Crystal structure of a guanine nucleotide exchange factor encoded by the scrub typhus pathogen
            <i>Orientia tsutsugamushi</i>

Lim, Christopher; Berk, Jason M.; Blaise, Alyssa M; Bircher, Josie; Koleske, Anthony J.; Hochstrasser, Mark; Xiong, Yong

doi:10.1073/pnas.2018163117

Cited by 8 publications

(3 citation statements)

References 46 publications

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“…S7A). This region in OtDUB binds clathrin adaptor-protein complexes AP-1 and AP-2 and harbors a cryptic Rac1 GEF domain ( 131 – 133 ). This indicates that cREM-1 proteins may have evolved from larger modular proteins with functions tailored to the eukaryotic cytosol, with repeat regions of these large effectors streamlining to smaller proteins encoded by tandem genes ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Metagenome diversity illuminates the origins of pathogen effectors

Lehman,

Verhoeve,

Driscoll

et al. 2024

mBio

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Recent metagenome-assembled genome (MAG) analyses have profoundly impacted Rickettsiology systematics. The discovery of basal lineages (novel families Mitibacteraceae and Athabascaceae) with predicted extracellular lifestyles exposed an evolutionary timepoint for the transition to host dependency, which seemingly occurred independent of mitochondrial evolution. Notably, these basal rickettsiae carry the Rickettsiales vir homolog ( rvh ) type IV secretion system and purportedly use rvh to kill congener microbes rather than parasitize host cells as described for later-evolving rickettsial pathogens. MAG analysis also substantially increased diversity for the genus Rickettsia and delineated a sister lineage (the novel genus Tisiphia ) that stands to inform on the emergence of human pathogens from protist and invertebrate endosymbionts. Herein, we probed Rickettsiales MAG and genomic diversity for the distribution of Rickettsia rvh effectors to ascertain their origins. A sparse distribution of most Rickettsia rvh effectors outside of Rickettsiaceae lineages illuminates unique rvh evolution from basal extracellular species and other rickettsial families. Remarkably, nearly every effector was found in multiple divergent forms with variable architectures, indicating profound roles for gene duplication and recombination in shaping effector repertoires in Rickettsia pathogens. Lateral gene transfer plays a prominent role in shaping the rvh effector landscape, as evinced by the discovery of many effectors on plasmids and conjugative transposons, as well as pervasive effector gene exchange between Rickettsia and Legionella species. Our study exemplifies how MAGs can yield insight into pathogen effector origins, particularly how effector architectures might become tailored to the discrete host cell functions of different eukaryotic hosts. IMPORTANCE While rickettsioses are deadly vector-borne human diseases, factors distinguishing Rickettsia pathogens from the innumerable bevy of environmental rickettsial endosymbionts remain lacking. Recent metagenome-assembled genome (MAG) studies revealed evolutionary timepoints for rickettsial transitions to host dependency. The rvh type IV secretion system was likely repurposed from congener killing in basal extracellular species to parasitizing host cells in later-evolving pathogens. Our analysis of MAG diversity for over two dozen rvh effectors unearthed their presence in some non-pathogens. However, most effectors were found in multiple divergent forms with variable architectures, indicating gene duplication and recombination-fashioned effector repertoires of Rickettsia pathogens. Lateral gene transfer substantially shaped pathogen effector arsenals, evinced by the discovery of effectors on plasmids and conjugative transposons, as well as pervasive effector gene exchanges between Rickettsia and Legionella species. Our study exemplifies how MAGs yield insight into pathogen effector origins and evolutionary processes tailoring effectors to eukaryotic host cell biology.

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Section: Resultsmentioning

confidence: 99%

Metagenome diversity illuminates the origins of pathogen effectors

Lehman,

Verhoeve,

Driscoll

et al. 2024

mBio

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“…Twenty four hours post plating, cells were fixed and stained as in Lim et al. ( 43 ). Cells were fixed for 5 min in 2% paraformaldehyde in cytoskeleton buffer (10 mM MES pH 6.8, 138 mM KCl, 3 mM MgCl 2 , 2 mM EGTA, 320 mM sucrose).…”

Section: Methodsmentioning

confidence: 99%

Autoinhibition of the GEF activity of cytoskeletal regulatory protein Trio is disrupted in neurodevelopmental disorder-related genetic variants

Bircher

Corcoran

Lam

et al. 2022

Journal of Biological Chemistry

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“…Scrub typhus is a life‐threatening vector‐borne disease caused by the bacterium Orientia tsutsugamushi , which is occasionally transmitted to humans during feeding of larval mites (Lim et al, 2020 ). The disease was traditionally thought to be restricted to a well‐defined geographic region called the “Asia‐Pacific tsutsugamushi triangle,” extending from far eastern Russia to northern Japan, northern Australia, the islands of the southwestern Pacific, and Afghanistan in the west (Kelly et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

Climate drives the spatiotemporal dynamics of scrub typhus in China

Ding

Wang

Hao

et al. 2022

Global Change Biology

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Scrub typhus is a climate-sensitive and life-threatening vector-borne disease that poses a growing public health threat. Although the climate-epidemic associations of many vector-borne diseases have been studied for decades, the impacts of climate on scrub typhus remain poorly understood, especially in the context of global warming.Here we incorporate Chinese national surveillance data on scrub typhus from 2010 to 2019 into a climate-driven generalized additive mixed model to explain the spatiotemporal dynamics of this disease and predict how it may be affected by climate change under various representative concentration pathways (RCPs) for three future time periods (the 2030s, 2050s, and 2080s). Our results demonstrate that temperature, precipitation, and relative humidity play key roles in driving the seasonal epidemic of scrub typhus in mainland China with a 2-month lag. Our findings show that the change of projected spatiotemporal dynamics of scrub typhus will be heterogeneous and will depend on specific combinations of regional climate conditions in future climate scenarios. Our results contribute to a better understanding of spatiotemporal dynamics of scrub typhus, which can help public health authorities refine their prevention and control measures to reduce the risks resulting from climate change.

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Crystal structure of a guanine nucleotide exchange factor encoded by the scrub typhus pathogen Orientia tsutsugamushi

Cited by 8 publications

References 46 publications

Metagenome diversity illuminates the origins of pathogen effectors

Metagenome diversity illuminates the origins of pathogen effectors

Autoinhibition of the GEF activity of cytoskeletal regulatory protein Trio is disrupted in neurodevelopmental disorder-related genetic variants

Climate drives the spatiotemporal dynamics of scrub typhus in China

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