Dataset Information

Genomics of host-pathogen interactions: challenges and opportunities across ecological and spatiotemporal scales.

ABSTRACT: Evolutionary genomics has recently entered a new era in the study of host-pathogen interactions. A variety of novel genomic techniques has transformed the identification, detection and classification of both hosts and pathogens, allowing a greater resolution that helps decipher their underlying dynamics and provides novel insights into their environmental context. Nevertheless, many challenges to a general understanding of host-pathogen interactions remain, in particular in the synthesis and integration of concepts and findings across a variety of systems and different spatiotemporal and ecological scales. In this perspective we aim to highlight some of the commonalities and complexities across diverse studies of host-pathogen interactions, with a focus on ecological, spatiotemporal variation, and the choice of genomic methods used. We performed a quantitative review of recent literature to investigate links, patterns and potential tradeoffs between the complexity of genomic, ecological and spatiotemporal scales undertaken in individual host-pathogen studies. We found that the majority of studies used whole genome resolution to address their research objectives across a broad range of ecological scales, especially when focusing on the pathogen side of the interaction. Nevertheless, genomic studies conducted in a complex spatiotemporal context are currently rare in the literature. Because processes of host-pathogen interactions can be understood at multiple scales, from molecular-, cellular-, and physiological-scales to the levels of populations and ecosystems, we conclude that a major obstacle for synthesis across diverse host-pathogen systems is that data are collected on widely diverging scales with different degrees of resolution. This disparity not only hampers effective infrastructural organization of the data but also data granularity and accessibility. Comprehensive metadata deposited in association with genomic data in easily accessible databases will allow greater inference across systems in the future, especially when combined with open data standards and practices. The standardization and comparability of such data will facilitate early detection of emerging infectious diseases as well as studies of the impact of anthropogenic stressors, such as climate change, on disease dynamics in humans and wildlife.

SUBMITTER: Napflin K

PROVIDER: S-EPMC6839515 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Genomics of host-pathogen interactions: challenges and opportunities across ecological and spatiotemporal scales.

Näpflin Kathrin K O'Connor Emily A EA Becks Lutz L Bensch Staffan S Ellis Vincenzo A VA Hafer-Hahmann Nina N Harding Karin C KC Lindén Sara K SK Olsen Morten T MT Roved Jacob J Sackton Timothy B TB Shultz Allison J AJ Venkatakrishnan Vignesh V Videvall Elin E Westerdahl Helena H Winternitz Jamie C JC Edwards Scott V SV

PeerJ 20191105

Evolutionary genomics has recently entered a new era in the study of host-pathogen interactions. A variety of novel genomic techniques has transformed the identification, detection and classification of both hosts and pathogens, allowing a greater resolution that helps decipher their underlying dynamics and provides novel insights into their environmental context. Nevertheless, many challenges to a general understanding of host-pathogen interactions remain, in particular in the synthesis and int ...[more]

PMID: 31720122

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Project description:PurposeCoccidioidomycosis (CM) is a systemic fungal disease caused by the dimorphic fungi Coccidioides immitis and Coccidioides posadasii. In its endemic areas of the United States, CM is growing as a public health challenge with a marked increase in incidence in the last 15 years. Although Coccidioides infection is asymptomatic in most cases, symptomatic pulmonary disease occurs in ~40% and disseminated coccidioidomycosis (DCM) occurs in ~1% of previously healthy children and adults. DCM is markedly more common in immunocompromised people, who often experience life-threatening disease despite use of antifungal medications. Although options for antifungal therapy have improved, lifelong therapy is needed for those who develop coccidioidal meningitis. The purpose of this article was to review the state of antifungal therapy and recent studies of host-pathogen interactions in CM in light of advances in immunomodulatory therapy.MethodsThe study included a review of PubMed and abstracts of the Coccidioidomycosis Study Group (years 2000-2019).FindingsCurrent therapy for CM relies upon azole and polyene antifungal agents. Murine models and studies of DCM in patients with monogenic primary immunodeficiency states and acquired immunodeficiency have revealed the importance of both innate and adaptive immune responses in the control of infections with Coccidioides species. In particular, defects in sensing of fungi and induction of cellular immune responses have been frequently reported. More recently, polymorphisms in key signaling pathways and in the generation of Th17 and Th1 immune responses have been linked with DCM.ImplicationsAntifungal therapy is sufficient to control disease in most cases of CM, but treatment failure occurs in cases of severe pulmonary disease and nonmeningeal disseminated disease. Lifelong therapy is recommended for meningitis in view of the very high risk of recurrence. Corticosteroid therapy is advised by some experts for severe pulmonary disease and for some neurologic complications of DCM. DCM is only rarely the result of a severe monogenic immunodeficiency. Case studies suggest that reorienting cellular immune responses or augmenting effector immune responses may help resolve DCM. Systematic investigation of immunotherapy for coccidioidomycosis is advisable and may help to address the recent marked increase in reports of the disease in endemic areas.

Project description:The goal of this project is to understand the etiology and pathology of host-pathogen interaction using high-throughput cellular phenotyping. By combining the expertise in pathogen biology, informatics and stem cell biology across the institute, this project will use targeted genetic modification in mouse embryonic stem cells to identify functions of host genes in innate immunity. We will also explore the biology of mouse embryonic stem cells and their differentiation into immune competent cells. To this end we will generate homozygous and inducible knockout lines in mouse embryonic stem cells, which will be differentiated into immune competent cells, such as macrophages or dendritic cells. These will be subjected to a panel of immune challenge and stimulation assays to characterise the functions of the disrupted genes. To identify new functions for mammalian genes in innate immunity we will:\Generate a panel of homozygous inducible gene knockout mouse ES cell lines working from a list of ca. 80 candidate genes (MGP phenotyping and GWAS hits). \Scale up differentiation protocols for immune challenge and stimulation assays.\Benchmark in vitro differentiated ES cell models against primary immune cells from selected MGP mouse lines and eventually against human iPS cells.\Screen a panel of 30 genetically modified cell lines in immunological challenge and stimulation assays, defining phenotypes at the cellular level by high content imaging, biochemically by assaying cytokine production, and at the molecular level by transcriptome analysis.\Define novel gene functions in innate immunity through network analysis of gene expression data from all challenged cell lines.\In the longer term scale up the production and phenotyping of genetically modified cell lines (mouse or human as appropriate).This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

Dataset Information

Genomics of host-pathogen interactions: challenges and opportunities across ecological and spatiotemporal scales.

Publications

Genomics of host-pathogen interactions: challenges and opportunities across ecological and spatiotemporal scales.

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