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At least 235 records · Page 13
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Modeling resistance to the broadly neutralizing antibody PGT121 in people living with HIV-1

PGT121 is a broadly neutralizing antibody in clinical development for the treatment and prevention of HIV-1 infection via passive administration. PGT121 targets the HIV-1 V3-glycan and demonstrated potent antiviral activity in a phase I clinical trial. Resistance to PGT121 monotherapy rapidly occurred in the majority of participants in this trial with the sampled rebound viruses being entirely resistant to PGT121 mediated neutralization. However, two individuals experienced long-term ART-free viral suppression following antibody infusion and retained sensitivity to PGT121 upon viral rebound. Here, we develop mathematical models of the HIV-1 dynamics during this phase I clinical trial. We utilize these models to understand the dynamics leading to PGT121 resistance and to identify the mechanisms driving the observed long-term viral control. Our modeling highlights the importance of the relative fitness difference between PGT121 sensitive and resistant subpopulations prior to treatment. Specifically, by fitting our models to data, we identify the treatment-induced competitive advantage of previously existing or newly generated resistant population as a primary driver of resistance. Finally, our modeling emphasizes the high neutralization ability of PGT121 in both participants who exhibited long-term viral control.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Drug-Inducible Gene Therapy Effectively Reduces Spontaneous Seizures in Kindled Rats but Creates Off-Target Side Effects in Inhibitory Neurons

Over a third of patients with temporal lobe epilepsy (TLE) are not effectively treated with current anti-seizure drugs, spurring the development of gene therapies. The injection of adeno-associated viral vectors (AAV) into the brain has been shown to be a safe and viable approach. However, to date, AAV expression of therapeutic genes has not been regulated. Moreover, a common property of antiepileptic drugs is a narrow therapeutic window between seizure control and side effects. Therefore, a long-term goal is to develop drug-inducible gene therapies that can be regulated by clinically relevant drugs. In this study, a first-generation doxycycline-regulated gene therapy that delivered an engineered version of the leak potassium channel Kcnk2 (TREK-M) was injected into the hippocampus of male rats. Rats were electrically stimulated until kindled. EEG was monitored 24/7. Electrical kindling revealed an important side effect, as even low expression of TREK M in the absence of doxycycline was sufficient to cause rats to develop spontaneous recurring seizures. Treating the epileptic rats with doxycycline successfully reduced spontaneous seizures. Localization studies of infected neurons suggest seizures were caused by expression in GABAergic inhibitory neurons. In contrast, doxycycline increased the expression of TREK-M in excitatory neurons, thereby reducing seizures through net inhibition of firing. These studies demonstrate that drug-inducible gene therapies are effective in reducing spontaneous seizures and highlight the importance of testing for side effects with pro-epileptic stressors such as electrical kindling. These studies also show the importance of evaluating the location and spread of AAV-based gene therapies in preclinical studies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Examining the role of glycoside hydrolases in local rheology of Pseudomonas aeruginosa biofilms

Current research strategies in the treatment of biofilm infections have focused on dispersal, in which bacteria are made to vacate the extracellular polymeric substance (EPS) surrounding them and return to a planktonic state where antimicrobial treatments are more effective. Glycoside hydrolases (GHs), which cleave bonds in EPS polysaccharides, have been shown to promote dispersal in Pseudomonas aeruginosa biofilms. The dispersal mechanism is possibly due to GHs’ ability to directly release bacteria from the EPS, disrupt EPS’ ability to regulate the environment, or reduce overall mechanical stability. In this work, passive microrheology is used to examine the relevance of the last mechanism by exploring the effects of three GHs (α-amylase, cellulase, and xylanase) known to disperse P. aeruginosa on local biofilm viscoelasticity. Compared to control studies in wild-type strains, it is found that treatment with all three GHs results in statistically relatively less elastic and stiffer biofilms, indicating that changes to mechanical stability may be a factor in effective dispersal. Both cellulase and xylanase were observed to have the greatest impact in creating a less stiff and elastic biofilm; these GHs have been observed to be effective at dispersal in the published results. Each GH was further tested on biofilms grown with strains that produced EPS missing specific polysaccharide components. Cellulase specifically targeted Psl, which forms the major structural and mechanical backbone of the EPS, explaining its efficacy in dispersal. However, xylanase did not appear to exhibit any affinity to any polysaccharide within the EPS based on the microrheology results. Overall, these results suggest that the local microrheology of the biofilms is impacted by GHs and that may be one of the factors that is causing the ability of these therapeutics to enhance dispersal.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Protein Factory on a Chip for Rapid Therapeutics

The potential for new, re-emerging, or engineered pandemic threats could challenge our nation's biosecurity, requiring rapid and flexible countermeasure development platforms. In healthcare, one of the main hindrances to the timely development of protein-based therapeutics for cancer, infectious disease, and other diseases has been a slow and expensive quality-controlled production stage. We present a protein-based technology that has the potential to address these crucial problems in biosecurity and healthcare by maximizing protein production and system portability, while minimizing production latency and cost. Specifically, we have developed a reusable, portable first-generation platform that leverages the advantages of cell-free protein synthesis (CFPS) and flow cells to create practical amounts of clinically relevant therapeutics. We have demonstrated that this technology is reusable and programmable, enabling a single platform that can synthesize multiple dosages of various therapeutics and vaccine in the field. Implementing this technology could mitigate pandemic threats by providing a rapidly-deployable (just-in-time), versatile (precision medicine) production of biologic therapeutics to the infected patient’s locale (point-of-care). In drug development, once promising drug variations are identified, the platform can be scaled to quickly produce practical amounts of protein for patient testing in the matter of days (vs. months) at a fraction of the cost of existing technology.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Diversity, taxonomy, and evolution of archaeal viruses of the class Caudoviricetes

The archaeal tailed viruses (arTV), evolutionarily related to tailed double-stranded DNA (dsDNA) bacteriophages of the class Caudoviricetes , represent the most common isolates infecting halophilic archaea. Only a handful of these viruses have been genomically characterized, limiting our appreciation of their ecological impacts and evolution. Here, we present 37 new genomes of haloarchaeal tailed virus isolates, more than doubling the current number of sequenced arTVs. Analysis of all 63 available complete genomes of arTVs, which we propose to classify into 14 new families and 3 orders, suggests ancient divergence of archaeal and bacterial tailed viruses and points to an extensive sharing of genes involved in DNA metabolism and counterdefense mechanisms, illuminating common strategies of virus–host interactions with tailed bacteriophages. Coupling of the comparative genomics with the host range analysis on a broad panel of haloarchaeal species uncovered 4 distinct groups of viral tail fiber adhesins controlling the host range expansion. The survey of metagenomes using viral hallmark genes suggests that the global architecture of the arTV community is shaped through recurrent transfers between different biomes, including hypersaline, marine, and anoxic environments.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Spray-induced gene silencing for disease control is dependent on the efficiency of pathogen RNA uptake

Recent discoveries show that fungi can take up environmental RNA, which can then silence fungal genes through environmental RNA interference. This discovery prompted the development of Spray-Induced Gene Silencing (SIGS) for plant disease management. In this study, we aimed to determine the efficacy of SIGS across a variety of eukaryotic microbes. We first examined the efficiency of RNA uptake in multiple pathogenic and non-pathogenic fungi, and an oomycete pathogen. We observed efficient double-stranded RNA (dsRNA) uptake in the fungal plant pathogens Botrytis cinerea, Sclerotinia sclerotiorum, Rhizoctonia solani, Aspergillus niger and Verticillium dahliae, but no uptake in Colletotrichum gloeosporioides, and weak uptake in a beneficial fungus, Trichoderma virens. For the oomycete plant pathogen, Phytophthora infestans, RNA uptake was limited and varied across different cell types and developmental stages. Topical application of dsRNA targeting virulence-related genes in pathogens with high RNA uptake efficiency significantly inhibited plant disease symptoms, whereas the application of dsRNA in pathogens with low RNA uptake efficiency did not suppress infection. Our results have revealed that dsRNA uptake efficiencies vary across eukaryotic microbe species and cell types. The success of SIGS for plant disease management can largely be determined by the pathogen's RNA uptake efficiency.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Agent-based Disease Surveillance and Transmission Model

The SARS-CoV-2 pandemic has driven a need for models that can predict transmission among populations and test the effectiveness of proposed interventions to control it such as testing, quarantining, vaccinations, and nonpharmaceutical interventions. Some questions of interest include:1. How rapidly will the virus spread if no action is taken? 2. How frequently should people be tested and quarantined if necessary? 3. Should unvaccinated persons be tested more frequently than the vaccinated? 4. If test results are delayed, how will that affect the spread? 5. How do test false negative rates affect the overall efficacy of testing programs? 6. How do constraints on testing resources impact the overall efficacy of testing programs? 7. How does the patient’s failure to recognize COVID symptoms and quarantine affect the spread? 8. What level of vaccination coverage is needed to suppress the epidemic? 9. What is the risk of a large outbreak (probability exceeding x infections)? 10. What is the cost effectiveness of interventions (dollars per avoided infection)? This report describes the structure of a discrete event simulation model that provides actionable information to address these questions. Parameter inputs and results of analyses have been reported in briefings provided to LLNL management and are not discussed here.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Changing temperature profiles and the risk of dengue outbreaks

As temperatures change worldwide, the pattern and competency of disease vectors will change, altering the global distribution of both the burden of infectious disease and the risk of the emergence of those diseases into new regions. To evaluate the risk of potential summer dengue outbreaks triggered by infected travelers under various climate scenarios, we develop an SEIR-type model, run numerical simulations, and conduct sensitivity analyses under a range of temperature profiles. Our model extends existing theoretical frameworks for studying dengue dynamics by introducing temperature dependence of two key parameters: the mosquito extrinsic incubation period and the lifespan of mosquitoes, which empirical data suggests are both highly temperature dependent. We find that changing temperature significantly alters dengue risk in an inverted U-shape, with temperatures in the range 27-31°C producing the highest risk. As temperatures increase beyond 31°C, the determinants of dengue risk begin to shift from mosquito biting rate and carrying capacity to the duration of the human infectious period, suggesting that changing temperatures not only alter dengue risk but also the potential efficacy of control measures. To illustrate the role of spatial and temporal temperature heterogeneity, we select five US cities where the primary dengue vector, the mosquito Aedes aegypti , has been observed, and which have had dengue cases in the past: Los Angeles, Houston, Miami, Brownsville, and Phoenix. Our analysis suggests that an increase of 3°C leads to an approximate doubling of the risk of dengue in Los Angeles and Houston, but a reduction of risk in Miami, Brownsville, and Phoenix due to extreme heat.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2022

Harnessing Particle Size‐Control and DNA‐Oligo Functionalization in ZIF‐76 for Biological Applications

Abstract Advanced therapeutics require novel nanocarriers to ensure their functionality is preserved during transit. Zeolitic imidazolate frameworks (ZIFs) have emerged as promising materials in this field owing to their combined biocompatibility, high porosity, and tunable chemistry. While a diverse family of ZIFs has been reported, few have been explored beyond the prototypical ZIF‐8. Herein, the size‐controlled synthesis of three distinct ZIF‐76 analogs is demonstrated, overcoming the unique synthetic challenges intrinsic to the lta topology and complex crystallization kinetics associated with the mixed linker approach. This assesses the materials’ platform effectiveness for intracellular delivery first by exploring the structural and colloidal stability in biologically relevant media. To circumvent particle aggregation, fluorescently labeled DNA oligonucleotides are post‐synthetically attached to the ZIF surface. This modification significantly improves the colloidal stability in media and facilitates particle internalization tracking. Finally, the particle‐cell interactions are assessed, revealing rapid cell membrane association with macrophages, but not lung epithelial cells, and ZIF accumulation within macrophages which increased over time. Importantly, this study outlines a generalized approach toward expanding the available library of ZIFs for biological applications, enabling the potential for targeted therapeutic delivery for intracellular infections treatment.

Deneff, Jacob I.↗
DOE OSTI2023

Ubiquitin-like conjugation by bacterial cGAS enhances anti-phage defence

Abstract cGAS is an evolutionarily conserved enzyme that has a pivotal role in immune defence against infection 1–3 . In vertebrate animals, cGAS is activated by DNA to produce cyclic GMP–AMP (cGAMP) 4,5 , which leads to the expression of antimicrobial genes 6,7 . In bacteria, cyclic dinucleotide (CDN)-based anti-phage signalling systems (CBASS) have been discovered 8–11 . These systems are composed of cGAS-like enzymes and various effector proteins that kill bacteria on phage infection, thereby stopping phage spread. Of the CBASS systems reported, approximately 39% contain Cap2 and Cap3 , which encode proteins with homology to ubiquitin conjugating (E1/E2) and deconjugating enzymes, respectively 8,12 . Although these proteins are required to prevent infection of some bacteriophages 8 , the mechanism by which the enzymatic activities exert an anti-phage effect is unknown. Here we show that Cap2 forms a thioester bond with the C-terminal glycine of cGAS and promotes conjugation of cGAS to target proteins in a process that resembles ubiquitin conjugation. The covalent conjugation of cGAS increases the production of cGAMP. Using a genetic screen, we found that the phage protein Vs.4 antagonized cGAS signalling by binding tightly to cGAMP (dissociation constant of approximately 30 nM) and sequestering it. A crystal structure of Vs.4 bound to cGAMP showed that Vs.4 formed a hexamer that was bound to three molecules of cGAMP. These results reveal a ubiquitin-like conjugation mechanism that regulates cGAS activity in bacteria and illustrates an arms race between bacteria and viruses through controlling CDN levels.

Science & Technology - Other Topics↗
DOE OSTI2024

Unveiling the Arsenal of Apple Bitter Rot Fungi: Comparative Genomics Identifies Candidate Effectors, CAZymes, and Biosynthetic Gene Clusters in Colletotrichum Species

The bitter rot of apple is caused by Colletotrichum spp. and is a serious pre-harvest disease that can manifest in postharvest losses on harvested fruit. In this study, we obtained genome sequences from four different species, C. chrysophilum, C. noveboracense, C. nupharicola, and C. fioriniae, that infect apple and cause diseases on other fruits, vegetables, and flowers. Our genomic data were obtained from isolates/species that have not yet been sequenced and represent geographic-specific regions. Genome sequencing allowed for the construction of phylogenetic trees, which corroborated the overall concordance observed in prior MLST studies. Bioinformatic pipelines were used to discover CAZyme, effector, and secondary metabolic (SM) gene clusters in all nine Colletotrichum isolates. We found redundancy and a high level of similarity across species regarding CAZyme classes and predicted cytoplastic and apoplastic effectors. SM gene clusters displayed the most diversity in type and the most common cluster was one that encodes genes involved in the production of alternapyrone. Our study provides a solid platform to identify targets for functional studies that underpin pathogenicity, virulence, and/or quiescence that can be targeted for the development of new control strategies. With these new genomics resources, exploration via omics-based technologies using these isolates will help ascertain the biological underpinnings of their widespread success and observed geographic dominance in specific areas throughout the country.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Cell surface crowding is a tunable energetic barrier to cell-cell fusion

Abstract Cell-cell fusion is fundamental to processes such as muscle formation and viral infection. An essential step in fusion is close membrane apposition, but cell membranes are crowded with proteins, glycoproteins, and glycolipids, which must be cleared before a fusion pore can be nucleated. Here, we find that cell surface crowding reduces fusogenicity independent of how fusion is driven. We estimate that crowding presents an energetic barrier to membrane apposition on the scale of ~$${100k}_{{\mbox{B}}}T$$ 100 k B T , greater than that of bare membrane fusion alone. We show that increasing cell surface crowding reduces fusion efficiency of PEG-mediated and fusogen-mediated cell-cell fusion, as well as synthetic membranes under force. Interestingly, we find that differentiating myoblasts naturally decrease their surface crowding prior to fusion. In this work, we show that cell surface crowding presents an underappreciated biophysical barrier that may be tuned developmentally and could be targeted externally to control tissue-specific cell-cell fusion.

Science & Technology - Other Topics↗
DOE OSTI2023

A potent and durable malaria transmission-blocking vaccine designed from a single-component 60-copy Pfs230D1 nanoparticle

Malaria transmission-blocking vaccines (TBVs) reduce disease transmission by breaking the continuous cycle of infection between the human host and the mosquito vector. Domain 1 (D1) of Pfs230 is a leading TBV candidate and comprises the majority of transmission-reducing activity (TRA) elicited by Pfs230. Here we show that the fusion of Pfs230D1 to a 60-copy multimer of the catalytic domain of dihydrolipoyl acetyltransferase protein (E2p) results in a single-component nanoparticle composed of 60 copies of the fusion protein with high stability, homogeneity, and production yields. The nanoparticle presents a potent human transmission-blocking epitope within Pfs230D1, indicating the antigen is correctly oriented on the surface of the nanoparticle. Two vaccinations of New Zealand White rabbits with the Pfs230D1 nanoparticle elicited a potent and durable antibody response with high TRA when formulated in two distinct adjuvants suitable for translation to human use. This single-component nanoparticle vaccine may play a key role in malaria control and has the potential to improve production pipelines and the cost of manufacturing of a potent and durable TBV.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Drug Resistance in Filarial Parasites Does Not Affect Mosquito Vectorial Capacity

Parasite drug resistance presents a major obstacle to controlling and eliminating vector-borne diseases affecting humans and animals. While vector-borne disease dynamics are affected by factors related to parasite, vertebrate host and vector, research on drug resistance in filarial parasites has primarily focused on the parasite and vertebrate host, rather than the mosquito. However, we expect that the physiological costs associated with drug resistance would reduce the fitness of drug-resistant vs. drug-susceptible parasites in the mosquito wherein parasites are not exposed to drugs. Here we test this hypothesis using four isolates of the dog heartworm (Dirofilaria immitis)—two drug susceptible and two drug resistant—and two vectors—the yellow fever mosquito (Aedes aegypti) and the Asian tiger mosquito (Ae. albopictus)—as our model system. Our data indicated that while vector species had a significant effect on vectorial capacity, there was no significant difference in the vectorial capacity of mosquitoes infected with drug-resistant vs. drug-susceptible parasites. Consequently, contrary to expectations, our data indicate that drug resistance in D. immitis does not appear to reduce the transmission efficiency of these parasites, and thus the spread of drug-resistant parasites in the vertebrate population is unlikely to be mitigated by reduced fitness in the mosquito vector.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Immune checkpoint analysis of T‐cell responses to pp65 and IE‐1 antigens in end‐stage lung diseases

Abstract Lung transplant (LTX) patients are at high risk of cytomegalovirus (CMV) infection, which is often associated with high mortality and morbidity. Reactivation of CMV causes cell injury due to the cytopathic effect of viral replication and triggering of T cell immunity. The aim of this study was to compare expression of immune checkpoints (ICs) (PD‐1, CTLA‐4, LAG‐3 and TIGIT) in CD4, CD8 and CD56 and activation markers CD137, CD154 and CD69 of end‐stage patients awaiting lung transplant. Eighteen pre‐LTX positive for anti‐CMV IgG titres and 18 healthy subjects were enrolled. IC and activation markers have been evaluated through flow cytometric analysis in HC and pre‐LTX patients. Reactive (QF+) and unreactive (QF−) patients were stratified according to QuantiFERON‐CMV assays. ICs' and activation markers' expression were determined before and after in vitro stimulation with pp‐65 and IE‐1 antigens. Lower expression of PD‐1 was observed in CD4 and CD8 cells of pre‐LTX patients than controls, whereas CTLA4 appeared upregulated in CD56 and CD8 cells. TIGIT is increased on the surface of CD4, CD8 and NK cells after peptide stimulation in QF‐negative patients and PD‐1 is only downregulated after stimulation in the QF‐positive patients. This study provides new evidence of immune dysregulation in patients with end‐stage lung disorders, particularly in relation to immune checkpoint cell biology. The change in QF+ mostly happens on cytotoxic cells NK and CD8, while the changes in QF− were observed in adaptive immune cells, including CD4 and CD8.

Bergantini, Laura↗
DOE OSTI2022

Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial

HIV-1 therapy with single or dual broadly neutralizing antibodies (bNAbs) has shown viral escape, indicating that at least a triple bNAb therapy may be needed for robust suppression of viremia. We performed a two-part study consisting of a single-center, randomized, double-blind, dose-escalation, placebo-controlled first-in-human trial of the HIV-1 V2-glycan-specific antibody PGDM1400 alone or in combination with the V3-glycan-specific antibody PGT121 in 24 adults without HIV in part 1, as well as a multi-center, open-label trial of the combination of PGDM1400, PGT121 and the CD4-binding-site antibody VRC07-523LS in five viremic adults living with HIV not on antiretroviral therapy (ART) in part 2. The primary endpoints were safety, tolerability and pharmacokinetics for both parts and antiviral activity among viremic adults living with HIV and not on ART for part 2 of the study. The secondary endpoints were changes in CD4 + T cell counts and development of HIV-1 sequence variations associated with PGDM1400, PGT121 and VRC07-523LS resistance in part 2. Intravenously administered PGDM1400 was safe and well-tolerated at doses up to 30 mg kg -1 and when given in combination with PGT121 and VRC07-523LS. A single intravenous infusion of 20 mg kg -1 of each of the three antibodies reduced plasma HIV RNA levels in viremic individuals by a maximum mean of 2.04 log10 copies per ml; however, viral rebound occurred in all participants within a median of 20 days after nadir. Rebound viruses demonstrated partial to complete resistance to PGDM1400 and PGT121 in vitro, whereas susceptibility to VRC07-523LS was preserved. Viral rebound occurred despite mean VRC07-523LS serum concentrations of 93 µg ml -1 . The trial met the pre-specified endpoints. Our data suggest that future bNAb combinations likely need to achieve broad antiviral activity, while also maintaining high serum concentrations, to mediate viral control.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

AeDES: a next-generation monitoring and forecasting system for environmental suitability of Aedes-borne disease transmission

Aedes-borne diseases, such as dengue and chikungunya, are responsible for more than 50 million infections worldwide every year, with an overall increase of 30-fold in the last 50 years, mainly due to city population growth, more frequent travels and ecological changes. In the United States of America, the vast majority of Aedes-borne infections are imported from endemic regions by travelers, who can become new sources of mosquito infection upon their return home if the exposed population is susceptible to the disease, and if suitable environmental conditions for the mosquitoes and the virus are present. Since the susceptibility of the human population can be determined via periodic monitoring campaigns, the environmental suitability for the presence of mosquitoes and viruses becomes one of the most important pieces of information for decision makers in the health sector. We present a next-generation monitoring and forecasting system for Aedes-borne diseases’ environmental suitability (AeDES) of transmission in the conterminous United States and transboundary regions, using calibrated ento-epidemiological models, climate models and temperature observations. After analyzing the seasonal predictive skill of AeDES, we briefly consider the recent Zika epidemic, and the compound effects of the current Central American dengue outbreak happening during the SARS-CoV-2 pandemic, to illustrate how a combination of tailored deterministic and probabilistic forecasts can inform key prevention and control strategies .

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2022

Tomato deploys defence and growth simultaneously to resist bacterial wilt disease

Abstract Plant disease limits crop production, and host genetic resistance is a major means of control. Plant pathogenic Ralstonia causes bacterial wilt disease and is best controlled with resistant varieties. Tomato wilt resistance is multigenic, yet the mechanisms of resistance remain largely unknown. We combined metaRNAseq analysis and functional experiments to identify core Ralstonia ‐responsive genes and the corresponding biological mechanisms in wilt‐resistant and wilt‐susceptible tomatoes. While trade‐offs between growth and defence are common in plants, wilt‐resistant plants activated both defence responses and growth processes. Measurements of innate immunity and growth, including reactive oxygen species production and root system growth, respectively, validated that resistant plants executed defence‐related processes at the same time they increased root growth. In contrast, in wilt‐susceptible plants roots senesced and root surface area declined following Ralstonia inoculation. Wilt‐resistant plants repressed genes predicted to negatively regulate water stress tolerance, while susceptible plants repressed genes predicted to promote water stress tolerance. Our results suggest that wilt‐resistant plants can simultaneously promote growth and defence by investing in resources that act in both processes. Infected susceptible plants activate defences, but fail to grow and so succumb to Ralstonia , likely because they cannot tolerate the water stress induced by vascular wilt.

Meline, Valerian↗