Research paperNHP-immunome: A translational research-oriented database of non-human primate immune system proteins
Introduction
Worldwide, the mouse is the most commonly used model in biomedical research; however, ≈80 million years of evolution [1] had resulted in unsurpassable molecular [2], anatomical [3] immunological [4] and neurological [5] differences between rodents and humans. These differences significantly limit the use of this model in the study and understanding of human disease, as well as the design of translational therapeutics for conditions with no homology in mice.
As new in silico technologies and in vitro assays had reduced the necessity of animals for research experimentation, guidelines from regulatory agencies in the United States and Europe still consider the results obtained in non-human primates (NHPs) as the gold standard to assess the safety and efficacy of therapies to be later used in humans. Also, data from the US Department of Agriculture in 2017 show that a record number of NHPs is being used in biomedical research (https://www.aphis.usda.gov/aphis/home/) making the design and implementation of tools allowing the scientific community to use NHPs in the most rational, relevant, efficient and humane way a crucial necessity.
Due to their evolutionary relatedness to human, non-human primates are currently used as animal models in a wide range of medical fields including infection biology [6], development of medical prosthetics [7], neuroscience [8], safety testing of pharmaceutical molecules [9], ophthalmology [10], vaccinology [11] and xenotransplantation [12], among others.
The molecular characterization of the NHP immunome is critical since most diseases where these animals are used as models have an important immune component. Efforts have been undertaken by us and other groups to define the coding sequence and allelic variation of proteins involved in antigen presentation and recognition in owl monkeys [13], [14], [15], [16], [17], [18], [19], [20], [21], [22] and rhesus macaques [23], [24]; however, a detailed description of immunome genes in different NHP species and a web-based platform to easily access this pivotal information for the biomedical community are urgently needed.
Our group has been using Aotus nancymaae for the past 28 years to model the infection course of the malaria parasite Plasmodium falciparum in humans and to test vaccine candidates against this disease that killed 445,000 people in 2016 only [25]. We had previously characterized Toll like receptor 9 [26], CD1b [27], CD45 [28], IL-2, IL-4, IL-6, IL-10, IFN-γ and TNF-α [29] from A. nancymaae; nevertheless, the sequencing of the owl monkey genome allows us now to take a deeper look into the homology of immune system components of this animal model in the fight against malaria.
Previous computational efforts led to the molecular characterization of the set of genes playing a role in the human immune response excluding those loci involved in antigen recognition (immunoglobulins and T cell receptors) and presentation (major histocompatibility complex) [30], [31], [32], [33]. In this study, we annotated and compiled the immunome of the chimpanzee (Pan troglodytes) and the rhesus macaque (Macaca mulatta), as well as the new-world common marmoset (Callithrix jacchus) and Nancy Ma’s night (Aotus nancymaae) monkeys based on their orthology (defined as the best hit resulting from a reciprocal Blast search) to the curated human immunome. We also took a step further and included a comprehensive analysis on the different immune protein isoforms expressed on these species based on the latest RNA-seq-assisted annotations available [34], [35]. Moreover, we looked at the human immune system components which are not expressed in NHPs and those human proteins with expressed orthologs in individual NHP species, as well as the human diseases associated to the genes encoding these proteins. Data access for the NHP research community is available in the NHP-immunome web resource (http://www.fidic.org.co:90/proyecto/).
Section snippets
Human and NHP protein datasets
UniProtIDs corresponding to 831 proteins of the Homo sapiens immunome were retrieved from the human Immunome database [32]. FASTA sequences for all the known protein isoforms (2082 isoforms) were downloaded from UniProt [36]. Complete predicted proteomes based on tissue-specific RNA-seq datasets (Table 1) from Pan troglodytes (80,807 sequences), Macaca mulatta (55,312 sequences), Callithrix jacchus (45,251 sequences) and Aotus nancymaae (47,568 sequences) were obtained from the NCBI release
The NHP immunome reflects the evolutionary history of NHPs and human
From the 831 genes of the human immunome analyzed for this study, 827 genes showed at least one expressed ortholog in one of the four NHP species. In comparison, from 2082 protein isoforms of the human immunome, 1313 had at least one expressed ortholog in an NHP (Fig. 1A, Table S3). Identity distribution analysis for orthologous isoforms found in the four NHPs showed that in chimpanzees, at least 50% of the immunome isoforms identified showed more than 99.2% identity to their corresponding
Discussion
Non-human primates are widely used in biomedical research and, during the past decade, have been regaining preponderance over other animal models (e.g. mice and rats) due to their phylogenetic relatedness to humans and the need to translate the findings of basic research into druggable targets and marketable therapies. In this study, we computationally characterized the protein components of the immune system of four species of NHPs (P. troglodytes, M. mulatta, C. jacchus and A. nancymaae)
References (57)
- et al.
Basic neuroscience research with nonhuman primates: a small but indispensable component of biomedical research
Neuron
(2014) - et al.
Structural analysis of owl monkey MHC-DR shows that fully-protective malaria vaccine components can be readily used in humans
Biochem. Biophys. Res. Commun.
(2017) - et al.
Immunome: a reference set of genes and proteins for systems biology of the human immune system
Cell Immunol.
(2006) - et al.
Generation of a variant of human interleukin-4 by alternative splicing
Mol. Immunol.
(1996) The chemokine system: redundancy for robust outputs
Immunol. Today
(1999)- et al.
Mammal madness: is the mammal tree of life not yet resolved?
Philos. Trans. R. Soc. Lond. B Biol. Sci.
(2016) - et al.
C. Mouse Genome Sequencing, Lineage-specific biology revealed by a finished genome assembly of the mouse
PLoS Biol
(2009) - et al.
Of mice and men: aligning mouse and human anatomies
AMIA Annu. Symp. Proc.
(2005) - et al.
Of mice and not men: differences between mouse and human immunology
J. Immunol.
(2004) - et al.
Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways
Proc. Natl. Acad. Sci. U.S.A.
(2010)