Biology subjects

Nair, A.

Publications and source records attributed to Nair, A..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Recovering ecological interactions by mining non-target data from whole genome re-sequencing projects

The study of parasitic species can shed light on aspects of their hosts ecology. Such interactions are however often unknown or understudied due to the difficulty to detect and/or quantify many infections. Whole-genome sequencing and re-sequencing data have been generated at an increasing rate and reduced costs over the last two decades. Projects based on whole organisms, like whole insect specimens, provide genomic material for the target taxon, but may also include sequencing reads from associated microbes and other parasites. Here, we screened for the presence of non-host reads in a collection of whole-genome (re-) sequence projects from the Glanville fritillary butterfly, Melitaea cinxia, a model organism in research on the ecology and evolution of species in spatially structured and fragmented landscapes. We identified infections with different bacteria and eukaryotic parasites, which are shared between populations and underly both previously known and new biotic interactions for this butterfly species. The bacterial symbiont Wolbachia, usually common in insects, was found at relatively low prevalence, while Spiroplasma was ubiquitous across samples from several European populations of the butterfly. Additionally, we confirmed expected rates of larval parasitism by at least two parasitoid wasps. Such results provide proof of principle that key ecological interactions can be uncovered efficiently from existing data, an important first step to characterising the role host-associated organisms play in shaping the ecology and evolutionary history of their host species.

ecology↗

bioRxiv2024

A versatile mouse model to advance human microglia transplantation research in neurodegenerative diseases

BackgroundRecent studies highlight the critical role of microglia in neurodegenerative disorders, and emphasize the need for humanized models to accurately study microglial responses. Human-mouse microglia xenotransplantation models are a valuable platform for functional studies and for testing therapeutic approaches, yet currently those models are only available for academic research. This hampers their implementation for the development and testing of medication that targets human microglia. MethodsWe developed the hCSF1Bdes mouse line suitable as new transplantation model available to be crossed to any disease model of interest. The hCSF1Bdes model created by CRISPR gene editing is RAG2 deficient and expresses human CSF1. Additional we crossed this model with two humanized App KI mice, the AppHu and the AppSAA . Flow cytometry, immunohistochemistry and bulk sequencing was used to study the response of microglia in the context of Alzheimers disease. ResultsOur results demonstrate the successful transplantation of iPSC-derived human microglia into the brains of hCSF1Bdes mice without triggering a NK-driven immune response. Furthermore we confirmed the multipronged response of microglia in the context of Alzheimers disease. The hCSF1Bdes and the crosses with the Alzheimers disease knock-in model AppSAA and the humanized App knock-in control mice, AppHu are deposited with EMMA and fully accessible to the research community. Conclusionthe hCSF1Bdes mouse is available for both non-profit and for-profit organisations, facilitating the use of the xenotransplantation paradigm for human microglia to study complex human disease.

neuroscience↗

bioRxiv2024

Dendritic cells accelerate CAR T cells in irradiated tumors through chimeric synapses

The persistence of adoptively transferred T cells is vital for anti-tumor efficacy. Chimeric antigen receptor (CAR) T cells can persist indefinitely when delivered to patients with B cell cancers and can confer long-term remission. For patients with solid tumors, however, sustaining CAR T cell activity remains a major challenge. This has been attributed in part to the immune microenvironment within solid tumors, though the contribution of specific immune subsets to resistance to CAR T cells is not clear. Here we resolve how the immunology of irradiated tumors dramatically enhances persistence and efficacy of CAR T cells targeted to advanced lung metastases in a syngeneic mouse model. Remarkably, CAR T cell persistence depended critically on dendritic cells (DC) that underwent trogocytic "antigen-dressing" of tumor target antigens and stimulated CAR T cells through the chimeric receptor. Furthermore, tumor irradiation increased antigen-dressing onto DCs. In the absence of functional DCs, CAR T cell activity in irradiated tumor was short-lived and tumors relapsed. These findings establish a critical mechanism through which DCs maintain the CAR T cell pool in irradiated tumors, thus supporting translation of this approach to advance CAR T cell therapy for solid tumors.

immunology↗

bioRxiv2024

The Elevated Expression of ORF75, a Lytic KSHV Gene, in Kaposi Sarcoma Lesions is Driven by a GC-rich DNA cis Element in its Promoter Region

The spindle cells of Kaposi sarcoma (KS) lesions primarily express Kaposi sarcoma herpesvirus (KSHV) latent genes with minimal expression of lytic genes. However, recent transcriptome analyses of KS lesions have shown high expression of KSHV open reading frame (ORF) 75, which is considered a late lytic gene based on analyses in primary effusion lymphoma (PEL) lines. ORF75 encodes a pseudo-amidotransferase that is part of the viral tegument, acts as a suppressor of innate immunity, and is essential for viral lytic replication. We assessed a representative KS lesion by RNAscope and found that ORF75 RNA was expressed in the majority of latency-associated nuclear antigen (LANA)-expressing cells. Luciferase fusion reporter constructs of the ORF75 promoter were analyzed for factors potentially driving its expression in KS. The ORF75 promoter construct showed high basal transcriptional activity in vitro in endothelial cells, mediated by a proximal consensus specificity protein 1 (Sp1) (GGGGCGGGGC) element along with two distal CCAAT boxes. Sp proteins formed complexes with the proximal consensus Sp1 element to activate ORF75 promoter transcription. We also found evidence that a repressive factor or factors in B cells, but not endothelial or epithelial cells, interacted with more distal elements in the ORF75 promoter region to repress constitutive ORF75 expression in B cells. Alternate forms of Sp1 were found to accumulate during latency and showed substantial enrichment during viral lytic replication in PEL cells and infected endothelial cells, but their functional significance is unclear. We also found that ORF75 can in turn upregulate its own expression and that of other KSHV genes. Thus, while ORF75 acts primarily as a lytic gene in PEL cell lines, Sp proteins induce substantial constitutive ORF75 transcription in infected endothelial cells and this can account for its high expression in KS lesions. Author SummaryIn our study, we explored KSHV ORF75, a tegument protein that is increasingly being appreciated as playing a vital role in KSHV replication and inactivating the innate immune response. ORF75 is characterized as a late lytic protein but has been recently found to be consistently expressed in Kaposis sarcoma (KS) lesions, which generally express only latent KSHV genes. Our findings reveal that ORF75 is constitutively expressed in endothelial and epithelial cells, and to a lesser extent B-cells. We found that constitutive expression of ORF75 is largely mediated by specificity (Sp) proteins binding to a proximal Sp1 site in the ORF75 promoter region. Moreover, we found that the lower expression of ORF75 in KSHV-infected B cells is due to suppressive factors acting at a more distal region of the ORF75 promoter. We further found that ORF75 can enhance expression of its own RNA as well as that of several other KSHV proteins, including replication and transcription activator (RTA) and latency associated nuclear antigen (LANA). This constitutive expression of ORF75, a late lytic gene, can explain how it can play such an important role in the earlier steps in KSHV lytic activation and underscores the importance of this gene.

microbiology↗

bioRxiv2024

Single-cell and spatial transcriptomics of vulvar lichen sclerosus reveal multicompartmental alterations in gene expression and signaling cross-talk

Vulvar diseases are a critical yet often neglected area of womens health, profoundly affecting patients quality of life and frequently resulting in long-term physical and psychological challenges. Lichen sclerosus (LS) is a chronic inflammatory skin disorder that predominantly affects the vulva, leading to severe itching, pain, scarring, and an increased risk of malignancy. Despite its profound impact on affected individuals, the molecular pathogenesis of vulvar LS (VLS) is not well understood, hindering the development of FDA-approved therapies. Here, we utilize single-cell and spatial transcriptomics to analyze lesional and non-lesional skin from VLS patients, as well as healthy control vulvar skin. Our findings demonstrate histologic, cellular, and molecular heterogeneities within VLS, yet highlight unifying molecular changes across keratinocytes, fibroblasts, immune cells, and melanocytes in lesional skin. They reveal cellular stress and damage in fibroblasts and keratinocytes, enhanced T cell activation and cytotoxicity, aberrant cell-cell signaling, and increased activation of the IFN, JAK/STAT, and p53 pathways in specific cell types. Using both monolayer and organotypic culture models, we also demonstrate that knockdown of select genes, which are downregulated in VLS lesional keratinocytes, partially recapitulates VLS-like stress-associated changes. Collectively, these data provide novel insights into the pathogenesis of VLS, identifying potential biomarkers and therapeutic targets for future research.

genomics↗

bioRxiv2024

Population coding of predator imminence in the hypothalamus

Hypothalamic VMHdmSF1 neurons are activated by predator cues and are necessary and sufficient for instinctive defensive responses. However, such data do not distinguish which features of a predator encounter are encoded by VMHdmSF1 neural activity. To address this issue, we imaged VMHdmSF1 neurons at single-cell resolution in freely behaving mice exposed to a natural predator in varying contexts. Our results reveal that VMHdmSF1 neurons do not represent different defensive behaviors, but rather encode predator identity and multiple predator-evoked internal states, including threat-evoked fear/anxiety; neophobia or arousal; predator imminence; and safety. Notably, threat and safety are encoded bi-directionally by anti-correlated subpopulations. Finally, individual differences in predator defensiveness are correlated with differences in VMHdmSF1 response dynamics. Thus, different threat-related internal state variables are encoded by distinct neuronal subpopulations within a genetically defined, anatomically restricted hypothalamic cell class. HighlightsO_LIDistinct subsets of VMHdmSF1 neurons encode multiple predator-evoked internal states. C_LIO_LIAnti-correlated subsets encode safety vs. threat in a bi-directional manner C_LIO_LIA population code for predator imminence is identified using a novel assay C_LIO_LIVMHdmSF1 dynamics correlate with individual variation in predator defensiveness. C_LI

neuroscience↗

bioRxiv2024

Intrinsic dynamics and neural implementation of a hypothalamic line attractor encoding an internal behavioral state

Line attractors are emergent population dynamics hypothesized to encode continuous variables such as head direction and internal states. In mammals, direct evidence of neural implementation of a line attractor has been hindered by the challenge of targeting perturbations to specific neurons within contributing ensembles. Estrogen receptor type 1 (Esr1)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) show line attractor dynamics in male mice during fighting. We hypothesized that these dynamics may encode continuous variation in the intensity of an internal aggressive state. Here, we report that these neurons also show line attractor dynamics in head-fixed mice observing aggression. We exploit this finding to identify and perturb line attractor-contributing neurons using 2-photon calcium imaging and holographic optogenetic perturbations. On-manifold perturbations demonstrate that integration and persistent activity are intrinsic properties of these neurons which drive the system along the line attractor, while transient off-manifold perturbations reveal rapid relaxation back into the attractor. Furthermore, stimulation and imaging reveal selective functional connectivity among attractor-contributing neurons. Intriguingly, individual differences among mice in line attractor stability were correlated with the degree of functional connectivity among contributing neurons. Mechanistic modelling indicates that dense subnetwork connectivity and slow neurotransmission are required to explain our empirical findings. Our work bridges circuit and manifold paradigms, shedding light on the intrinsic and operational dynamics of a behaviorally relevant mammalian line attractor.

neuroscience↗

bioRxiv2024

Constitutive Endolysosomal Perforation in Neurons allows Induction of alpha-Synuclein Aggregation by Internalized Pre-Formed Fibrils

The endocytic pathway is both an essential route of molecular uptake in cells and a potential entry point for pathology-inducing cargo. The cell-to-cell spread of cytotoxic aggregates, such as those of -synuclein (-syn) in Parkinsons Disease (PD), exemplifies this duality. Here we used a human iPSC-derived induced neuronal model (iNs) prone to death mediated by aggregation in late endosomes and lysosomes of endogenous -syn, seeded by internalized pre-formed fibrils of -syn (PFFs). This PFF-mediated death was not observed with parental iPSCs or other non-neuronal cells. Using live-cell optical microscopy to visualize the read out of biosensors reporting endo-lysosome wounding, we discovered that up to about 10% of late endosomes and lysosomes in iNs exhibited spontaneous constitutive perforations, regardless of the presence of internalized PFFs. This wounding, absent in parental iPSCs and non-neuronal cells, corresponded to partial damage by nanopores in the limiting membranes of a subset of endolysosomes directly observed by volumetric focused ion beam scanning electron microscopy (FIB-SEM) in iNs and in CA1 pyramidal neurons from mouse brain, and not found in iPSCs or in other non-neuronal cells in culture or in mouse liver and skin. We suggest that the compromised limiting membranes in iNs and neurons in general are the primary conduit for cytosolic -syn to access PFFs entrapped within endo-lysosomal lumens, initiating PFF-mediated -syn aggregation. Significantly, eradicating the intrinsic endolysosomal perforations in iNs by inhibiting the endosomal Phosphatidylinositol-3-Phosphate/Phosphatidylinositol 5-Kinase (PIKfyve kinase) using Apilimod or Vacuolin-1 markedly reduced PFF-induced -syn aggregation, despite PFFs continuing to enter the endolysosomal compartment. Crucially, this intervention also diminished iN death associated with PFF incubation. Our results reveal the surprising presence of intrinsically perforated endo-lysosomes in neurons, underscoring their crucial early involvement in the genesis of toxic -syn aggregates induced by internalized PFFs. This discovery offers a basis for employing PIKfyve kinase inhibition as a potential therapeutic strategy to counteract synucleinopathies.

cell biology↗

bioRxiv2023

Closed-loop microstimulations of the orbitofrontal cortex during real-life gaze interaction enhance dynamic social attention

The prefrontal cortex is extensively involved in social exchange. During dyadic gaze interaction, multiple prefrontal areas exhibit neuronal encoding of social gaze events and context-specific mutual eye contact, supported by a widespread neural mechanism of social gaze monitoring. To explore causal manipulation of real-life gaze interaction, we applied weak closed-loop microstimulations that were precisely triggered by specific social gaze events to three prefrontal areas in monkeys. Microstimulations of orbitofrontal cortex (OFC), but not dorsomedial prefrontal or anterior cingulate cortex, enhanced momentary dynamic social attention in the spatial dimension by decreasing distance of ones gaze fixations relative to partner monkeys eyes. In the temporal dimension, microstimulations of OFC reduced the inter-looking interval for attending to another agent and the latency to reciprocate others directed gaze. These findings demonstrate that primate OFC serves as a functionally accessible node in controlling dynamic social attention and suggest its potential for a therapeutic brain interface.

neuroscience↗

bioRxiv2023

Neuropeptide Signaling Is Required To Implement A Line Attractor Encoding A Persistent Internal Behavioral State

Internal states drive survival behaviors, but their neural implementation is not well understood. Recently we identified a line attractor in the ventromedial hypothalamus (VMH) that represents an internal state of aggressiveness. Line attractors can be implemented by recurrent connectivity and/or neuromodulatory signaling, but evidence for the latter is scant. Here we show that neuropeptidergic signaling is necessary for line attractor dynamics in this system, using a novel approach that integrates cell type-specific, anatomically restricted CRISPR/Cas9-based gene editing with microendoscopic calcium imaging. Co-disruption of receptors for oxytocin and vasopressin in adult VMH Esr1+ neurons that control aggression suppressed attack, reduced persistent neural activity and eliminated line attractor dynamics, while only modestly impacting neural activity and sex- or behavior-tuning. These data identify a requisite role for neuropeptidergic signaling in implementing a behaviorally relevant line attractor. Our approach should facilitate mechanistic studies in neuroscience that bridge different levels of biological function and abstraction.

neuroscience↗

bioRxiv2023

In situ cryoET reveals inhibitor-induced perturbations in Pf80S GTPase interactions

Malaria parasites rely heavily on rapid, high fidelity protein synthesis to infect and replicate in human erythrocytes, making translation an attractive target for new antimalarials. Here, we have determined in situ structures of Pf80S ribosomes in thirteen conformational and compositional states from cryoFIB-milled Plasmodium falciparum-infected human erythrocytes across the stages of asexual intraerythrocytic parasite replication. We observe eight active translation intermediates, enabling us to define the native malarial translation elongation cycle, which surprisingly features a bifurcation at the decoding stage of the cycle that has not previously been described. Examination of perturbations in the distribution of ribosomes among these states in the presence of a malaria-specific translation inhibitor suggests that the inhibitor impedes PfeEF2 and PfeEF1 interactions with the ribosome. We integrated our in situ cryoET data with proteomic and ultrastructural data to arrive at a deeper understanding of malarial translation, which will inform development of new therapies.

biophysics↗

bioRxiv2023

Periodic hypothalamic attractor-like dynamics during the estrus cycle

Cyclic changes in hormonal state are well-known to regulate mating behavior during the female reproductive cycle, but whether and how these changes affect the dynamics of neural activity in the female brain is largely unknown. The ventromedial hypothalamus, ventro-lateral subdivision (VMHvl) contains a subpopulation of VMHvlEsr1+,Npy2r- neurons that controls female sexual receptivity. Longitudinal single cell calcium imaging of these neurons across the estrus cycle revealed that overlapping but distinct subpopulations were active during proestrus (mating-accepting) vs. non-proestrus (rejecting) phases. Dynamical systems analysis of imaging data from proestrus females uncovered a dimension with slow ramping activity, which generated approximate line attractor-like dynamics in neural state space. During mating, the neural population vector progressed along this attractor as male mounting and intromission proceeded. Attractor-like dynamics disappeared in non-proestrus states and reappeared following re-entry into proestrus. They were also absent in ovariectomized females but were restored by hormone priming. These observations reveal that hypothalamic line attractor-like dynamics are associated with female sexual receptivity and can be reversibly regulated by sex hormones, demonstrating that attractor dynamics can be flexibly modulated by physiological state. They also suggest a potential mechanism for the neural encoding of female sexual arousal.

neuroscience↗

bioRxiv2023

Multiplexed fluorescence and scatter detection with single cell resolution using on-chip fiber optics for droplet microfluidic applications

Droplet microfluidics has emerged as a critical component of several high-throughput single cell analysis techniques in biomedical research and diagnostics. However, while there has been significant progress in the individual assays being developed, multi-parametric optical sensing of droplets and their encapsulated contents remains challenging. The current common approach of microscopy based high-speed imaging of droplets is technically complex and requires expensive instrumentation limiting their large-scale adoption. Here we have adapted the principles of the widely established technique of flow cytometry to a novel optofluidic setup - the OptiDrop platform, with on-chip detection of scatter and multiple fluorescence signals from microfluidic droplets and their contents using optical fibers. The highly customizable on-chip optical fiber-based signal detection system enables simplified, miniaturized, low-cost, multi-parametric sensing of optical signals with high sensitivity and single cell resolution within each droplet. Our work on differential expression analysis of the Major Histocompatibility Complex (MHC) protein in response to IFN{gamma} stimulation further demonstrates the OptiDrop platforms capabilities in sensitively detecting cell surface biomarkers using fluorescently labeled antibodies. The OptiDrop platform thus combines the versatility of flow cytometry with the power of droplet microfluidics to provide wide-ranging optical sensing solutions for research and diagnostics.

bioengineering↗

bioRxiv2023

Myeloid Zfhx3 Deficiency Protects Against Hypercapnia-induced Suppression of Host Defense Against Influenza A Virus

Hypercapnia, elevation of the partial pressure of CO2 in blood and tissues, is a risk factor for mortality in patients with severe acute and chronic lung diseases. We previously showed that hypercapnia inhibits multiple macrophage and neutrophil antimicrobial functions, and that elevated CO2 increases the mortality of bacterial and viral pneumonia in mice. Here, we show that normoxic hypercapnia downregulates innate immune and antiviral gene programs in alveolar macrophages (AMOs). We also show that zinc finger homeobox 3 (Zfhx3), mammalian ortholog of zfh2, which mediates hypercapnic immune suppression in Drosophila, is expressed in mouse and human MOs. Deletion of Zfhx3 in the myeloid lineage blocked the suppressive effect of hypercapnia on immune gene expression in AMOs and decreased viral replication, inflammatory lung injury and mortality in hypercapnic mice infected with influenza A virus. Our results establish Zfhx3 as the first known mammalian mediator of CO2 effects on immune gene expression and lay the basis for future studies to identify therapeutic targets to interrupt hypercapnic immunosuppression in patients with advanced lung diseases. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/530480v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@f6f907org.highwire.dtl.DTLVardef@577795org.highwire.dtl.DTLVardef@6c0068org.highwire.dtl.DTLVardef@8ebb72_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

An approximate line attractor in the hypothalamus that encodes an aggressive internal state

The hypothalamus plays a key role in regulating innate behaviors. It is widely believed to function as a system of labeled lines, containing behavior-specific neurons with characteristic transcriptomic and connectomic profiles. This view however fails to explain why, although activation of estrogen receptor-1 (Esr1) expressing neurons in the ventromedial hypothalamus (VMHvl) promotes aggression, few VMHvl neurons are tuned to attack. To address this paradox, we adopted an unsupervised dynamical systems framework to analyze population activity among VMHvlEsr1 neurons during aggression. We discovered that this activity contains an "integration" dimension exhibiting slow-ramping dynamics and persistent activity that correlates with escalating aggressiveness. These dynamics are implemented as an approximate line attractor in state space. Our analysis suggests a function for VMHvl to encode the intensity of behavior-relevant motive states using line attractors. This view reconciles observational and perturbational studies of VMHvl, and reveals a new mode of neural computation in the hypothalamus.

neuroscience↗

bioRxiv2022

Collagen remodeling dictates pancreatic cancer bioenergetics and outcome through DDR1 activation or degradation

Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer that frequently progresses by liver metastasis1. Cancer-associated fibroblasts (CAF), extracellular matrix (ECM), and type I collagen (Col I) support2-5 or restrain PDAC progression and may impede blood supply and nutrient availability6-8. The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers escape nutrient limitation remain poorly understood. Here we show that matrix metalloprotease (MMP)-cleaved or intact Col I (cCol I and iCol I, respectively) exert opposing effects on PDAC bioenergetics, macropinocytosis (MP), tumor growth and liver metastasis. While cCol I activates DDR1 (discoidin domain receptor-1)-NF-{kappa}B-p62-NRF2 signaling to promote PDAC growth, iCol I triggers DDR1 degradation and restrains PDAC growth. Patients whose tumors are enriched in iCol I and low in DDR1 and NRF2 have improved median survival compared to those enriched in cCol I, DDR1 and NRF2. Inhibition of DDR1-stimulated NF-{kappa}B or mitochondrial biogenesis blocked tumorigenesis in wildtype mice but not in mice expressing MMP-resistant Col I. In summary, the diverse effects of tumor stroma on PDAC growth, metastasis, and patient survival are mediated through the Col I-DDR1-NF-{kappa}B-NRF2-mitochondrial biogenesis pathway, presenting multiple new opportunities for PDAC therapy.

cancer biology↗

bioRxiv2022

Molecular Dynamics simulation of TDP-43 RRM in the presence and absence of RNA

Structural characterization of the prion prone TAR DNA Binding protein (TDP)-43 has been challenging since its intrinsically disordered regions represents 15-30% of the total protein. TDP-43 is a nucleic acid binding protein with an N-terminal domain, two RNA Recognition Motifs (RRM1 and RRM2) and the C-terminal domain. In this study, we seek to define possible new targetable sites on the apo structure of TDP-43 RRM domains. To do so, we used molecular dynamic (MD) simulations on the NMR solved TDP-43RRM1-2 structure bound to RNA to predict the apo structure. Contact analysis of TDP-43 showed that while the integrity of the individual domains was maintained upon RNA removal, a decrease in interdomain contacts was observed. Moreover, we compared apo TDP-43 structures obtained from MD to AlphaFold 2 (AF2) predicted TDP-43 structures and found differences in loop regions. A Sitemap analysis identified five druggable sites for the RNA bound structure solved by NMR, while fewer sites were identified following MD simulations and AF2 predicted apo structures.

biophysics↗

bioRxiv2021

Geminiviral βC1 orchestrates organellar genomic instability to augment viral infection by hijacking host RecA

Chloroplast is the site for transforming light energy to chemical energy. It also acts as a production unit for a variety of defense-related molecules. These defense moieties are necessary to mount a successful counter defence against pathogens including viruses. Geminiviruses disrupt chloroplast homeostasis as a basic strategy for their successful infection inducing vein-clearing, mosaics and chlorosis in infected plants. Here we show that a geminiviral pathogenicity determinant protein {beta}C1 directly interferes with plastid homeostasis. {beta}C1 was capable of inducing organelle-specific nuclease to degrade plastid genome as well as diverted functions of RecA1 protein, a major player in plastid genome maintenance. {beta}C1 interacted with RecA1 in plants and its homolog in bacteria to reduce the ability of host cells to maintain genomic integrity under stresses. Further, reduction in the coding capacity of plastids severely affected retrograde signalling necessary for viral perception and activation of defense. Induction of chloroplast-specific nuclease by {beta}C1 is similar to phosphate starvation-response in which nucleotides are recycled to augment synthesis of new, potentially viral, DNA. These results indicate the presence of a novel strategy in which a viral protein alters host defence by targeting regulators of chloroplast DNA. We predict that the mechanism identified here might have similarities in other plant-pathogen interactions. One line summary{beta}C1 alters plastid genome metabolism.

plant biology↗