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Evolutionary theory predicts a late-life decline in the force of natural selection, possibly leading to late-life deregulations of the immune system. A potential outcome of such deregulations is the inability to produce specific immunity against target pathogens. We tested this possibility by infecting multiple

Genetic variation for resistance and disease tolerance has been described in a range of species. In Drosophila melanogaster , genetic variation in mortality following systemic Drosophila C virus (DCV) infection is driven by large-effect polymorphisms in the restriction factor pastrel (pst) . However, it is unclear if pst contributes to disease tolerance. We investigated systemic DCV challenges spanning nine orders of magnitude, in males and females of 10 Drosophila Genetic Reference Panel lines carrying either a susceptible (S) or resistant (R) pst allele. We find among-line variation in fly survival, viral load and disease tolerance measured both as the ability to maintain survival (mortality tolerance) and reproduction (fecundity tolerance). We further uncover novel effects of pst on host vigour, as flies carrying the R allele exhibited higher survival and fecundity even in the absence of infection. Finally, we found significant genetic variation in the expression of the JAK-STAT ligand upd3 and the epigenetic regulator of JAK-STAT G9a. However, while G9a has been previously shown to mediate tolerance of DCV infection, we found no correlation between the expression of either upd3 or G9a on fly tolerance or resistance. Our work highlights the importance of both resistance and tolerance in viral defence.

Invertebrates lack the specialized immune-memory cells responsible for vertebrate-like acquired immunity. However, there is increasing evidence that past infection by the same pathogen can ‘prime’ the insect immune response, resulting in improved survival upon reinfection. The mechanisms underlying these phenomenological accounts of priming are diverse, and often not completely clear. Here, we investigated the generality, specificity and mechanistic basis of immune priming in the fruit flyDrosophila melanogasterwhen infected with the gram-negative bacterial pathogenProvidencia rettgeri. We further explore the epidemiological consequences of immune priming and find it has the potential to curtail pathogen transmission by reducing pathogen shedding. We find that priming inDrosophilais a long-lasting, pathogen-specific response, occurring in several fly genetic backgrounds and is particularly stronger in male flies. Mechanistically, we find that the enhanced survival of individuals primed with an initial non-lethal bacterial inoculum coincides with a transient decrease in bacterial loads, and that this is likely driven by the IMD-responsive antimicrobial-peptideDiptericin-Bin the fat body. Further, we show that whileDiptericinsare required as the effector of bacterial clearance, it is not solely sufficient for immune priming, and requires regulation by the peptidoglycan recognition proteinsPGRP-LB, PGRP-LCandPGRP-LE. We discuss potential explanations for the observed sex differences in priming, and discuss the epidemiological consequences of innate immune priming in invertebrates.Author summaryImmunisation using attenuated or inactivated pathogens remains one of the most successful public health practices to reduce the incidence of infectious diseases. Immunisation works because humans and other vertebrate animals have evolved an immune response capable of specific immune memory, which ensures a strong, precise, and effective response to a secondary infection. While invertebrates lack the vertebrate-like specialized immune memory cells responsible for acquired immunity, there is now substantial evidence that invertebrates are capable of immune priming, characterised by improved survival to a pathogenic infection following an initial exposure to an attenuated or inactivated pathogen. Here, we investigated the occurrence, generality, specificity and mechanistic basis of immune priming in fruit flies when infected with the gram-negative pathogenProvidencia rettgeri. We find that priming with an initial non-lethal bacterial inoculum results increased survival after a secondary lethal challenge with the same live bacterial pathogen, and that this protective response may last at least two weeks after the initial exposure, is particularly strong in male flies, and occurs in several genetic backgrounds. We also find that primed flies shed less pathogen during infection, suggesting that priming can be a useful tool to reduce pathogen transmission in insects.

Evolutionary theory predicts a late-life decline in the force of natural selection, possibly leading to late-life deregulations of the immune system. A potential outcome of such deregulations is the inability to produce specific immunity against target pathogens. We tested this possibility by infecting multiple Drosophila melanogaster lines (with bacterial pathogens) across age groups, where either individual or different combinations of Imd- and Toll-inducible antimicrobial peptides (AMPs) were deleted using CRISPR gene editing. We show a high degree of non-redundancy and pathogen-specificity of AMPs in young flies: in some cases, even a single AMP could confer complete resistance. However, ageing led to drastic reductions in such specificity to target pathogens, warranting the action of multiple AMPs across Imd and Toll pathways. Moreover, use of diverse AMPs either lacked survival benefits or even accompanied survival costs post-infection. These features were also sexually dimorphic: females required a larger repertoire of AMPs than males but extracted equivalent survival benefits. Finally, age-specific expansion of the AMP-repertoire was accompanied with ageing-induced downregulation of negative-regulators of the Imd pathway and damage to renal function post-infection, as features of poorly regulated immunity. Overall, we could highlight the potentially non-adaptive role of ageing in producing less-specific AMP responses, across sexes and pathogens.

Mitochondria are organelles that produce cellular energy in the form of ATP through oxidative phosphorylation, and this primary function is conserved among many taxa. Locomotion is a trait that is highly reliant on metabolic function and expected to be greatly affected by disruptions to mitochondrial performance. To this end, we aimed to examine how activity and sleep vary between Drosophila melanogaster strains with different geographic origins, how these patterns are affected by mitochondrial DNA (mtDNA) variation, and how breaking up co-evolved mito-nuclear gene combinations affect the studied activity traits. Our results demonstrate that Drosophila strains from different locations differ in sleep and activity, and that females are generally more active than males. By comparing activity and sleep of mtDNA variants introgressed onto a common nuclear background in cytoplasmic hybrid (cybrid) strains, we were able to quantify the among-line variance attributable to mitochondrial DNA, and we establish that mtDNA variation affects both activity and sleep, in a sex-specific manner. Altogether our study highlights the important role that mitochondrial genome variation plays on organismal physiology and behaviour.

Identifying how infection modifies host behaviours that determine social contact networks is important for understanding heterogeneity in infectious disease dynamics. Here, we investigate whether group social behaviour is modified during bacterial infection in fruit flies ( Drosophila melanogaster ) according to pathogen species, infectious dose, host genetic background and sex. In one experiment, we find that systemic infection with four different bacterial species results in a reduction in the mean pairwise distance within infected female flies, and that the extent of this change depends on pathogen species. However, susceptible flies did not show any evidence of avoidance in the presence of infected flies. In a separate experiment, we observed genetic- and sex-based variation in social aggregation within infected, same-sex groups, with infected female flies aggregating more closely than infected males. In general, our results confirm that bacterial infection induces changes in fruit fly behaviour across a range of pathogen species, but also highlight that these effects vary between fly genetic backgrounds and can be sex-specific. We discuss possible explanations for sex differences in social aggregation and their consequences for individual variation in pathogen transmission.

Mitochondria participate in various cellular processes including energy metabolism, apoptosis, stress responses, inflammation and immunity. While mitochondrial dysfunction contributes to many diseases, mitochondrial perturbations can also be beneficial, a phenomenon coined mitohormesis. We investigated how mitochondrial variation contributes to the heterogeneity of infection outcomes and whether moderate mitochondrial dysfunction could benefit immune-challenged individuals. We took three approaches to model variation in mitochondrial oxidative phosphorylation (OXPHOS) in Drosophila melanogaster: i) inherited natural mitochondrial DNA (mtDNA) variation present in all tissues; ii) sporadic, tissue-specific silencing of OXPHOS-related genes and iii) systemic pharmacological inhibition of OXPHOS, and studied their effects on the cell-mediated innate immune response. When perturbing mitochondrial function, we detected signs of activated cellular innate immunity without infection and upon infection the perturbation caused enhanced immune response. Our data indicate that mitochondrial dysfunction can be beneficial in immune-challenged individuals when it is mild enough and does not cause complications to the host, and ultimately causes variation in infection outcomes between individuals.Author summaryMitochondria are eukaryotic cell organelles involved in various cellular processes including metabolism and cell signaling. The role of mitochondria and the variation of mitochondrial function in immune responses have been increasingly studied across various models. Mitochondrial dysfunction, originating from either the nuclear or the mitochondrial genome, is generally considered harmful for the organism. What is not yet well understood is how immune responses are affected by mitochondrial dysfunction, for example in the context of mitochondrial disease. Here, we show that in the fruit fly Drosophila melanogaster mild systemic or immune cell -specific mitochondrial perturbations enhance the innate immune response of the host to parasitoids. Furthermore, we show that due to the mitochondrial perturbations the cell-mediated immune system of the host is activated in the absence of infection and makes the immune responses more efficient upon infection. Importantly, our results demonstrate that mitochondrial genome variation is one of the underlying factors contributing to the variation in infection outcomes among individuals. Our results therefore contribute to the understanding of innate immunity, by providing information about the genetic causes underlying the variation seen in the response to infections.

Dietary restriction (DR), limiting calories or specific nutrients without malnutrition, extends lifespan across diverse taxa. Traditionally, this lifespan extension has been explained as a result of diet-mediated changes in the trade-off between lifespan and reproduction, with survival favoured when resources are scarce. However, a recently proposed alternative suggests that the selective benefit of the response to DR is the maintenance of reproduction. This hypothesis predicts that lifespan extension is a side effect of benign laboratory conditions, and DR individuals would be frailer and unable to deal with additional stressors, and thus lifespan extension should disappear under more stressful conditions. We tested this by rearing outbred female fruit flies (Drosophila melanogaster) on 10 different protein:carbohydrate diets. Flies were either infected with a bacterial pathogen (Pseudomonas entomophila), injured with a sterile pinprick or unstressed. We monitored lifespan, fecundity and measures of ageing. DR extended lifespan and reduced reproduction irrespective of injury and infection. Infected flies on lower protein diets had particularly poor survival. Exposure to infection and injury did not substantially alter the relationship between diet and ageing patterns. These results do not provide support for lifespan extension under DR being a side effect of benign laboratory conditions. This article is protected by copyright. All rights reserved.

Evolutionary theory predicts a late-life decline in the force of natural selection, possibly leading to late-life deregulations of the immune system. A potential outcome of such immune-deregulation is the inability to produce specific immunity against target pathogens. We tested this possibility by infecting multiple Drosophila melanogaster lines (with bacterial pathogens) across age-groups, where either individual or different combinations of Imd- and Toll-inducible antimicrobial peptides (AMPs) were deleted using CRISPR gene editing. We show a high degree of non-redundancy and pathogen-specificity of AMPs in young flies: in some cases, even a single AMP could confer complete resistance. In contrast, ageing led to a complete loss of such specificity, warranting the action of multiple AMPs across Imd- and Toll-pathways during infections. Moreover, use of diverse AMPs either had no survival benefits, or even accompanied survival costs post-infection. These features were also sexually dimorphic: females expressed a larger repertoire of AMPs than males, but extracted equivalent survival benefits. Finally, age-specific expansion of the AMP-pool was associated with downregulation of negative-regulators of the Imd-pathway and a potential damage to renal function, as features of poorly-regulated immunity, Overall, we could establish ageing as an important driver of nonspecific AMP responses, across sexes and bacterial infections.

Genetic variation for both resistance and disease tolerance has been described in a range of species infected with bacterial, viral and fungal pathogens. In Drosophila melanogaster, genetic variation in mortality following systemic Drosophila C Virus (DCV) infection has been shown to be driven by large effect polymorphisms in the viral restriction factor pastrel (pst). However, it is unclear if pst impacts variation in DCV titres (i.e. resistance), or if it also contributes to disease tolerance. We investigated systemic infection across a range of DCV challenge doses spanning nine orders of magnitude, in males and females of ten Drosophila Genetic Reference Panel (DGRP) lines carrying either a susceptible (S) or resistant (R) pst allele. Our results uncover among-line variation in fly survival, viral titers, and disease tolerance measured both as the ability to maintain survival (mortality tolerance) and reproduction (fecundity tolerance). We confirm the role of pst in resistance, as fly lines with the resistant (R) pst allele experienced lower viral titers, and we uncover novel effects of pst on host vigor, as flies carrying the R allele exhibited higher survival and fecundity even in the absence of infection. Finally, we found significant variation in the expression of the JAK-STAT ligand upd3 and the epigenetic regulator of JAK-STAT G9a. While G9a has been previously shown to mediate tolerance of DCV infection, we found no correlation between the expression of either upd3 or G9a on fly tolerance or resistance. Our work highlights the importance of both resistance and tolerance in viral defence.

Identifying how infection modifies host behaviours that determine social contact networks is important for understanding heterogeneity in infectious disease dynamics. Here, we investigate whether group social behaviour is modified during bacterial infection in Drosophila melanogaster, an established system for behavioural genetics, according to pathogen species, infectious dose, host genetic background and sex. We find that systemic infection with four different bacterial species results in a reduction in the mean pairwise distance within infected flies, and that the extent of this change depends on the infectious dose in a pathogen-specific way. In the presence of infected conspecifics, susceptible flies also tended to aggregate throughout time, but did not show any evidence of avoiding infected flies. We also observed genetic- and sex-based variation in social aggregation, with infected female flies aggregating more closely than infected males. In general, our results confirm that bacterial infection induces changes in fruit fly behaviour across a range of pathogen species, but also highlight that these effects vary between fly genetic backgrounds and can be sex-specific. We discuss possible explanations for sex differences in social aggregation and their consequences for individual variation in pathogen transmission.

The Gram-negative bacterium

Helicobacter pylori is a common component of the human stomach microbiota, possibly dating back to the speciation of Homo sapiens. A history of pathogen evolution in allopatry has led to the development of genetically distinct H. pylori subpopulations, associated with different human populations, and more recent admixture among H. pylori subpopulations can provide information about human migrations. However, little is known about the degree to which some H. pylori genes are conserved in the face of admixture, potentially indicating host adaptation, or how virulence genes spread among different populations. We analyzed H. pylori genomes from 14 countries in the Americas, strains from the Iberian Peninsula, and public genomes from Europe, Africa, and Asia, to investigate how admixture varies across different regions and gene families. Whole-genome analyses of 723 H. pylori strains from around the world showed evidence of frequent admixture in the American strains with a complex mosaic of contributions from H. pylori populations originating in the Americas as well as other continents. Despite the complex admixture, distinctive genomic fingerprints were identified for each region, revealing novel American H. pylori subpopulations. A pan-genome Fst analysis showed that variation in virulence genes had the strongest fixation in America, compared with non-American populations, and that much of the variation constituted non-synonymous substitutions in functional domains. Network analyses suggest that these virulence genes have followed unique evolutionary paths in the American populations, spreading into different genetic backgrounds, potentially contributing to the high risk of gastric cancer in the region., This work was supported by “Consejo Nacional de Ciencia y Tecnología” (CONACYT; no. 576951) grant to ZYM-R, and by Magnus Bergvalls Foundation and Swedish Society for Medical Research (SSMF) to KT. SKS and BP are funded by the Medical Research Council (MR/L015080/1). Supported in part by the US National Cancer Institute National Cancer Institute to DRM (P01 CA028842, R01 CA190612, K07 CA125588, P30 CA068485). We are very grateful to Daniel Falush (Unit of Statistical Genetics of Bacteria, Institut Pasteur of Shanghai) for his critical input during the analysis of the presented data. We acknowledge the Aklavik H. pylori Project Planning Committee (Northwest Territories, Canada) for providing input on our presentation of this analysis.

In patients presenting to the operating room with a saddle pulmonary embolism for noncardiac surgery, it is best to take a multidisciplinary approach and involve the cardiac and vascular surgeons.

Campylobacter coli and C. jejuni, the causing agents of campylobacteriosis, are described to be undergoing introgression events, i.e., the transference of genetic material between different species, with some isolates sharing almost a quarter of its genome. The participation of phages in introgression events and consequent impact on host ecology and evolution remain elusive. Three distinct prophages, named C. jejuni integrated elements 1, 2, and 4 (CJIE1, CJIE2, and CJIE4), are described in C. jejuni. Here, we identified two unreported prophages, Campylobacter coli integrated elements 1 and 2 (CCIE1 and CCIE2 prophages), which are C. coli homologues of CJIE1 and CJIE2, respectively. No induction was achieved for both prophages. Conversely, induction assays on CJIE1 and CJIE2 point towards the inducibility of these prophages. CCIE2-, CJIE1-, and CJIE4-like prophages were identified in a Campylobacter spp. population of 840 genomes, and phylogenetic analysis revealed clustering in three major groups: CJIE1-CCIE1, CJIE2-CCIE2, and CJIE4, clearly segregating prophages from C. jejuni and C. coli, but not from human- and nonhuman-derived isolates, corroborating the flowing between animals and humans in the agricultural context. Punctual bacteriophage host-jumps were observed in the context of C. jejuni and C. coli, and although random chance cannot be fully discarded, these observations seem to implicate prophages in evolutionary introgression events that are modulating the hybridization of C. jejuni and C. coli species., F.F.V. is funded by Fundação para a Ciência e a Tecnologia (FCT) through an Assistant Researcher grant CEECIND/03023/2017, and a project grant (PTDC/BTM-SAL/28978/2017) that supported this work. The work is partially supported by National funds from FCT, projects UIDB/04138/2020 and UIDP/04138/2020. Campylobacter strains were sequenced under the GenomePT project (POCI-01-0145-FEDER-022184), supported by COMPETE 2020—Operational Programme for Competitiveness and Internationalization (POCI), Lisboa Portugal Regional Operational Programme (Lisboa2020), Algarve Portugal Regional Operational Programme (CRESC Algarve2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and by FCT. This work was also supported by Fundos FEDER through the Programa Operacional Factores de Competitividade—COMPETE and by Fundos Nacionais through the FCT within the scope of the project UID/BIM/00009/2019 (Centre for Toxicogenomics and Human Health-ToxOmics).

Erratum in: Nat Commun. 2023 Mar 20;14(1):1539. doi: 10.1038/s41467-023-37302-5. Helicobacter pylori lives in the human stomach and has a population structure resembling that of its host. However, H. pylori fromEurope and the Middle East trace substantially more ancestry from modern African populations than the humans that carry them. Here, we use a collection of Afro-Eurasian H. pylori genomes to show that this African ancestry is due to at least three distinct admixture events. H. pylori from East Asia, which have undergone little admixture, have accumulated many more non-synonymous mutations than African strains. European and Middle Eastern bacteria have elevated African ancestry at the sites of these mutations, implying selection to remove them during admixture. Simulations show that population fitness can be restored after bottlenecks bymigration and subsequent admixture of small numbers of bacteria from non-bottlenecked populations. We conclude that recent spread of African DNA has been driven by deleterious mutations accumulated during the original out-of-Africa bottleneck. This work was supported by Sequencing Grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan (221S0002, 18KK0266, 19H03473, 21H00346 and 22H02871) to Y.Y. F.F.V. is financed by FCT through Assistant Researcher grant CEECIND/03023/2017 and a project grant PTDC/BTM-TEC/3238/ 2020. I.K. studentship was funded by the National Strategic Reference Framework Operational Program “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014-2020, project No. MIS5002486) and sequencing of strains was supported by the InfeNeutra Project (NSRF 2007-2013, project no. MIS450598) of the Ministry of Culture and Edu- cation, Greece. K.T. and the sequencing of KI isolates was supported by Erik Philip-Sörensen Foundation grant G2016-08, and Swedish Society for Medical research (SSMF). All primary bioinformatics and parts of the comparative genomics were performed on resources provided by Swedish National Infrastructure for Computing (SNIC) through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under projects snic2018-8-24 and uppstore2017270. Work by S.S. was supported by the German Research Foundation (DFG, project number 158 989 968–SFB 900/A1) and by the Bavarian Ministry of Sci- ence and the Arts in the framework of the Bavarian Research Network “New Strategies Against Multi-Resistant Pathogens by Means of Digital Networking—bayresq.net”. D.F. was supported by Shanghai Municipal Science and Technology Major Project No. 2019SHZDZX02. info:eu-repo/semantics/publishedVersion

Mitochondria are organelles that produce cellular energy in the form of ATP through oxidative phosphorylation, and this primary function is conserved between many taxa. Locomotion is a trait that is highly reliant on metabolic function and expected to be greatly affected by disruptions to mitochondrial performance. To this end, we aimed to examine how activity and sleep vary between Drosophila melanogaster strains with different geographic origins, how these patterns are affected by mitochondrial DNA (mtDNA) variation, and how breaking up co-evolved mito-nuclear gene combinations affect the studied activity traits. The results demonstrate that Drosophila strains from different locations differ in sleep and activity, and the extent of variation differs between sexes, females in general being more active. By comparing activity and sleep of mtDNA variants introgressed onto a common nuclear background in cytoplasmic hybrid (cybrid) strains, we establish that mtDNA variation affects both traits, sex specifically. Furthermore, by using previously published mtDNA copy number data, we detected a positive correlation between mtDNA copy number and the activity levels of the cybrid flies. Altogether, our study shows that both mtDNA variation and mitonuclear interactions affect activity and sleep patterns, highlighting the important role that both genomes play on life-history trait evolution.

The insect gut is frequently exposed to pathogenic threats and must not only clear these potential infections, but also tolerate relatively high microbe loads. In contrast to the mechanisms that eliminate pathogens, we currently know less about the mechanisms of disease tolerance. We investigated how well-described mechanisms that prevent, signal, control or repair damage during infection contribute to the phenotype of disease tolerance. We established enteric infections with the bacterial pathogen Pseudomonas entomophila in transgenic lines of Drosophila melanogaster fruit flies affecting dcy (a major component of the peritrophic matrix), upd3 (a cytokine-like molecule), irc (a negative regulator of reactive oxygen species) and egfr 1 (epithelial growth factor receptor). Flies lacking dcy experienced the highest mortality, while loss of function of either irc or upd3 reduced tolerance in both sexes. The disruption of egfr 1 resulted in a severe loss in tolerance in male flies but had no substantial effect on the ability of female flies to tolerate P. entomophila infection, despite carrying greater microbe loads than males. Together, our findings provide evidence for the role of damage limitation mechanisms in disease tolerance and highlight how sexual dimorphism in these mechanisms could generate sex differences in infection outcomes.

Early-life conditions have profound effects on many life-history traits, where early-life diet affects both juvenile development, and adult survival and reproduction. Early-life diet also has consequences for the ability of adults to withstand environmental challenges such as starvation, temperature and desiccation. However, it is less well known how early-life diet influences the consequences of infection in adults. Here we test whether varying the larval diet of female Drosophila melanogaster (through altering protein to carbohydrate ratio, P:C) influences the long-term consequences of injury and infection with the bacterial pathogen Pseudomonas entomophila. Given previous work manipulating adult dietary P:C, we predicted that adults from larvae raised on higher P:C diets would have increased reproduction, but shorter lifespans and an increased rate of ageing, and that the lowest larval P:C diets would be particularly detrimental for adult survival in infected individuals. For larval development, we predicted that low P:C would lead to a longer development time and lower viability. We found that early-life and lifetime egg production were highest at intermediate to high larval P:C diets, but this was independent of injury and infection. There was no effect of larval P:C on adult survival. Larval development was quickest on intermediate P:C and egg-to-pupae and egg-to-adult viability were slightly higher on higher P:C. Overall, despite larval P:C affecting several measured traits, we saw no evidence that larval P:C altered the consequence of infection or injury for adult survival or early-life and lifetime reproduction. Taken together, these data suggest that larval diets appear to have a limited impact on the adult life history consequences of infection.

Disease tolerance describes a hosts ability to maintain health independently of the ability to clear microbe loads. However, we currently know little about the mechanisms that underlie disease tolerance or how known mechanisms of tissue damage signalling and repair may contribute to variation in tolerance. The Jak/Stat pathway plays a pivotal role in Drosophila humoral innate immunity, signalling tissue damage and triggering cellular renewal, making it a potential mechanism underlying the disease tolerance phenotype. Here, we show that disrupting the Jak/Stat pathway in Drosophila melanogaster alters disease tolerance during Pseudomonas entomophila systemic infection. Overall, flies with disrupted Jak/Stat show variation in survival that is not explained by variation in pathogen loads. For instance, mutations disrupting the function of ROS producing dual oxidase (duox) or the negative regulator of Jak/Stat, Socs36E render males less tolerant to systemic bacterial infection but not females. We also investigated whether the negative regulator of Jak/Stat, G9a which has previously been associated with tolerance of viral infections is also implicated in tolerance of bacterial infection. While female flies lacking G9a showed higher mortality and reduced bacterial clearance, disease tolerance did not differ between G9a mutants and the wildtype. This suggests that G9a does not affect tolerance during systemic bacterial infection as it appears to do with viral infection. Overall, our findings highlight that Jak/Stat signalling mediates disease tolerance during systemic bacterial infection and that this response differs between males and females. Our work therefore suggests that differences in Jak/Stat mediated disease tolerance may be a potential source of sexually dimorphic response to infection in Drosophila.

Disease tolerance is an infection phenotype where hosts show relatively high health despite harbouring elevated pathogen loads. Compared to the mechanisms of immune clearance our knowledge of the mechanisms underlying increased tolerance remains incomplete. Variation in the ability to reduce immunopathology may explain why some hosts can tolerate higher pathogen burdens with reduced pathology. Negative immune regulation would therefore appear to be a clear candidate for a mechanism underlying disease tolerance but this has not been tested directly for bacterial infections. Here, we examined how the negative regulation of the immune deficiency (IMD) pathway affects disease tolerance in Drosophila melanogaster when infected with the gram-negative bacterial pathogen Pseudomonas entomophila. We find that UASRNAi-mediated reduced expression of the negative regulators of IMD (pirk and caudal) severely reduced the ability to tolerate infection in both males and females across a wide range of infectious doses. While flies unable to regulate the IMD response exhibited higher expression of antimicrobial peptides and lower bacterial loads as expected, this was not accompanied by a proportional reduction in mortality. Instead, tolerance (measured as fly survival relative to its microbe load) was drastically reduced, likely due to the combination of increased immunopathology and cytotoxicity of elevated AMP expression. Our results therefore highlight that in addition to regulating an efficient pathogen clearance response, negative regulators of IMD also contribute to disease tolerance.

Simple Summary Interval training (IT) is a popular training strategy recognized by its positive effects on metabolic and cardiovascular system. However, there seems no consensus regarding the effects of IT on immune system parameters. Therefore, we aimed to summarize the evidence regarding the effects of IT on the immune system. As our many findings, an IT acutely promote a transitory change on immune cell count followed by reduced function. The magnitude of these changes seems to vary in accordance with IT type. On the other hand, the regular practice of IT might contribute to improve immune function without apparent change on immune cell count. Abstract Purpose: To summarize the evidence regarding the acute and chronic effects of interval training (IT) in the immune system through a systematic review with meta-analysis. Design: Systematic review with meta-analysis. Data source: English, Portuguese and Spanish languages search of the electronic databases Pubmed/Medline, Scopus, and SciELO. Eligibility criteria: Studies such as clinical trials, randomized cross-over trials and randomized clinical trials, investigating the acute and chronic effects of IT on the immune outcomes in humans. Results: Of the 175 studies retrieved, 35 were included in the qualitative analysis and 18 in a meta-analysis. Within-group analysis detected significant acute decrease after IT on immunoglobulin A (IgA) secretory rate (n = 115; MD = −15.46 µg·min−1; 95%CI, −28.3 to 2.66; p = 0.02), total leucocyte count increase (n = 137; MD = 2.58 × 103 µL−1; 95%CI, 1.79 to 3.38; p < 0.001), increase in lymphocyte count immediately after exercise (n = 125; MD = 1.3 × 103 µL−1; 95%CI, 0.86 to 1.75; p < 0.001), and decrease during recovery (30 to 180 min post-exercise) (n = 125; MD = −0.36 × 103 µL−1;−0.57 to −0.15; p < 0.001). No effect was detected on absolute IgA (n = 127; MD = 47.5 µg·mL−1; 95%CI, −10.6 to 105.6; p = 0.11). Overall, IT might acutely reduce leucocyte function. Regarding chronic effects IT improved immune function without change leucocyte count. Conclusion: IT might provide a transient disturbance on the immune system, followed by reduced immune function. However, regular IT performance induces favorable adaptations on immune function.

Glutaredoxin, Grx, is a small protein containing an active site cysteine pair and was discovered in 1976 by Arne Holmgren. The Grx system, comprised of Grx, glutathione, glutathione reductase, and NADPH, was first described as an electron donor for Ribonucleotide Reductase but, from the first discovery in E.coli, the Grx family has impressively grown, particularly in the last two decades. Several isoforms have been described in different organisms (from bacteria to humans) and with different functions. The unique characteristic of Grxs is their ability to catalyse glutathione-dependent redox regulation via glutathionylation, the conjugation of glutathione to a substrate, and its reverse reaction, deglutathionylation. Grxs have also recently been enrolled in iron sulphur cluster formation. These functions have been implied in various physiological and pathological conditions, from immune defense to neurodegeneration and cancer development thus making Grx a possible drug target. This review aims to give an overview on Grxs, starting by a phylogenetic analysis of vertebrate Grxs, followed by an analysis of the mechanisms of action, the specific characteristics of the different human isoforms and a discussion on aspects related to human physiology and diseases., LC, FTO and VB would like to dedicate this work to the memory of Professor Arne Holmgren, discoverer of glutaredoxin, a reference in redox research, a great mentor and storyteller. It was a privilege to work and learn from him. The authors want to thank also all the excellent scientists with whom Arne worked for their contribution to increases the knowledge about glutaredoxins. The authors thank Dr Colin Miller for proofreading the manuscript. LC was supported by the Swedish Cancer Society (961), the Swedish Research Council Medicine (13X-3529) and a grant from the Swedish Fulbright Commission (2020). VB and FFV are supported by iMed.ULisboa’s strategic project (UIDP/04138/2020; UIDB/04138/2020), financed by national funds from Fundação para a Ciência e Tecnologia, Portugal (FCT; www.fct.pt). VB is financed by national funds via Fundação para a Ciência e Tecnologia through Norma Transitória - DL57/2016/CP1376/CT002. FFV is financed by Fundação para a Ciência e Tecnologia through Assistant Researcher grant CEECIND/03023/2017.

The Brazilian Amazonia is a region covered by an extensive mosaic of tropical forests conditioned by different topographical and hydro-edaphic features. Although studies relating environmental determinants of structure and floristic composition are systematically evolving in the region, there is no doubt that there are still information gaps due to the lack of research in peripheric areas of the Amazonia. The seasonally flooded areas of the state of Roraima situated on rio Branco-rio Negro basin, northern Brazilian Amazonia, still are deprived of such information. In this way, this work had as objective determine the physical and soil chemical attributes, and the flooding periodicity that characterize different forest types dispersed in a topographic gradient located in an area on the north of rio Branco-rio Negro basin. Soil samples (0-60 cm) were collected along a 2.7 km transect (31.1-64.8 m a.s.l.) crossing three different forest types: (i) mosaic between treed and forested shade-loving (La+Ld), (ii) area of ecological tension between forested shade-loving and open ombrophilous forest (LO) and (iii) open ombrophilous forest (Ab+As). The results indicated different soil classes and flooding periodicity for each forest type observed: Entisols Fluvents (La+Ld, 3-4 months flooded), Entisols Quartzipsamments (LO, 1-2 months) and Yellow Ultisols (Ab+As, no flooding). All analyzed soils were defined as nutrient-poor areas, especially those located on low altitude, characterized for higher hydrological restrictions (seasonal flooding) aggregating forest types of lower structural patterns (e.g. La+Ld). Soils on low altitude were also characterized as those with the highest percentage of fine sand and silt, while soil free of seasonal flooding (Yellow Ultisols) presented the highest levels of clay and coarse sand, always associated with the ombrophilous forests (higher structural patterns). These results improve our understanding of the environmental factors conditioning different forest types in this peripheral region of Amazonia, suggesting that ecosystems with higher hydro-edaphic restrictions are a strong indicator of forest types with lower structural patterns.

All genomes mutate but the consequences of the resulting deleterious mutational load are poorly understood. Helicobacter pylori lives in the human stomach, has a higher mutation rate than most bacteria and has accompanied anatomically modern humans in migrations including the out-of-Africa expansion more than 50,000 years ago. H. pylori from East Asia have accumulated at least 500 more non-synonymous mutations than African strains, which we propose is due to reduced efficacy of selection during the out-of-Africa bottleneck. H. pylori from Europe and the Middle East trace a substantially higher fraction of ancestry from modern African populations than the humans that carry them, which we find is due to at least three separate admixture events. African ancestry is elevated at positions in the genome where non-synonymous mutations are at high frequency in Asia. We propose that this is due to replacement of deleterious mutations that accumulated during the bottleneck, with the high overall African ancestry proportion due to clonal expansion of strains of African origin. We use simulations to show that a Muller9s ratchet like effect can lead to long-term segregation of deleterious mutations within bacterial populations after a bottleneck, despite high rates of homologous recombination, but that population fitness can be restored by migration of small numbers of bacteria from non-bottlenecked populations. Our results demonstrate that population bottlenecks can have long-term genomic and demographic consequences, even in species with enormous population sizes.

Successful management of Cesarean Delivery complicated by emergent CPB and AVR requires meticulous multidisciplinary planning. This case also represents the volatility that can arise from severe aortic regurgitation during pregnancy.

Here, we present the draft genome sequences of 29 Colombian Helicobacter pylori strains. These strains were isolated in Bogotá, Colombia, from patients diagnosed with chronic gastritis. The genomic characterization of these strains will provide more information on the genetic composition of H. pylori strains from Colombia., We thank the entities that financially supported the development of this work. A.B.M. is a recipient of a scholarship from the Centro de Estudios Interdisciplinarios Básicos y Aplicados (CEIBA) Foundation, Colombia; and A.B.M., C.A., J.S., and A.A.T.-R. are recipients of a project grant (120380763025/2018) from MinCiencias, Colombia. The work is partially supported by Research Vice-Rectory, Pontificia Universidad Javeriana (PPTA_7676) and F.P.I.T. BanRepCultural (project 3956). F.F.V. is financed by national funds from the Fundação para a Ciência e a Tecnologia (FCT) through an assistant researcher grant (CEECIND/03023/2017), a project grant (PTDC/BTM-SAL/28978/2017), and projects UIDB/04138/2020 and UIDP/04138/2020; these funds partially supported this work. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Parental care is a key component of an organism’s reproductive strategy that is thought to trade-off with allocation toward immunity. Yet, it is unclear how caring parents respond to pathogens: do infected parents reduce care as a sickness behavior or simply from being ill or do they prioritize their offspring by maintaining high levels of care? To address this issue, we investigated the consequences of infection by the pathogen Serratia marcescens on mortality, time spent providing care, reproductive output, and expression of immune genes of female parents in the burying beetle Nicrophorus vespilloides. We compared untreated control females with infected females that were inoculated with live bacteria, immune-challenged females that were inoculated with heat-killed bacteria, and injured females that were injected with buffer. We found that infected and immune-challenged females changed their immune gene expression and that infected females suffered increased mortality. Nevertheless, infected and immune-challenged females maintained their normal level of care and reproductive output. There was thus no evidence that infection led to either a decrease or an increase in parental care or reproductive output. Our results show that parental care, which is generally highly flexible, can remain remarkably robust and consistent despite the elevated mortality caused by infection by pathogens. Overall, these findings suggest that infected females maintain a high level of parental care, a strategy that may ensure that offspring receive the necessary amount of care but that might be detrimental to the parents’ own survival or that may even facilitate disease transmission to offspring.

Ostreococcus tauri is a ubiquitous marine pico-eukaryote that is susceptible to lysis upon infection by its species specific Ostreococcus tauri viruses (OtVs). In natural populations of O. tauri, costs of resistance are usually invoked to explain the persistence or reappearance of susceptible individuals in resistant populations. Given the low costs of resistance measured in laboratory experiments with the O. tauri/OtV system to date, the question remains of why susceptible individuals persist in the wild at all. Epidemiological models of host and pathogen population dynamics are one useful approach to understand the conditions that can allow the coexistence of susceptible and resistant hosts. We used a SIR (Susceptible-Infected-Resistant) model to investigate epidemiological dynamics under different laboratory culturing regimes that are commonly used in the O.tauri/OtV system. When taking into account serial transfer (i.e. batchcycle lengths) and dilution rates as well as different resistance costs, our model predicts that no susceptible cells should be detected under any of the simulated conditions – this is consistent with laboratory findings. We thus considered an alternative model that is not used in laboratory experiments, but which incorporates one key process in natural populations: host populations are periodically re-seeded with new infective viruses. In this model, susceptible individuals re-occurred in the population, despite low costs of resistance. This suggests that periodic attack by new viruses, rather than (or in addition to) costs of resistance, may explain the high proportion of susceptible hosts in natural populations, and underlie the discrepancy between laboratory studies and observations of fresh isolates.ImportanceIn natural samples of Ostreococcus sp. and its associated viruses, susceptible hosts are common. However, in laboratory experiments, fully resistant host populations readily and irreversibly evolve. Laboratory experiments are powerful methods for studying process because they offer a stripped-down simplification of a complex system, but this simplification may be an oversimplification for some questions. For example, laboratory and field systems of marine microbes and their viruses differ in population sizes and dynamics, mixing or migration rates, and species diversity, all of which can dramatically alter process outcomes. We demonstrate the utility of using epidemiological models to explore experimental design and to understand mechanisms underlying host-virus population dynamics. We highlight that such models can be used to form strong, testable hypotheses about which key elements of natural systems need to be included in laboratory systems to make them simplified, rather than oversimplified, versions of the processes we use them to study.