Rewilding immunology

doi:10.1126/science.abb8664

GSTDTAP > 气候变化

DOI	10.1126/science.abb8664
	Rewilding immunology
	Andrew S. Flies; Wild Comparative Immunology Consortium
	2020-07-03
发表期刊	Science
出版年	2020
英文摘要	The common origin of all species provides a wealth of history recorded in DNA and a lens for understanding human biology. Immunology research has traditionally used rodents as the model of choice. However, translational success has not met its full potential. Broadening immunology research to integrate comparative approaches across species and environments can amplify the potential of immunology to improve the lives of humans and other animals. Additionally, it can lead to discoveries that are not possible in a restricted set of model organisms and environments. For example, the contemporary vaccine era arose from observing human-animal interactions in a real-world environment (cowpox infection protected milkmaids from smallpox). Most emerging infectious diseases (EIDs) originate in domestic and wild animals ([ 1 ][1]), and the coronavirus disease 2019 (COVID-19) pandemic is a stark reminder of the need to think more holistically about the health of humans and animals. The architecture of the immune system is an intricate network that has evolved over millions of years. Although no model organism can replicate all aspects of health and disease in another species, comparison of DNA and protein sequences across the tree of life is a straightforward and cost-effective means to select the most appropriate animal models for the question at hand (see the figure). For example, the current era of cancer immunotherapy was ushered in by the success of therapies that targeted the immune checkpoint protein cytotoxic T lymphocyte–associated protein 4 (CTLA4). Of the 134 mammals and 76 birds with CTLA4 orthologs listed in the National Center for Biotechnology Information Gene database, the key ligand binding motif (Met-Tyr-Pro-Pro-Pro-Tyr) in CTLA4 is identical in all 76 bird species and 131 of 134 mammals. Pigs ( Sus scrofa ) are common large-animal models for human pathologies and xenografts (implantation of tissue from another species), but they are one of the three species that have a divergent ligand-binding motif in CTLA4 ([ 2 ][2]). Accounting for differences in key immunoregulatory genes among experimental species can be easily integrated into the experimental design stage of the research process. The lack of reagents, such as monoclonal antibodies, for most species has historically been a barrier to integrating new species into the biomedical research cycle. However, the increasing number of fully sequenced genomes allows rapid comparison of gene networks across more than 200 species. De novo transcriptome assemblies can provide transcript sequences and expression patterns of species for which full genome sequence databases are unavailable, so that recombinant proteins can be quickly produced for protein-based immunology in species of interest ([ 3 ][3]). ![Figure][4] Real-world immunology feedback cycle Expanding the breadth of immunology to include more species and environments could benefit biomedical research. Phylogenetic analysis identifies appropriate model species. Successful laboratory mouse experiments replicated in “dirty” mice or natural disease models can stimulate a dynamic feedback cycle that improves preparedness for emerging infectious diseases, conservation efforts, and discovery of compounds that are not present in a restricted set of model species. GRAPHIC: V. ALTOUNIAN/ SCIENCE Funding constraints that limit development of specific reagents for every species can be overcome through a systematic effort to develop and characterize antibodies, nanobodies, or aptamers that bind to conserved protein motifs across taxonomic orders. This can reduce the number of reagents that need to be developed and enhance research efficiency by reducing the need for individual laboratories to sift out cross-reactive reagents for their species of interest. For example, antibodies that bind the conserved regions of proteins (such as CTLA4 ligand-binding motif) could potentially be used for immunophenotyping and functional assays in most vertebrate species. Standardized reagent panels that can be used for serological assays of immunoglobulins [such as immunoglobulin A (IgA), IgE, IgG, and IgM] and can identify key cell types (such as resident memory T cells) will allow meaningful comparison across species and larger taxonomic groups. The reagent development process itself has been simplified by the astute but serendipitous discovery of heavy chain–only antibodies in camels ( Camelus dromedarius ) ([ 4 ][5]). This new class of single-domain antibodies, also called nanobodies, streamlined the antibody-engineering process by allowing the production of high-affinity single-domain proteins. This allowed the creation of easy-to-use nanobody libraries that can be probed for binding to target proteins. For example, a nanobody library derived from a llama ( Lama glama ) that was immunized with the severe acute respiratory syndrome coronavirus (SARS-CoV, which causes SARS) spike protein that mediates target-cell entry has yielded a nanobody that binds to a conserved receptor-binding domain of the spike protein of SARS-CoV and SARS-CoV-2 (which causes COVID-19) ([ 5 ][6]). Furthermore, this nanobody has shown promising therapeutic potential after simple engineering to convert it to a bivalent human IgG Fc-fusion protein that has two linked nanobodies that bind the spike protein. In addition to integrating new species, integrating natural environments into animal studies can enhance understanding of the complex interplay between the host immune system, microbiota, and environment. For example, cohousing inbred laboratory mice with “dirty” mice from a pet shop resulted in mice with immunophenotypes that more closely resemble adult humans ([ 6 ][7]). Moving laboratory mice into outdoor enclosures revealed that immunological differences among laboratory mouse ( Mus musculus ) genotypes and phenotypes quickly disappeared in this more natural setting ([ 7 ][8]). Like the “dirty” mouse models, wild animals ranging from mice to spotted hyenas ( Crocuta crocuta ) generally exhibit a more mature, antigen-experienced immunophenotype than that of captive animals ([ 8 ][9], [ 9 ][10]), providing a more realistic view of the development and regulation of the vertebrate immune system. Although environmental variation increases experimental noise, advances in analytical techniques, statistics, and computational power are capable of sifting through this variation ([ 10 ][11]). Treatment outcomes that can be replicated in natural or wild settings have a higher probability of translating into real-world medical breakthroughs. Using this environmental filter in the early stages of biomedical research could increase efficiency by eliminating ineffective treatments before they progress to large-animal models and clinical trials. The concept that humans, nonhuman animals, and environments are linked biologically, culturally, and economically has recently become more formally recognized as “One Health.” For example, dogs and cats share homes, infections, and aspects of their microbiotas with their owners and thus can provide a “common garden” to tease apart genetic and environmental factors that regulate immune function. This can be accomplished without the need for expensive laboratory studies by integrating local veterinary clinics into research studies and asking pet owners for consent to collect minimally invasive tissue samples from their pets. Documenting the progression and resolution of immune responses to pathogens such as Salmonella , noroviruses, and SARS-CoV-2 in pet owners and their pets in parallel could reveal evolutionary patterns and insight into cross-species pathogen transmission ([ 11 ][12]). Proactive investment in comparative immunology can provide the historical baselines, tissue archives, and tools for more efficient responses to disease outbreaks. For example, an equine influenza outbreak in August 2007 in Australia incurred nearly $800 million in direct and indirect costs before eradication by June 2008 ([ 12 ][13]). Comparative immunology studies in horses and vaccine testing against influenza years before the outbreak facilitated a swift and effective emergency response. The variety of distinct mechanisms that wildlife species have evolved to deal with infectious diseases are a virtually untapped resource. For example, bats ( Chiroptera ) are a taxonomic order of interest because of their reservoir capacity for viral zoonotic diseases, such as SARS, Ebola, Hendra, Nipah, and rabies. Bats have distinct genomic features and expression patterns of genes associated with antiviral immune responses, including interferon cytokines and natural killer cell receptors. Despite the potential for comparative immunology studies to provide mechanistic insight into how some bats control or tolerate viruses, bat immunology studies remain limited. New pathways and compounds can be discovered in species even more distantly related to humans. For example, a ribonuclease discovered in northern leopard frogs ( Rana pipiens ) ([ 13 ][14]) has demonstrated in vivo therapeutic effects against mesothelioma in humans and in vitro antiviral activity against SARS-CoV and is currently in human trials for treating adenoviral conjunctivitis. Integrating new species and real-world environments into the broader immunology research paradigm will benefit not only human health but will also provide much needed resources for veterinary medicine and conservation efforts. The unprecedented loss of biodiversity in the past century was due to many factors but has been amplified by wildlife diseases. For example, chytridiomycosis, a fungal pathogen that has spread across the globe ([ 14 ][15]), is responsible for the decline of more than 500 amphibian species and the extinction of more than 90. Understanding amphibian immunology can contribute to conservation efforts to halt the spread of the pathogen and develop prophylactic and therapeutic disease management options ([ 15 ][16]). Evolution has been solving life-and-death problems for billions of years, and discovery of these creative solutions is only possible if research focus is expanded. A logical starting point for the expansion is to rigorously assess how current model species and environments reflect the true biology of human and animal diseases; when existing models are not adequate, new species and environments should be used. The future direction of this field should focus on real-world immunology scenarios that can maintain or accelerate the current progress of biomedical research without negatively affecting conservation efforts and generating new ethical concerns. The time is right for veterinarians, wildlife biologists, and disease ecologists to identify the key immunological questions and barriers in their research and then seek out people from other disciplines with the expertise and technical skills to overcome those barriers. However, the full potential of this emerging field cannot be achieved without support from the wider research community and funding agencies. Critical to this effort will be the willingness of immunologists to apply their scientific curiosity to the tree of life to help stimulate a dynamic interdisciplinary feedback cycle with impact for human health, EIDs, conservation, and translational research. [science.sciencemag.org/content/369/6499/37/suppl/DC1][17] 1. [↵][18]1. K. E. 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Flies for comments and edits on the manuscript and all participants in the 2019 Wild and Comparative workshop. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计	被引频次：16[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281868
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Andrew S. Flies,Wild Comparative Immunology Consortium. Rewilding immunology[J]. Science,2020.
APA	Andrew S. Flies,&Wild Comparative Immunology Consortium.(2020).Rewilding immunology.Science.
MLA	Andrew S. Flies,et al."Rewilding immunology".Science (2020).