Explore the vast range of titles available.

Analysis of whole-genome sequencing data from 163 vervet monkeys from Africa and the Caribbean shows high diversity among taxa and identifies signatures of selection. Selection signals affect viral processes, and genes that show response to SIV in vervets but not macaques have elevated selection scores. Vervet monkeys are among the most widely distributed nonhuman primates, show considerable phenotypic diversity, and have long been an important biomedical model for a variety of human diseases and in vaccine research. Using whole-genome sequencing data from 163 vervets sampled from across Africa and the Caribbean, we find high diversity within and between taxa and clear evidence that taxonomic divergence was reticulate rather than following a simple branching pattern. A scan for diversifying selection across taxa identifies strong and highly polygenic selection signals affecting viral processes. Furthermore, selection scores are elevated in genes whose human orthologs interact with HIV and in genes that show a response to experimental simian immunodeficiency virus (SIV) infection in vervet monkeys but not in rhesus macaques, suggesting that part of the signal reflects taxon-specific adaptation to SIV.

Manipulating plasma lipids Recent work in mice has shown that microRNA-33a is an important regulator of lipid metabolism and that its inhibition can increase plasma high-density lipoprotein (HDL) and decrease atherosclerosis. Rayner et al . take an important step in translating these findings to non-human primates (African green monkeys), which, like humans and unlike mice, express both miR-33a and miR-33b. They find that anti-miR-33 is effective at inhibiting both miR-33a and miR-33b. As seen in the mouse studies, anti-miR33 raised plasma HDL but had the additional beneficial effect of reducing very low-density lipoprotein triglycerides, making this type of 'antagomir' therapy a candidate method of treating dyslipidaemias that increase cardiovascular disease risk. Cardiovascular disease remains the leading cause of mortality in westernized countries, despite optimum medical therapy to reduce the levels of low-density lipoprotein (LDL)-associated cholesterol. The pursuit of novel therapies to target the residual risk has focused on raising the levels of high-density lipoprotein (HDL)-associated cholesterol in order to exploit its atheroprotective effects 1 . MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of lipid metabolism and are thus a new class of target for therapeutic intervention 2 . MicroRNA-33a and microRNA-33b (miR-33a/b) are intronic miRNAs whose encoding regions are embedded in the sterol-response-element-binding protein genes SREBF2 and SREBF1 (refs 3–5 ), respectively. These miRNAs repress expression of the cholesterol transporter ABCA1, which is a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL levels 3 , 4 , 5 and providing protection against atherosclerosis 6 ; however, extrapolating these findings to humans is complicated by the fact that mice lack miR-33b, which is present only in the SREBF1 gene of medium and large mammals. Here we show in African green monkeys that systemic delivery of an anti-miRNA oligonucleotide that targets both miR-33a and miR-33b increased hepatic expression of ABCA1 and induced a sustained increase in plasma HDL levels over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in fatty acid oxidation ( CROT , CPT1A , HADHB and PRKAA1 ) and reduced the expression of genes involved in fatty acid synthesis ( SREBF1 , FASN, ACLY and ACACA ), resulting in a marked suppression of the plasma levels of very-low-density lipoprotein (VLDL)-associated triglycerides, a finding that has not previously been observed in mice. These data establish, in a model that is highly relevant to humans, that pharmacological inhibition of miR-33a and miR-33b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglyceride levels for the treatment of dyslipidaemias that increase cardiovascular disease risk.

Animal models are an integral part of the drug development and evaluation process. However, they are unsurprisingly imperfect reflections of humans, and the extent and nature of many immunological differences are unknown. With the rise of targeted and biological therapeutics, it is increasingly important that we understand the molecular differences in the immunological behavior of humans and model organisms. However, very few antibodies are raised against non-human primate antigens, and databases of cross-reactivity between species are incomplete. Thus, we screened 332 antibodies in five immune cell populations in blood from humans and four non-human primate species generating a comprehensive cross-reactivity catalog that includes cell type-specificity. We used this catalog to create large mass cytometry universal cross-species phenotyping and signaling panels for humans, along with three of the model organisms most similar to humans: rhesus and cynomolgus macaques and African green monkeys; and one of the mammalian models most widely used in drug development: C57BL/6 mice. As a proof-of-principle, we measured immune cell signaling responses across all five species to an array of 15 stimuli using mass cytometry. We found numerous instances of different cellular phenotypes and immune signaling events occurring within and between species, and detailed three examples (double-positive T cell frequency and signaling; granulocyte response to Bacillus anthracis antigen; and B cell subsets). We also explore the correlation of herpes simian B virus serostatus on the immune profile. Antibody panels and the full dataset generated are available online as a resource to enable future studies comparing immune responses across species during the evaluation of therapeutics.

The humoral arm of innate immunity includes diverse molecules with antibody-like functions, some of which serve as disease severity biomarkers in coronavirus disease 2019 (COVID-19). The present study was designed to conduct a systematic investigation of the interaction of human humoral fluid-phase pattern recognition molecules (PRMs) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of 12 PRMs tested, the long pentraxin 3 (PTX3) and mannose-binding lectin (MBL) bound the viral nucleocapsid and spike proteins, respectively. MBL bound trimeric spike protein, including that of variants of concern (VoC), in a glycan-dependent manner and inhibited SARS-CoV-2 in three in vitro models. Moreover, after binding to spike protein, MBL activated the lectin pathway of complement activation. Based on retention of glycosylation sites and modeling, MBL was predicted to recognize the Omicron VoC. Genetic polymorphisms at the MBL2 locus were associated with disease severity. These results suggest that selected humoral fluid-phase PRMs can play an important role in resistance to, and pathogenesis of, COVID-19, a finding with translational implications.Stravalaci et al. examined recognition of SARS-CoV-2 by human soluble innate pattern recognition receptor. They report that pentraxin 3 and mannose-binding protein recognize viral nucleoprotein and spike, respectively. Mannose-binding lectin has antiviral activity, and human genetic polymorphisms of MBL2 are associated with more severe COVID-19.

Fevers are considered an adaptive response by the host to infection. For gregarious animals, however, fever and the associated sickness behaviors may signal a temporary loss of capacity, offering other group members competitive opportunities. We implanted wild vervet monkeys (Chlorocebus pygerythrus) with miniature data loggers to obtain continuous measurements of core body temperature. We detected 128 fevers in 43 monkeys, totaling 776 fever-days over a 6-year period. Fevers were characterized by a persistent elevation in mean and minimum 24-h body temperature of at least 0.5 °C. Corresponding behavioral data indicated that febrile monkeys spent more time resting and less time feeding, consistent with the known sickness behaviors of lethargy and anorexia, respectively. We found no evidence that fevers influenced the time individuals spent socializing with conspecifics, suggesting social transmission of infection within a group is likely. Notably, febrile monkeys were targeted with twice as much aggression from their conspecifics and were six times more likely to become injured compared to afebrile monkeys. Our results suggest that sickness behavior, together with its agonistic consequences, can carry meaningful costs for highly gregarious mammals. The degree to which social factors modulate the welfare of infected animals is an important aspect to consider when attempting to understand the ecological implications of disease.

Nelson Freimer and colleagues analyze gene expression data from multiple tissue samples combined with genotype data from vervet monkeys to catalog expression quantitative trait loci (eQTLs). They generate a transcriptome resource analogous to the GTEx project and perform comparative and eQTL enrichment analyses for various traits. By analyzing multitissue gene expression and genome-wide genetic variation data in samples from a vervet monkey pedigree, we generated a transcriptome resource and produced the first catalog of expression quantitative trait loci (eQTLs) in a nonhuman primate model. This catalog contains more genome-wide significant eQTLs per sample than comparable human resources and identifies sex- and age-related expression patterns. Findings include a master regulatory locus that likely has a role in immune function and a locus regulating hippocampal long noncoding RNAs (lncRNAs), whose expression correlates with hippocampal volume. This resource will facilitate genetic investigation of quantitative traits, including brain and behavioral phenotypes relevant to neuropsychiatric disorders.

In numerous social species, males direct aggression towards female group members during intergroup fights, and this behaviour is commonly thought to function as mate guarding, even though males often target non-receptive females. In studying intergroup fights in a wild population of vervet monkeys, we found that male intragroup aggression was primarily directed towards individuals who had either just finished exhibiting, or were currently attempting to instigate intergroup aggression. Targeted females were less likely to instigate intergroup aggression in the future, indicating that male intragroup aggression functioned as coercion (when directed towards those who were currently trying to instigate a fight) and punishment (when directed towards those who had recently fought). These manipulative tactics effectively prevented intergroup encounters from escalating into fights and often de-escalated ongoing conflicts. Males who were likely sires were those most likely to use punishment/coercion, particularly when they were wounded, and, therefore, less able to protect vulnerable offspring should a risky intergroup fight erupt. This work, along with our previous finding that females use punishment and rewards to recruit males into participating in intergroup fights, highlights the inherent conflict of interest that exists between the sexes, as well as the role that social incentives can play in resolving this conflict. Furthermore, unlike other studies which have found punishment to be used asymmetrically between partners, these works represent a novel example of reciprocal punishment in a non-human animal.

HIV emerged following cross-species transmissions of simian immunodeficiency viruses (SIVs) that naturally infect non-human primates (NHPs) from Africa. While HIV replication and CD4 + T-cell depletion lead to increased gut permeability, microbial translocation, chronic immune activation, and systemic inflammation, the natural hosts of SIVs generally avoid these deleterious consequences when infected with their species-specific SIVs and do not progress to AIDS despite persistent lifelong high viremia due to long-term coevolution with their SIV pathogens. The benign course of natural SIV infection in the natural hosts is in stark contrast to the experimental SIV infection of Asian macaques, which progresses to simian AIDS. The mechanisms of non-pathogenic SIV infections are studied mainly in African green monkeys, sooty mangabeys, and mandrills, while progressing SIV infection is experimentally modeled in macaques: rhesus macaques, pigtailed macaques, and cynomolgus macaques. Here, we focus on the distinctive features of SIV infection in natural hosts, particularly (1): the superior healing properties of the intestinal mucosa, which enable them to maintain the integrity of the gut barrier and prevent microbial translocation, thus avoiding excessive/pathologic immune activation and inflammation usually perpetrated by the leaking of the microbial products into the circulation; (2) the gut microbiome, the disruption of which is an important factor in some inflammatory diseases, yet not completely understood in the course of lentiviral infection; (3) cell population shifts resulting in target cell restriction (downregulation of CD4 or CCR5 surface molecules that bind to SIV), control of viral replication in the lymph nodes (expansion of natural killer cells), and anti-inflammatory effects in the gut (NKG2a/c + CD8 + T cells); and (4) the genes and biological pathways that can shape genetic adaptations to viral pathogens and are associated with the non-pathogenic outcome of the natural SIV infection. Deciphering the protective mechanisms against SIV disease progression to immunodeficiency, which have been established through long-term coevolution between the natural hosts and their species-specific SIVs, may prompt the development of novel therapeutic interventions, such as drugs that can control gut inflammation, enhance gut healing capacities, or modulate the gut microbiome. These developments can go beyond HIV infection and open up large avenues for correcting gut damage, which is common in many diseases.

Natural hosts of simian immunodeficiency virus (SIV) avoid AIDS despite lifelong infection. Here, we examined how this outcome is achieved by comparing a natural SIV host, African green monkey (AGM) to an AIDS susceptible species, rhesus macaque (RM). To asses gene expression profiles from acutely SIV infected AGMs and RMs, we developed a systems biology approach termed Conserved Gene Signature Analysis (CGSA), which compared RNA sequencing data from rectal AGM and RM tissues to various other species. We found that AGMs rapidly activate, and then maintain, evolutionarily conserved regenerative wound healing mechanisms in mucosal tissue. The wound healing protein fibronectin shows distinct tissue distribution and abundance kinetics in AGMs. Furthermore, AGM monocytes exhibit an embryonic development and repair/regeneration signature featuring TGF-β and concomitant reduced expression of inflammatory genes compared to RMs. This regenerative wound healing process likely preserves mucosal integrity and prevents inflammatory insults that underlie immune exhaustion in RMs. Here, the authors compare gene expression signatures in rectal tissues of African green monkeys (AGMs) and rhesus macaques (RMs) acutely infected with simian immunodeficiency virus and find that AGMs rapidly activate and maintain evolutionarily conserved regenerative wound healing mechanisms.

Animal paths are analogous to intractable mathematical problems like the Traveling Salesman Problem (TSP) and the shortest path problem (SPP). Both the TSP and SPP require an individual to find the shortest path through multiple targets but the TSP demands a return to the start, while the SPP does not. Vervet monkeys are very efficient in solving TSPs but this species is a multiple central place forager that does not always return to the same sleeping site and thus theoretically should be selected to find solutions to SPPs rather than TSPs. We examined path choice by wild vervets in an SPP experimental array where the shortest paths usually differed from those consistent with common heuristic strategies, the nearest-neighbor rule (NNR-go to the closest resource that has not been visited), and the convex hull (put a mental loop around sites, adding inner targets in order of distance from the edge)-an efficient strategy for TSPs but not SPPs. In addition, humans solving SPPs use an initial segment strategy (ISS-choose the straightest path at the beginning, only turning when necessary) and we looked at vervet paths consistent with this strategy. In 615 trials by single foragers, paths usually conformed to the NNR and rarely the slightly more efficient convex hull, supporting that vervets may be selected to solve SPPs. Further, like humans solving SPPs, vervets showed a tendency to use the ISS. Paths consistent with heuristics dropped off sharply, and use of the shortest path increased, when heuristics led to longer paths showing trade-offs in efficiency versus cognitive load. Two individuals out of 17, found the shortest path most often, showing inter-individual variation in path planning. Given support for the NNR and the ISS, we propose a new rule-of-thumb termed the \"region heuristic\" that vervets may apply in multi-destination routes.