaded box contains gene categories for which the distributions of rank effects differ significantly between LPS and Gard conditions (Wilcoxon test: Benjamini–Hochberg FDR-corrected P < 9 × 10−3). (C) Rank effects in the LPS (x-axis) vs. Gard (y-axis) conditions, for genes in the GO category “type I interferon signaling pathway” that were rank-associated in the LPS condition, Gard condition, or both. Labeled genes show cases in which rank effects are directionally reversed in LPS- vs. Gard-stimulated samples, including key master regulators of the response to virus, such as STAT1. In B and C, all genes affected by rank at an FDR of ≤20% are plotted; the overall pattern is qualitatively unchanged at a more stringent FDR threshold.
Fig. 3.
Fig. 3.
TF-binding sites enriched near rank-associated genes differ between LPS- and Gard-challenged cells. (A) In the LPS condition, predicted NF-κB and NF-κB subunit (RelA/RelB/p50/p65) binding sites are enriched in the promoter regions (5 kb upstream of gene transcription start sites) of genes that are up-regulated by LPS and more highly expressed in low-ranking females (Top), while predicted IRF and STAT1 binding sites dominate the enriched categories for genes that are up-regulated by LPS but more highly expressed in high-ranking females (Bottom). (B) This polarization disappears in the Gard condition, where predicted NF-κB, NF-κB subunit, IRF, and STAT1 binding sites are all enriched in the promoter regions of genes that are up-regulated by Gard and more highly expressed in low-ranking individuals (Top), with no clear signature of immune-related TF binding site enrichment among genes that are up-regulated by Gard but more highly expressed in high-ranking individuals (Bottom). Enrichment analyses shown here include all rank-associated genes at an FDR <20%. Error bars represent 95% confidence interval; TFs in yellow indicate enrichment at an FDR <10% (P < 1.3 × 10−3).
Fig. 4.
Fig. 4.
Social history effects on immune gene regulation. (A) Number of past rank-associated genes (FDR <10%) more highly expressed in previously high-ranking females (top bars) or low-ranking females (bottom bars), within condition. (B) Distribution of plasticity scores (Θ) for each condition for the top 1,000 rank-associated genes (SI Appendix, Materials and Methods and Fig. S7). (C) Current rank effects (x-axis) on expression of the TF FOSL1, which is involved in the type I IFN response (49), are strongest in females who were previously of high rank and weakest in females who were previously of low rank (βinteraction = 0.54, FDR-corrected P = 0.01). (D) Predicted current rank effects (SI Appendix, Materials and Methods) for low-past rank and high-past rank females (based on the mean Elo scores for the lowest-ranking and highest-ranking females in phase I groups). Distributions show estimated effect sizes across 1,079 genes for which we identified a significant current rank–past rank interaction effect in the control condition. Current rank effects were systematically larger in females who were previously high-ranking than in females who were previously low-ranking (Wilcoxon test, P < 2.2 × 10−16).
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