Host Tolerance Research Articles

Role of NK cells in circadian regulation of lung inflammation

Abstract Circadian rhythms form an anticipatory system wherein various aspects of cellular physiology oscillate across a 24hrs period; these rhythms have been known to modulate various facets of immunity. We have previously shown that mice infected with Influenza A virus (IAV) at dusk had 3-fold higher mortality than littermates infected at dawn--a hallmark of circadian regulation. This time-of-day specific protection was lost when NK cells were depleted just before the infection, suggesting a role of NK cells in mediating the circadian regulation of IAV infection. We investigated the mechanism underlying the role of NK cells, both cell-intrinsic or extrinsic in circadian regulation of lung injury. We noted that viral clearance was unaffected, but immunopathology was markedly worse in the NK depleted mice than the controls. Next, we investigated the effect of the loss of the circadian clock on NK cell behavior and found that splenic and pulmonary NK cells in naïve mice with a disrupted circadian clock have a less mature phenotype than control NK cells with intact clock. Our transcriptomic profiling of NK cells sorted from clock-intact versus clock-disrupted animals revealed that several genes that regulate cell cycle progression and functional maturity of NK cells were differentially expressed across the two groups. Pulmonary NK cells from clock mutant mice were less mature than clock-intact mice. Finally, the Ncr1cre+Bmal1fl/flmice (core clock gene Bmal1deleted in NK cells) infected with IAV had higher mortality through heightened immunopathology but not delayed viral clearance. In summary, these data show that NK cell-autonomous clock boost host tolerance to mediate circadian protection from IAV infection. Supported by grants from NIH (R01HL155934-01A1, R01HL147472, R01AI137062-01)

PGLYRP1-mIgG2a-Fc inhibits macrophage activation via AKT/NF-κB signaling and protects against fatal lung injury during bacterial infection

Severe bacterial pneumonia leads to acute respiratory distress syndrome (ARDS), with a high incidence rate and mortality. It is well-known that continuous and dysregulatedmacrophage activation is vital for aggravating the progression of pneumonia. Here, we designed and produced an antibody-like molecule, peptidoglycan recognition protein 1-mIgG2a-Fc (PGLYRP1-Fc). PGLYRP1 was fused to the Fc region of mouse IgG2a with high binding to macrophages. We demonstrated that PGLYRP1-Fc ameliorated lung injury and inflammation in ARDS, without affecting bacterial clearance. Besides, PGLYRP1-Fc reduced AKT/nuclear factor kappa-B (NF-κB) activation via the Fc segment bound Fc gamma receptor (FcγR)-dependent mechanism, making macrophage unresponsive, and immediately suppressed proinflammatory response upon bacteria or lipopolysaccharide (LPS) stimulus in turn. These results confirm that PGLYRP1-Fc protects against ARDS by promoting host tolerance with reduced inflammatory response and tissue damage, irrespective of the host's pathogen burden, and provide a promising therapeutic strategy for bacterial infection.

Pollen as Bee Medicine: Is Prevention Better than Cure?

To face environmental stressors such as infection, animals may display behavioural plasticity to improve their physiological status through ingestion of specific food. In bees, the significance of medicating pollen may be limited by their ability to exploit it. Until now, studies have focused on the medicinal effects of pollen and nectar after forced-feeding experiments, overlooking spontaneous intake. Here, we explored the medicinal effects of different pollen on Bombus terrestris workers infected by the gut parasite Crithidia bombi. First, we used a forced-feeding experimental design allowing for the distinction between prophylactic and therapeutic effects of pollen, considering host tolerance and resistance. Then, we assessed whether bumble bees favoured medicating resources when infected to demonstrate potential self-medicative behaviour. We found that infected bumble bees had a lower fitness but higher resistance when forced to consume sunflower or heather pollen, and that infection dynamics was more gradual in therapeutic treatments. When given the choice between resources, infected workers did not target medicating pollen, nor did they consume more medicating pollen than uninfected ones. These results emphasize that the access to medicating resources could impede parasite dynamics, but that the cost-benefit trade-off could be detrimental when fitness is highly reduced.

Infectious disease ecology and evolution in a changing world.

Infectious disease ecology and evolution in a changing world.

Monkeypox virus replication underlying circadian rhythm networks.

The mammalian brain has an endogenous central circadian clock that regulates central and peripheral cellular activities. At the molecular level, this day-night cycle induces the expression of upstream and downstream transcription factors that influence the immune system and the severity of viral infections over time. In addition, there are also circadian effects on host tolerance pathways. This stimulates adaptation to normal changes in environmental conditions and requirements (including light and food). These rhythms influence the pharmacokinetics and efficacy of therapeutic drugs and vaccines. The importance of circadian systems in regulating viral infections and the host response to viruses is currently of great importance for clinical management. With the knowledge gained from the COVID-19 pandemic, it is important to address any outbreak of viral infection that could become endemic and to quickly focus research on any knowledge gaps. For example, responses to booster vaccination COVID-19 may have different time-dependent patterns during circadian cycles. There may be a link between reactivation of latently infected viruses and regulation of circadian rhythms. In addition, mammals may show different seasonal antiviral responses in winter and summer. This article discusses the importance of the host circadian clock during monkeypox infection and immune system interactions.

Species interactions, stability, and resilience of the gut microbiota - Helminth assemblage in horses

The nature and strength of interactions entertained among helminths and their host gut microbiota remain largely unexplored. Using 40 naturally infected Welsh ponies, we tracked the gut microbiota-cyathostomin temporal dynamics and stability before and following anthelmintic treatment and the associated host blood transcriptomic response. High shedders harbored 14 species of cyathostomins, dominated by Cylicocyclus nassatus. They exhibited a highly diverse and temporal dynamic gut microbiota, with butyrate-producing Clostridia likely driving the ecosystem steadiness and host tolerance toward cyathostomins infection. However, anthelmintic administration sharply bent the microbial community. It disrupted the ecosystem stability and the time-dependent network of interactions, affecting longer term microbial resilience. These observations highlight how anthelmintic treatments alter the triangular relationship of parasite, host, and gut microbiota and open new perspectives for adding nutritional intervention to current parasite management strategies.

Novel epidemiological model of gastrointestinal nematode infection to assess grazing cattle resilience by integrating host growth, parasite, grass and environmental dynamics

Gastrointestinal nematode (GIN) infections are ubiquitous and often cause morbidity and reduced performance in livestock. Emerging anthelmintic resistance and increasing change in climate patterns require evaluation of alternatives to traditional treatment and management practices. Mathematical models of parasite transmission between hosts and the environment have contributed towards the design of appropriate control strategies in ruminants, but have yet to account for relationships between climate, infection pressure, immunity, resources, and growth. Here, we develop a new epidemiological model of GIN transmission in a herd of grazing cattle, including host tolerance (body weight and feed intake), parasite burden and acquisition of immunity, together with weather-dependent development of parasite free-living stages, and the influence of grass availability on parasite transmission. Dynamic host, parasite and environmental factors drive a variable rate of transmission. Using literature sources, the model was parametrised for Ostertagia ostertagi, the prevailing pathogenic GIN in grazing cattle populations in temperate climates. Model outputs were validated on published empirical studies from first season grazing cattle in northern Europe. These results show satisfactory qualitative and quantitative performance of the model; they also indicate the model may approximate the dynamics of grazing systems under co-infection by O. ostertagi and Cooperia oncophora, a second GIN species common in cattle. In addition, model behaviour was explored under illustrative anthelmintic treatment strategies, considering impacts on parasitological and performance variables. The model has potential for extension to explore altered infection dynamics as a result of management and climate change, and to optimise treatment strategies accordingly. As the first known mechanistic model to combine parasitic and free-living stages of GIN with host feed-intake and growth, it is well suited to predict complex system responses under non-stationary conditions. We discuss the implications, limitations and extensions of the model, and its potential to assist in the development of sustainable parasite control strategies.

A Sterility-Mortality Tolerance Trade-Off Leads to Within-Population Variation in Host Tolerance.

While experimental studies have demonstrated within-population variation in host tolerance to parasitism, theoretical studies rarely predict for polymorphism to arise. However, most theoretical models do not consider the crucial distinction between tolerance to the effects of infection-induced deaths (mortality tolerance) and tolerance to the parasite-induced reduction in the reproduction of infected hosts (sterility tolerance). While some studies have examined trade-offs between host tolerance and resistance mechanisms, none has considered a correlation within different tolerance mechanisms. We assume that sterility tolerance and mortality tolerance are directly traded-off in a host population subjected to a pathogen and use adaptive dynamics to study their evolutionary behaviour. We find that such a trade-off between the two tolerance strategies can drive the host population to branch into dimorphic strains, leading to coexistence of strains with sterile hosts that have low mortality and fully fertile with high mortality rates. Further, we find that a wider range of trade-off shapes allows branching at intermediate- or high-infected population size. Our other significant finding is that sterility tolerance is maximised (and mortality tolerance minimised) at an intermediate disease-induced mortality rate. Additionally, evolution entirely reverses the disease prevalence pattern corresponding to the recovery rate, compared to when no strategies evolve. We provide novel predictions on the evolutionary behaviour of two tolerance strategies concerning such a trade-off.

The reproductive status determines tolerance and resistance to Mycobacterium marinum in Drosophila melanogaster.

Sex and reproductive status of the host have a major impact on the immune response against infection. Our aim was to understand their impact on host tolerance or resistance in the systemic Mycobacterium marinum infection of Drosophila melanogaster. We measured host survival and bacillary load at time of death, as well as expression by quantitative real-time polymerase chain reaction of immune genes (diptericin and drosomycin). We also assessed the impact of metabolic and hormonal regulation in the protection against infection by measuring expression of upd3, impl2 and ecR. Our data showed increased resistance in actively mating flies and in mated females, while reducing their tolerance to infection. Data suggests that Toll and immune deficiency (Imd) pathways determine tolerance and resistance, respectively, while higher basal levels of ecR favours the stimulation of the Imd pathway. A dual role has been found for upd3 expression, linked to increased/decreased mycobacterial load at the beginning and later in infection, respectively. Finally, impl2 expression has been related to increased resistance in non-actively mating males. These results allow further assessment on the differences between sexes and highlights the role of the reproductive status in D. melanogaster to face infections, demonstrating their importance to determine resistance and tolerance against M. marinum infection.

Understanding tobamovirus-plant interactions: implications for breeding resistance to tomato brown rugose fruit virus

The genus Tobamovirus comprises a group of single-stranded RNA viruses that affect a wide variety of vegetables of economic importance. Tobamoviruses express a series of proteins that interact with the plant’s cellular machinery, allowing viral infection; during incompatible interactions, active defense is mediated by host proteins encoded by resistance genes. The genes conferring viral resistance and tolerance in non-susceptible hosts have been studied for their ability to transfer desired resistance traits to different crops. The N gene from Nicotiana spp., the repertoire of Tm genes in Solanum spp., the L locus from Capsicum spp., and TOM genes are the most studied genetic sequences for understanding resistance to tobamoviruses. Through classical plant breeding and genetic engineering techniques, it has been possible to introgress these resistance genes (R) into new species. However, new reports highlight the ability of tobamoviruses to overcome R-mediated defense. One of the most notorious recent cases is the tomato brown rugose fruit virus (ToBRFV). The main characteristic of ToBRFV is its capacity to overcome the resistance mediated by the Tm-22 gene, resulting in a limited repertoire of options to combat the virus. To defeat emerging viruses, it is necessary to apply the knowledge from other tobamoviruses-host relationships and use new technologies such as genome-wide association studies (GWAS) to understand and associate the architecture of resistance genes present in the Solanaceae family for the benefit of plant breeding. Although new genomic tools such as CRISPR systems open the possibility of coping with viral diseases, there are no commercial ToBRFV-resistant tomato varieties. Hence, the world’s leading seed suppliers compete to develop and bring these varieties to market.

Identity and density of parasite exposures alter the outcome of coinfections: Implications for management

Abstract Although research has focused on density‐dependent responses of hosts to single‐parasite infections, hosts are exposed to numerous parasites simultaneously under natural conditions and if these exposures lead to infections, they can threaten host populations and ecosystem stability. Moreover, spatiotemporal variation in abundance of co‐occurring parasites might influence host infection intensity. If interactions are consistent between different coinfecting parasites, then these patterns could give managers another tool to control disease spread and even predict problematic disease emergences. We investigated how parasite density and identity alter within‐host coinfection dynamics. To test this, we simultaneously exposed Cuban treefrogs Osteopilus septentrionalis as a model amphibian species to all pairwise combinations of three problematic parasites that commonly coinfect amphibians: the fungus Batrachochytrium dendrobatidis (Bd), the nematode Aplectana hamatospicula and Ranavirus. Hosts were exposed to one parasite at a fixed dose and another parasite at a range of five doses. Higher doses of Bd decreased Ranaviral and A. hamatospicula loads, but Bd load was not influenced by the dose of either parasite. Ranaviral load was negatively associated with A. hamatospicula dose, but A. hamatospicula load was not affected by Ranaviral dose. We found that all the pairwise coinfections were dependent on parasite density and that pairwise interactions were highly asymmetric—strong in one direction and weak in the other—consistent with interactions dominating food webs. Synthesis and applications: We also revealed that the exposure dose of A. hamatospicula was positively associated with host tolerance to Bd infection and negatively associated with Ranaviral load in hosts. Ranavirus and Bd cause mass die‐offs in amphibians, but A. hamatospicula does not. Therefore, in systems where these parasites coexist, maintaining or increasing densities of A. hamatospicula could reduce the negative effects of Bd and Ranavirus infections. Additionally, if these asymmetric and density‐dependent patterns from community ecology are applicable to other amphibian coinfections or coinfections in other systems, this should allow conservation organizations and resource managers to predict outbreaks and manage host declines associated with deadly parasites by modifying the abundance of coinfecting parasites that might be easier to manage.

AcdS gene of Bacillus cereus enhances salt tolerance of seedlings in tobacco (Nicotiana tabacum L.)

Previous studies show that 1-aminocyclopropane-1-carboxylate (ACC) deaminase can facilitate the growth and stress tolerance of hosts by reducing ethylene levels. In this study, the acdS gene encoding ACC deaminase from Bacillus cereus (HK012) was cloned and transformed into tobacco (Nicotiana tabacum L.) by the leaf disc method using Agrobacterium. Molecular detection and physiological analysis of the transgenic tobacco plants were performed. Our results showed the acdS gene was integrated into the tobacco genome and fluorescence microscopy showed that the fusion protein was located on the cell membrane of tobacco root. Compared with control, the transgenic plants showed increases in plant height, root length, dry weight, fresh weight and chlorophyll content; and significant increases in the concentration of proline of 55.15% and 42.7% under salt stress conditions (150 mmol L−1 and 300 mmol L−1 NaCl, respectively). The superoxide dismutase, peroxidase, catalase and ACC deaminase activities of transgenic tobacco were higher than those of control tobacco at 150 and 300 mmol L−1 salt concentrations. Transgenic tobacco seedlings expressing the acdS gene of B. cereus HK012 showed higher salt tolerance than the control plants. The obtained results suggest that the acdS gene of B. cereus can be used to promote salt tolerance in glycophytes by using biotechnology strategies.

Arbuscular mycorrhizal fungal‐induced tolerance is determined by fungal identity and pathogen density

Societal Impact StatementPlant‐parasitic nematodes are a major concern for global food security, and many existing control options are being phased out due to adverse impacts on the environment. Here, we show that although application of arbuscular mycorrhizal fungi (AMF) increases host tolerance to these parasites, these benefits decrease as the parasite burden increases, limiting long‐term benefits. This effect was consistent between experiments in the glasshouse and in the field environment, demonstrating the relevance of research into usable technologies. Our findings have potential to aid decision making regarding application of AMF inocula for optimum results in agricultural systems.Summary Plant‐parasitic nematodes are a leading global threat to crop production and food security aims. Control strategies based on nematicides and fertilisers are increasingly undesirable due to economic and environmental impacts. Arbuscular mycorrhizal fungi (AMF) may induce host tolerance against pests such as the potato cyst nematode (PCN). Here, we determined the impact of PCN density on the tolerance induced by AMF‐host interactions. Additionally, we evaluated the effects of five AMF inocula on PCN fitness though glasshouse and field trials. Greater PCN densities reduce the increased tolerance that AMF may confer on their hosts. This may be due to reduced mycorrhizal colonisation of hosts under higher PCN infection and potentially a threshold at which the presence of PCN severely impacts fungal growth. When tested in the field, the outcomes of AMF inoculation on crop yields were still positive. Inoculation of soil in the field also increased PCN multiplication, suggesting that AMF‐induced tolerance may become reduced in the near future when the threshold PCN density is reached. Addition of AMF to agricultural soils may provide a short‐term benefit yet lead to a long‐term detriment by increasing PCN populations. The effects observed were driven by only one out of the five introduced AMF species, indicating that the remaining species were redundant for this application. This raises important considerations for future application of AMF inocula in agricultural systems and aids our understanding of how widely used ‘beneficial’ soil amendments impact the agricultural ecosystem.

Divergence in host–parasite interactions during the cane toad's invasion of Australia

AbstractCoevolutionary host–parasite “arms races” can be disrupted by new evolutionary forces imposed by biological invasions, affecting both host and parasite densities, as well as their traits. The spread of cane toads (Rhinella marina) and their parasitic lungworm (Rhabdias pseudosphaerocephala) across tropical Australia provides an ideal opportunity to study a perturbed host–parasite system. We conducted a cross‐infection experiment using common‐garden‐reared toads and lungworms from three regions (comprising long‐established, intermediate, and recently invaded sites across tropical Australia) to quantify traits of the parasite (infectivity and virulence) and the host (resistance and tolerance). Specifically, we assessed whether patterns of host–parasite co‐adaptation were better explained by spatial distances versus time since the separation of host and parasite populations. Infection success was highest when toads from long‐established populations were exposed to lungworms from close to the invasion front and lowest when frontal toads were exposed to parasites from older populations. This suggests that both parasite infectivity and host resistance have increased over the course of invasion. In contrast, most virulence/tolerance traits have not consistently increased or decreased during invasion. Higher parasite burdens were associated with increased feeding performance in toads and faster growth in lungworms, counter‐intuitive results that suggest host manipulation by the parasite.

Resistance, tolerance and competence for a root pathogen in six woody species

The outcome of host–pathogen interactions depends on host defence and pathogen infection strategies. On the host side, two strategies, resistance and tolerance, have long been identified. They differ in their underlying mechanisms and their effects on pathogens. However, the dynamics of disease transmission also rely on host competence. This trait, defined as the ability of the host to allow pathogen transmission, is rarely studied for pathogen-supporting plants. We assessed the competence for Phytophthora cinnamomi of seedlings of five Quercus and one Castanea species and studied how this trait is correlated with resistance and tolerance. P. cinnamomi is responsible for the chestnut ink disease, alongside with Phytophthora × cambivora, which has a much less generalist behaviour. Each seedling was inoculated in minirhizotrons by root–mycelium contact and phenotyped for its resistance, tolerance and competence. The amount of necrosis (lesion length), the effect of infection on plant performance (root growth) and the sporangia number were measured. Moreover, we developed a droplet digital (dd) PCR assay to quantify the pathogen within host tissues near the inoculation point. This measure was used as a proxy of pathogen load. We were thus able to relate individual host competence to the pathogen content measured in the same root fragment. No significant correlation between the phenotyped traits was found at the individual level. However, at the species level, the least competent species (Q. robur, Q. petraea) proved to be the most resistant. These results may have important implications for management of chestnut and oak ecosystems threatened by ink disease.

Metabolic reprogramming consequences of sepsis: adaptations and contradictions

During sepsis, the importance of alterations in cell metabolism is underappreciated. The cellular metabolism, which has a variable metabolic profile in different cells and disease stages, is largely responsible for the immune imbalance and organ failure associated with sepsis. Metabolic reprogramming, in which glycolysis replaces OXPHOS as the main energy-producing pathway, is both a requirement for immune cell activation and a cause of immunosuppression. Meanwhile, the metabolites produced by OXPHOS and glycolysis can act as signaling molecules to control the immune response during sepsis. Sepsis-induced "energy shortage" leads to stagnated cell function and even organ dysfunction. Metabolic reprogramming can alleviate the energy crisis to some extent, enhance host tolerance to maintain cell survival functions, and ultimately increase the adaptation of cells during sepsis. However, a switch from glycolysis to OXPHOS is essential for restoring cell function. This review summarized the crosstalk between metabolic reprogramming and immune cell activity as well as organ function during sepsis, discussed the benefits and drawbacks of metabolic reprogramming to show the contradictions of metabolic reprogramming during sepsis, and assessed the feasibility of treating sepsis through targeted metabolism. Using metabolic reprogramming to achieve metabolic homeostasis could be a viable therapy option for sepsis.

TLR2, TLR4, and NLRP3 mediated the balance between host immune-driven resistance and tolerance in Staphylococcus aureus-infected mice

Staphylococcus aureus (S. aureus) is a gram-positive pathogen that can cause infectious diseases in mammals. S. aureus-induced host innate immune responses have a relationship with Toll-like receptor 2 (TLR2), TLR4, and Nod-like receptor pyrin domain-containing protein 3 (NLRP3). However, the detailed roles of TLR2, TLR4, and NLRP3 in regulating the host inflammatory response to S. aureus infection remain unclear. Our data indicated that the S. aureus-induced mortality was aggravated by deficiency of TLR2, TLR4, and NLRP3 in mice. In the subsequent experiment, we found that during S. aureus infection, the roles of TLR2, TLR4, and NLRP3 seemed to be different at multiple timepoints. The deficiency of TLR2, TLR4, or NLRP3 attenuated the expression of High-mobility group box protein 1 (HMGB1) and Hyaluronic acid-binding protein 2 (HABP2), which is accompanied by decreased proinflammatory cytokine (TNF-α), chemokine (RANTES), and anti-inflammatory cytokine (IL-10) production in lungs and serum at 3 h and 6 h post-infection. However, with S. aureus infection prolonged (24 h post-infection), the trend was diametrically opposite. The results showed that deficiency of TLR2, TLR4, or NLRP3 aggravated HABP2 and HMGB1 expression, which is accompanied by enhanced proinflammatory cytokine (TNF-α), chemokine (RANTES), and anti-inflammatory cytokine (IL-10) production in lungs and serum. These results were consistent with the data observed in S. aureus-infected bone marrow-derived macrophages (BMDMs). All these results suggested that during S. aureus infection, TLR2, TLR4, and NLRP3 has time-dependent effect in regulating the balance between immune-driven resistance and tolerance.

Genome-Wide Identification and Analysis of the Heat-Shock Protein Gene Superfamily in Bemisia tabaci and Expression Pattern Analysis under Heat Shock

Simple SummaryBemisia tabaci MED is an invasive pest that had caused considerable economic damage in the past decades. Its successful colonization is closely related to heat-shock proteins (HSPs), which are related to heat resistance. In this study, 33 BtaHsps were identified based on the sequenced genome of B. tabaci MED belonging to six HSP families, among which 22 BtaHsps were newly identified. Analysis of the secondary structure and evolutionary relationship showed that they were all closely related. In addition, BtaHsp90A3 of the HSP90 family was screened by analyzing the expression level changes of these genes under 42 °C heat shock and RNAi was performed on the BtaHsp90A3. The results showed that the silencing of BtaHsp90A3 is closely related to the heat resistance of B. tabaci MED. Taken together, this study conducted an in-depth identification of BtaHsps that clarifies their evolutionary relationships and their response to thermal stress in B. tabaci MED.The thermal tolerance of Bemisia tabaci MED, an invasive whitefly species with worldwide distribution, plays an important role in its ecological adaptation during the invasion process. Heat-shock proteins (HSPs) are closely related to heat resistance. In this study, 33 Hsps (BtaHsps) were identified based on sequenced genome of B. tabaci MED belonging to six HSP families, among which 22 Hsps were newly identified. The secondary structures of a further 22 BtaHsps were also predicted. The results of RT-qPCR showed that heat shock could affect the expression of 14 of the 22 Hsps newly identified in this study. Among them, the expression level of six Hsps increased under 42 °C treatment. As the unstudied gene, BtaHsp90A3 had the highest increase rate. Therefore, BtaHsp90A3 was chosen for the RNAi test, and silencing BtaHsp90A3 by RNAi decreased the survival rate of adult B. tabaci at 42 °C. The results indicated that only a few Hsps were involved in the thermal tolerance of host whitefly although many Hsps would response under heat stress. This study conducted a more in-depth and comprehensive identification that demonstrates the evolutionary relationship of BtaHsps and illustrates the response of BtaHsps under the influence of thermal stress in B. tabaci MED.

Enhancers of Host Immune Tolerance to Bacterial Infection Discovered Using Linked Computational and Experimental Approaches.

Current therapeutic strategies against bacterial infections focus on reduction of pathogen load using antibiotics; however, stimulation of host tolerance to infection in the presence of pathogens might offer an alternative approach. Computational transcriptomics and Xenopus laevis embryos are used to discover infection response pathways, identify potential tolerance inducer drugs, and validate their ability to induce broad tolerance. Xenopus exhibits natural tolerance to Acinetobacter baumanii, Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pneumoniae bacteria, whereas Aeromonas hydrophila and Pseudomonas aeruginosa produce lethal infections. Transcriptional profiling leads to definition of a 20‐gene signature that discriminates between tolerant and susceptible states, as well as identification of a more active tolerance response to gram negative compared to gram positive bacteria. Gene pathways associated with active tolerance in Xenopus, including some involved in metal ion binding and hypoxia, are found to be conserved across species, including mammals, and administration of a metal chelator (deferoxamine) or a HIF‐1α agonist (1,4‐DPCA) in embryos infected with lethal A. hydrophila increased survival despite high pathogen load. These data demonstrate the value of combining the Xenopus embryo infection model with computational multiomics analyses for mechanistic discovery and drug repurposing to induce host tolerance to bacterial infections.

Mutations of γCOP Gene Disturb Drosophila melanogaster Innate Immune Response to Pseudomonas aeruginosa.

Drosophila melanogaster (the fruit fly) is a valuable experimental platform for modeling host–pathogen interactions. It is also commonly used to define innate immunity pathways and to understand the mechanisms of both host tolerance to commensal microbiota and response to pathogenic agents. Herein, we investigate how the host response to bacterial infection is mirrored in the expression of genes of Imd and Toll pathways when D. melanogaster strains with different γCOP genetic backgrounds are infected with Pseudomonas aeruginosa ATCC 27853. Using microarray technology, we have interrogated the whole-body transcriptome of infected versus uninfected fruit fly males with three specific genotypes, namely wild-type Oregon, γCOPS057302/TM6B and γCOP14a/γCOP14a. While the expression of genes pertaining to Imd and Toll is not significantly modulated by P. aeruginosa infection in Oregon males, many of the components of these cascades are up- or downregulated in both infected and uninfected γCOPS057302/TM6B and γCOP14a/γCOP14a males. Thus, our results suggest that a γCOP genetic background modulates the gene expression profiles of Imd and Toll cascades involved in the innate immune response of D. melanogaster, inducing the occurrence of immunological dysfunctions in γCOP mutants.