Biology subjects

Lin, Y.-P.

Publications and source records attributed to Lin, Y.-P..

30 records · Page 2Linked to original sources

bioRxiv2022

Co-infection of Ehrlichia with B. burgdorferi drives emergency myelopoiesis and promotes Lyme arthritis

Lyme disease is caused by the extracellular pathogen Borrelia burgdorferi (Bb), transmitted by the Ixodes scapularis tick. Approximately one-third of infected individuals develop arthritis of weight-bearing joints, though it is unclear why some patients develop arthritis and severe systemic disease while others do not. C57BL/6 (B6) mice are susceptible to Bb infection but do not develop arthritis, providing an in vivo model to evaluate mechanisms regulating development of Lyme arthritis. We demonstrate here that co-infection of B6 mice with the tick-borne pathogens Bb and Ehrlichia muris (Em) induced significant arthritis. Although co-infection did not impact bacterial burden or growth of either pathogen, the resultant Lyme arthritis in co-infected mice correlated with significant hematologic disturbances. Whereas single Bb infection elicited no overt hematologic changes, Em infection resulted in thrombocytopenia, lymphopenia, monocytosis, and granulocytosis, which was consistently observed in mice co-infected with both Bb and Em. Hematologic changes correlated with profound changes to the hematopoietic stem and progenitor cell (HSPC) populations in Em-infected mice. Most notable were dramatic reductions in populations of HSPCs committed to myeloid-biased differentiation. Co-infection resulted in persistent hematologic changes and bone marrow inflammation. Our data demonstrate for the first time that B6 mice, resistant to developing Lyme arthritis, exhibit severe joint pathology in the presence of a second pathogen, correlating with persistent emergency myelopoiesis. Our data support the conclusion that pathogen burden is not sufficient for disease and specific inflammatory signals and cells regulate the development of Lyme arthritis. ImportanceTick-borne illnesses, historically relegated to specific geographic areas, are increasing in prevalence and distribution. Borrelia burgdorferi causes Lyme disease, the most common tick-borne illness in North America, characterized by debilitating arthritis, carditis, and neurologic complications. It remains unclear why certain infected individuals develop severe disease while others are only mildly symptomatic. Human monocytic ehrlichiosis (HME) is another tick-borne disease that often results in profound illness and severe hematological disturbances. We show here that co-infection of B6 mice, resistant to Lyme arthritis, with Borrelia burgdorferi and Ehrlichia muris, used to model HME, results in the development of severe arthritis and emergency myelopoiesis. Our work suggests that immune activation driven by co-infection contributes to the development of Lyme arthritis.

immunology↗

bioRxiv2022

CspZ FH-binding sites as epitopes promote antibody-mediated Lyme borreliae clearance

Transmitted by ticks, the bacterium Borrelia burgdorferi sensu lato (Bbsl) is the causative agent of Lyme disease (LD), the most common vector-borne disease in the Northern hemisphere. No effective vaccines are currently available. Bbsl produces the CspZ protein that binds to the complement inhibitor, Factor H (FH), promoting evasion of the host complement system. We previously showed that while vaccination with CspZ did not protect mice from Bb infection, mice can be protected after immunization with CspZ-Y207A/Y211A (CspZ-YA), a CspZ mutant protein without FH-binding activity. To further study the mechanism of this protection, herein we evaluated both poly-and monoclonal antibodies recognizing CspZ FH-binding or non-FH-binding sites. We found that the anti-CspZ antibodies that recognize the FH-binding sites (i.e., block FH-binding activity) more efficiently eliminate Bbsl in vitro than those that bind to the non-FH-binding sites, and passive inoculation with anti-FH binding site antibodies eradicated Bbsl in vivo. Antibodies against non-FH-binding sites did not have the same effect. These results emphasize the importance of CspZ FH-binding sites in triggering a protective antibody response against Bbsl in future LD vaccines.

immunology↗

bioRxiv2022

Phylogenomic diversity elucidates mechanistic insights into Lyme borreliae host association

Host association- the selective adaptation of pathogens to specific host species - evolves through constant interactions between host and pathogens, leaving a lot yet to be discovered on immunological mechanisms and genomic determinants. The causative agents of Lyme disease (LD) are spirochete bacteria composed of multiple species of the Borrelia burgdorferi sensu lato complex, including B. burgdorferi (Bb), the main LD pathogen in North America - a useful model for the study of mechanisms underlying host-pathogen association. Host adaptation requires pathogens ability to evade host immune responses, such as complement, the first-line innate immune defense mechanism. We tested the hypothesis that different host adapted phenotypes among Bb strains are linked to polymorphic loci that confer complement evasion traits in a host-specific manner. We first examined the survivability of 20 Bb strains in sera in vitro and/or bloodstream and tissues in vivo from rodent and avian LD models. Three groups of complement-dependent host association phenotypes emerged. We analyzed complement-evasion genes, identified a priori among all strains and sequenced and compared genomes for individual strains representing each phenotype. The evolutionary history of ospC loci is correlated with host-specific complement-evasion phenotypes, while comparative genomics suggests several gene families and loci are potentially involved in host association. This multidisciplinary work provides novel insights into the functional evolution of host adapted phenotypes, building a foundation for further investigation of the immunological and genomic determinants of host association. IMPORTANCEHost association is the phenotype that is commonly found in many pathogens that preferential survive in particular hosts. The Lyme disease (LD) causing agent, B. burgdorferi (Bb), is an ideal model to study host association, as Bb is mainly maintained in nature through rodent and avian hosts. A widespread yet untested concept posits that host association in Bb strains is linked to Bb functional genetic variation conferring evasion to complement, an innate defense mechanism in vertebrate sera. Here, we tested this concept by grouping 20 Bb strains into three complement-dependent host association phenotypes based on their survivability in sera and/or bloodstream and distal tissues in rodent and avian LD models. Phylogenomic analysis of these strains further correlated several gene families and loci, including ospC, with host-specific complement-evasion phenotypes. Such multifaceted studies thus pave the road to further identify the determinants of host association, providing mechanistic insights into host-pathogen interaction.

microbiology↗

bioRxiv2022

Host adaptation drives genetic diversity in a vector-borne disease system

The range of hosts a pathogen can infect is a key trait influencing human disease risk and reservoir host infection dynamics. Borrelia burgdorferi sensu stricto (Bb), an emerging zoonotic pathogen, causes Lyme disease and is widely considered a host generalist, commonly infecting mammals and birds. Yet the extent of intraspecific variation in Bb host breadth, its role in determining host competence and potential implications to human infection remain unclear. We conducted a long-term study of Bb diversity, defined by the polymorphic ospC locus, across white-footed mice, passerine birds, and tick vectors leveraging long-read amplicon sequencing. Our results reveal strong variation in host breadth across Bb genotypes, exposing a spectrum of genotype-specific host-adapted phenotypes. We found support for multiple niche polymorphism maintaining Bb diversity in nature and little evidence of temporal shifts in genotype dominance, as would be expected under negative frequency-dependent selection. Passerine birds support the circulation of several human invasive strains in the local tick population and harbor greater Bb genotypic diversity compared to white-footed mice. Mouse-adapted Bb genotypes exhibited longer persistence in individual mice compared to non-adapted genotypes and infection communities infecting individual mice preferentially became dominated by mouse-adapted genotypes over time. We posit that intraspecific variation in Bb host breadth and specificity helps maintain overall species fitness in response to transmission by a generalist vector. Because pathogen genotypes vary in host breadth and result in diverse human disease manifestations, our findings indicate that a more nuanced definition of host competence incorporating local genotype frequency is warranted. SignificanceLyme disease is the most common vector-borne disease in the US with a causative agent (Borrelia burgdorferi) exhibiting high genetic diversity that partially correlates with human disease manifestations. Understanding the extent of host specificity in pathogens is critical for evaluating disease risk, but host specificity and mechanisms maintaining genetic diversity in Bb are unknown. We show that Bb genotypes exhibit variable host adaptation to white-footed mice and passerine birds, two common reservoir hosts, which appears to promote high intraspecific pathogen diversity. Conversely, we find limited evidence of negative frequency-dependent selection, an alternative mechanism for diversity maintenance. Our results reveal cryptic intraspecies host breadth variation and suggest that evaluating host competence depends on the frequency of host-adapted genotypes in local environments.

microbiology↗

bioRxiv2022

The climatic constrains of the historical global spread of mungbean

While the domestication history has been investigated in many crops, the process of cultivation range expansion and factors governing this process received relatively little attention. Here using mungbean (Vigna radiata var. radiata) as a test case, we investigated the genomes of more than one thousand accessions to illustrate climatic adaptations role in dictating the unique routes of cultivation range expansion. Despite the geographical proximity between South and Central Asia, genetic evidence suggests mungbean cultivation first spread from South Asia to Southeast, East, and finally reached Central Asia. Combining evidence from demographic inference, climatic niche modeling, plant morphology, and records from ancient Chinese sources, we showed that the specific route was shaped by the unique combinations of climatic constraints and farmer practices across Asia, which imposed divergent selection favoring higher yield in the south but short-season and more drought-tolerant accessions in the north. Our results suggest that mungbean did not radiate from the domestication center as expected purely under human activity, but instead the spread of mungbean cultivation is highly constrained by climatic adaptation, echoing the idea that human commensals are more difficult to spread through the south-north axis of continents.

evolutionary biology↗

bioRxiv2022

Neurobeachin controls the asymmetric subcellular distribution of electrical synapse proteins

The subcellular positioning of synapses and their specialized molecular compositions form the fundamental basis of neural circuits. Like chemical synapses, electrical synapses are constructed from an assortment of adhesion, scaffolding, and regulatory molecules, yet little is known about how these molecules localize at specified subcellular neuronal compartments. Here we investigated the relationship between the autism- and epilepsy-associated gene Neurobeachin, neuronal gap junction channelforming Connexins, and the scaffold ZO1. Using the zebrafish Mauthner circuit we found Neurobeachin localizes to the electrical synapse independent of ZO1 and Connexins. By contrast, we show Neurobeachin is required postsynaptically for the robust localization of ZO1 and Connexins. We demonstrate Neurobeachin binds ZO1 but not Connexins. Finally, we find Neurobeachin is required to restrict postsynaptic electrical synapse proteins to dendrites. These findings reveal a mechanism for the asymmetric synaptic localization of electrical synapse components providing a basis for the subcellular specialization of neuronal gap junctions.

neuroscience↗

bioRxiv2021

De novo SNP calling reveals the candidate genes regulating days to flowering through interspecies GWAS of Amaranthus genus

Amaranths serve as pseudo cereals and also as traditional leafy vegetables worldwide. In addition to high vigor and richness in nutrients, drought and salinity tolerance of amaranth makes it a promising vegetable to acclimatize to the effects of global climate change. The World Vegetable Center genebank conserves about 1,000 amaranth accessions and various agronomic properties of these accessions were recorded during seed regeneration over decades. In this study, we verified the taxonomic annotation of the germplasm based on a 15K SNP set. Besides, in the assumption that the yield components of grain amaranths are different from those of leaf amaranths, we observed that grain amaranths presented larger inflorescences and earlier flowering than leaf amaranths. Dual-purpose amaranth showed larger leaves than leaf amaranths and later flowering than grain amaranths, which seemed reasonable because farmers can harvest more leaves during the prolonged vegetable stage, which also provides recovery time to enrich grain production. Considering frequent interspecies hybridization among grain amaranth complex, we proposed an interspecies GWAS for days to flowering, identifying a AGL20/SOC1 homolog. Meanwhile, another GWAS using only A. tricolor accessions revealed six candidate genes homologous to lba1, bri1, sgs1 and fca. These homologous genes were involved in the regulation of flowering time in Arabidopsis. This study revealed the usefulness of genotypes for species demarcation in the genus Amaranthus and the potential of interspecies GWAS to detect QTLs across different species, opening up the possibility of targeted introduction of specific genetic variants into different Amaranthus species.

genomics↗

bioRxiv2021

Wolbachia in scale insects: a distinct pattern of infection frequencies and potential transfer routes via ant associates

Wolbachia is one of the most successful endosymbiotic bacteria of arthropods. Known as the "master of manipulation", Wolbachia can induce a wide range of phenotypes in its host that can have far-reaching ecological and evolutionary consequences and may be exploited for disease and pest control. However, our knowledge of Wolbachias distribution and infection rate is unevenly distributed across arthropod groups such as scale insects. We fitted a distribution of within-species prevalence of Wolbachia to our data and compared it to distributions fitted to an up-to-date dataset compiled from surveys across all arthropods. The estimated distribution parameters indicate a Wolbachia infection frequency of 43.6% (at a 10% prevalence threshold) in scale insects. Prevalence of Wolbachia in scale insects follows a distribution similar to exponential decline (most species are predicted to have low prevalence infections), in contrast to the U-shaped distribution estimated for other taxa (most species have a very low or very high prevalence). We observed no significant associations between Wolbachia infection and scale insect traits. Finally, we screened for Wolbachia in scale insects ecological associates. We found a positive correlation between Wolbachia infection in scale insects and their ant associates, pointing to a possible route of horizontal transfer of Wolbachia. Originality-Significance StatementBy creating metadata of Wolbachia infection in arthropods and applying a fitting an advanced mathematical model on the estimated infection frequency in scale insects, a unique pattern of infection prevalence was detected. In addition, ant-scale insect trophallaxis interaction was suggested as a plausible route of Wolbachia transfer

microbiology↗

bioRxiv2021

Host tropism determination by convergent evolution of immunological evasion in the Lyme disease system

Microparasites selectively adapt in some hosts, known as host tropism. Transmitted through ticks and carried mainly by mammals and birds, the Lyme disease (LD) bacterium is a well-suited model to study such tropism. LD bacteria species vary in host ranges through mechanisms eluding characterization. By feeding ticks infected with different LD bacteria species, utilizing feeding chambers and live mice and quail, we found species-level differences of bacterial transmission. These differences localize on the tick blood meal, and complement, a defense in vertebrate blood, and a bacterial polymorphic protein, CspA, which inactivates complement by binding to a host complement inhibitor, FH. CspA selectively confers bacterial transmission to vertebrates that produce FH capable of allele-specific recognition. Phylogenetic analyses revealed convergent evolution as the driver of such findings, which likely emerged during the last glacial maximum. Our results identify LD bacterial determinants of host tropism, defining an evolutionary mechanism that shapes host-microparasite associations.

microbiology↗

bioRxiv2020

Cellular and immunological mechanisms mediate reservoir host specialization by genotypically variable microparasites

Host specialization is an ecological and evolutionary process by which a pathogen becomes differentially adapted to a subset of hosts, restricting its host range. For parasites transmitted by generalist vectors, host specialization is not expected to evolve because of the decreased survival of those parasites in inadequate hosts. Thus, parasites may develop adaptation strategies, resulting in host specialization. The causative agents of Lyme disease are multiple species of bacteria, Borrelia burgdorferi sensu lato species complex (Bbsl), and are suitable for examining host specialization as birds and rodents were found to carry different species of these bacteria. Debate exists on whether host specialization occurs among these strains within a particular species of Bbsl, such as B. burgdorferi sensu stricto (Bbss). Current evidence supports some Bbss strains are widespread in white-footed mice but others are in non-rodent vertebrates, such as birds. To recapitulate specialization in the laboratory and define the mechanisms for host specialization, we introduced different genotypes of Bbss via tick transmission to American robins and white-footed mice, the Lyme disease reservoirs in North America. Among these strains, we found distinct levels of spirochete presence in the bloodstream and tissues and maintenance by these animals in a host-dependent fashion. We showed that the late stage persistence of these strains largely corresponds to bacterial survival at early infection onsets. We also demonstrated that those early survival phenotypes correspond to spirochete adhesiveness, evasion of complement-mediated killing in sera, and/or not triggering high levels of pro-inflammatory cytokines and antibodies. Our findings thus link host competence to Bbss with spirochete genotypic variation of adhesiveness and inducing/escaping host immune responses, illuminating the potential mechanisms that dictate host specialization. Such information will provide a foundation for further investigation into multi-disciplinary processes driving host specialization of microparasites. AUTHOR SUMMARYHost specialization arises when microparasites adapt to a subset of available hosts, restricting the host ranges they can infect. The mechanisms and selective pressures for the evolution of host specialization remain unclear. The causative agent of Lyme disease (LD), the bacteria species complex of Borrelia burgdorferi sensu lato, is adapted to different vertebrates. However, whether such a differential host adaption also applies to each genotype within the same species is under debate. Further, the mechanisms that drive such host specialization are unclear. We thus introduced three genotypes of one LD bacteria species (B. burgdorferi sensu stricto) individually via tick bite to American robins and white-footed mice, the most common LD reservoirs in North America. We found that these genotypes differed in the persistent maintenance by those reservoirs and occurred in a host-specific fashion. The ability of those bacteria for long-term maintenance was linked with their capability to attach to cells and a lack of induction of high levels of immune responses at early infection onsets. This work demonstrates the potential mechanisms that dictate host specialization of LD bacteria circulating in natural populations. Such information will pave the road to define the molecular, ecological, and evolutionary determinants that drive host-microparasite interactions.

microbiology↗

bioRxiv2019

Divergence in Thermostability of Arabidopsis Mitochondrial Nucleotide Exchange Factors Encoded by Duplicate Genes, MGE1 and MGE2

The divergence of duplicate genes links to organismic adaptation. In Arabidopsis thaliana two nuclear genes encode mitochondrial GrpEs, MGE1 and MGE2, the nucleotide exchange factors of DnaK/HSP70 chaperone. MGE1 and MGE2 are duplicate genes originated from a whole genome duplication event. They respond differentially to high temperature; MGE2 is heat-inducible and is required for Arabidopsis seedlings to tolerate prolonged heat stress, while MGE1 is constitutively expressed. Heterologous expression of MGE2 but not MGE1 restored the growth of E. coli grpE mutant cells at elevated temperatures, suggesting that MGE2 is more thermostable than MGE1. In this study, we directly compared the thermostability of the purified recombinant MGE1 and MGE2 by circular dichroism spectroscopy. The temperature midpoints of the unfolding transition (Tm) of MGE1 and MGE2 were about 38 and 46 {degrees}C, respectively, indicating that MGE2 is remarkably more stable than MGE1 at higher temperature. Domain swapping between the two homologous proteins showed that the N-terminal region, including an unstructured sequence and a long -helix domain, is the major determinant of the thermostability. Although MGE2 contains a conserved sequence derived from an exonized intron within the N-terminus unstructured region, deletion of this sequence did not substantially affect protein thermostability in vitro and complementation of E. coli and Arabidopsis heat sensitive mutants. Taken together, our results suggest that Arabidopsis MGE1 and MGE2 had diverged not only in transcriptional response but also in the thermostability of the encoded proteins, which may contribute to adaptation of plants to higher temperatures.

evolutionary biology↗

bioRxiv2018

Assessment of population differentiation and linkage disequilibrium in Solanum pimpinellifolium using genome-wide high-density SNP markers

To mine new favorable alleles for tomato breeding, we investigated the feasibility of utilizing Solanum pimpinellifolium as a diverse panel of genome-wide association study through the restriction site-associated DNA sequencing technique. Previous attempts to conduct genome-wide association study using S. pimpinellifolium were impeded by an inability to correct for population stratification and by lack of high-density markers to address the issue of rapid linkage disequilibrium decay. In the current study, a set of 24,330 SNPs was identified using 99 S. pimpinellifolium accessions from the Tomato Genetic Resource Center. Approximately 84% PstI site-associated DNA sequencing regions were located in the euchromatic regions, resulting in the tagging of most SNPs on or near genes. Our genotypic data suggested that the optimum number of S. pimpinellifolium ancestral subpopulations was three, and accessions were classified into seven groups. In contrast to the SolCAP SNP genotypic data of previous studies, our SNP genotypic data consistently confirmed the population differentiation, achieving a relatively uniform correction of population stratification. Moreover, as expected, rapid linkage disequilibrium decay was observed in S. pimpinellifolium, especially in euchromatic regions. Approximately two-thirds of the flanking SNP markers did not display linkage disequilibrium. Our result suggests that higher density of molecular markers and more accessions are required to conduct the genome-wide association study utilizing the Solanum pimpinellifolium collection.

genetics↗