Programmed necrosis in the cross talk of cell death and inflammation.

Cell proliferation and cell death are integral elements in maintaining homeostatic balance in metazoans. Disease pathologies ensue when these processes are disturbed. A plethora of evidence indicates that malfunction of cell death can lead to inflammation, autoimmunity, or immunodeficiency. Programmed necrosis or necroptosis is a form of nonapoptotic cell death driven by the receptor interacting protein kinase 3 (RIPK3) and its substrate, mixed lineage kinase domain-like (MLKL). RIPK3 partners with its upstream adaptors RIPK1, TRIF, or DAI to signal for necroptosis in response to death receptor or Toll-like receptor stimulation, pathogen infection, or sterile cell injury. Necroptosis promotes inflammation through leakage of cellular contents from damaged plasma membranes. Intriguingly, many of the signal adaptors of necroptosis have dual functions in innate immune signaling. This unique signature illustrates the cooperative nature of necroptosis and innate inflammatory signaling pathways in managing cell and organismal stresses from pathogen infection and sterile tissue injury.

In Leishmania major, the Homolog of the Oncogene PES1 May Play a Critical Role in Parasite Infectivity.

Leishmaniasis is a neglected tropical disease caused by Leishmania spp. The improvement of existing treatments and the discovery of new drugs remain ones of the major goals in control and eradication of this disease. From the parasite genome, we have identified the homologue of the human oncogene PES1 in Leishmania major (LmjPES). It has been demonstrated that PES1 is involved in several processes such as ribosome biogenesis, cell proliferation and genetic transcription. Our phylogenetic studies showed that LmjPES encodes a highly conserved protein containing three main domains: PES N-terminus (shared with proteins involved in ribosomal biogenesis), BRCT (found in proteins related to DNA repair processes) and MAEBL-type domain (C-terminus, related to erythrocyte invasion in apicomplexan). This gene showed its highest expression level in metacyclic promastigotes, the infective forms; by fluorescence microscopy assay, we demonstrated the nuclear localization of LmjPES protein. After generating mutant parasites overexpressing LmjPES, we observed that these clones displayed a dramatic increase in the ratio of cell infection within macrophages. Furthermore, BALB/c mice infected with these transgenic parasites exhibited higher footpad inflammation compared to those inoculated with non-overexpressing parasites.

Progress and challenges in aminoacyl-tRNA synthetase-based therapeutics.

Aminoacyl-tRNA synthetases (ARSs) are universal enzymes that catalyze the attachment of amino acids to the 3' ends of their cognate tRNAs. The resulting aminoacylated tRNAs are escorted to the ribosome where they enter protein synthesis. By specifically matching amino acids to defined anticodon sequences in tRNAs, ARSs are essential to the physical interpretation of the genetic code. In addition to their canonical role in protein synthesis, ARSs are also involved in RNA splicing, transcriptional regulation, translation, and other aspects of cellular homeostasis. Likewise, aminoacylated tRNAs serve as amino acid donors for biosynthetic processes distinct from protein synthesis, including lipid modification and antibiotic biosynthesis. Thanks to the wealth of details on ARS structures and functions and the growing appreciation of their additional roles regulating cellular homeostasis, opportunities for the development of clinically useful ARS inhibitors are emerging to manage microbial and parasite infections. Exploitation of these opportunities has been stimulated by the discovery of new inhibitor frameworks, the use of semi-synthetic approaches combining chemistry and genome engineering, and more powerful techniques for identifying leads from the screening of large chemical libraries. Here, we review the inhibition of ARSs by small molecules, including the various families of natural products, as well as inhibitors developed by either rational design or high-throughput screening as antibiotics and anti-parasitic therapeutics.

CCR5 and CCR5Δ32 in bacterial and parasitic infections: Thinking chemokine receptors outside the HIV box.

The CCR5 molecule was reported in 1996 as the main HIV-1 co-receptor. In that same year, the CCR5Δ32 genetic variant was described as a strong protective factor against HIV-1 infection. These findings led to extensive research regarding the CCR5, culminating in critical scientific advances, such as the development of CCR5 inhibitors for the treatment of HIV infection. Recently, the research landscape surrounding CCR5 has begun to change. Different research groups have realized that, since CCR5 has such important effects in the chemokine system, it could also affect other different physiological systems. Therefore, the effect of reduced CCR5 expression due to the presence of the CCR5Δ32 variant began to be further studied. Several studies have investigated the role of CCR5 and the impacts of CCR5Δ32 on autoimmune and inflammatory diseases, various types of cancer, and viral diseases. However, the role of CCR5 in diseases caused by bacteria and parasites is still poorly understood. Therefore, the aim of this article is to review the role of CCR5 and the effects of CCR5Δ32 on bacterial (brucellosis, osteomyelitis, pneumonia, tuberculosis and infection by Chlamydia trachomatis) and parasitic infections (toxoplasmosis, leishmaniasis, Chagas disease and schistosomiasis). Basic information about each of these infections was also addressed. The neglected role of CCR5 in fungal disease and emerging studies regarding the action of CCR5 on regulatory T cells are briefly covered in this review. Considering the "renaissance of CCR5 research," this article is useful for updating researchers who develop studies involving CCR5 and CCR5Δ32 in different infectious diseases.

Non-Viral Parasites Associated with Carcinogenesis.

Cancer is a proficient evader of the immune system and is responsible for a high number of deaths annually. Most of these cancer cases are associated with genetic mutations, viruses, radiations or other carcinogenic substances like tobacco smoke. However, a significant number of cases arise as a result of infection by certain parasitic organisms other than viruses. This review tries to explore various less studied mechanisms by which these parasites induce cancer and lead to its progression. The changes brought by organisms in the genetic makeup are enumerated along with the effects of various protein products synthesised by these organisms.

Mechanistic model of evolutionary rate variation en route to a nonphotosynthetic lifestyle in plants.

Because novel environmental conditions alter the selection pressure on genes or entire subgenomes, adaptive and nonadaptive changes will leave a measurable signature in the genomes, shaping their molecular evolution. We present herein a model of the trajectory of plastid genome evolution under progressively relaxed functional constraints during the transition from autotrophy to a nonphotosynthetic parasitic lifestyle. We show that relaxed purifying selection in all plastid genes is linked to obligate parasitism, characterized by the parasite's dependence on a host to fulfill its life cycle, rather than the loss of photosynthesis. Evolutionary rates and selection pressure coevolve with macrostructural and microstructural changes, the extent of functional reduction, and the establishment of the obligate parasitic lifestyle. Inferred bursts of gene losses coincide with periods of relaxed selection, which are followed by phases of intensified selection and rate deceleration in the retained functional complexes. Our findings suggest that the transition to obligate parasitism relaxes functional constraints on plastid genes in a stepwise manner. During the functional reduction process, the elevation of evolutionary rates reaches several new rate equilibria, possibly relating to the modified protein turnover rates in heterotrophic plastids.

Migrants and allergy: a new view of the atopic march.

Summary: Atopy is the result of the influence of environmental factors on genetically predisposed individuals. Migration flows represent an interesting model to study the possible reciprocal roles of genes and environment. In this review the following issues influencing the development of allergic sensitization and/or atopic disorders in migrants will be rooted out: 1) ethnicity, genetic polymorphisms and risk of atopy; 2) double faceted effects of parasitic infestations; 3) biodiversity loss and industrial progress. Moreover, an extensive revision of the literature about the relationship between the migratory status and allergy development is provided.

Parasitic Protozoa: Unusual Roles for G-Quadruplexes in Early-Diverging Eukaryotes.

Guanine-quadruplex (G4) motifs, at both the DNA and RNA levels, have assumed an important place in our understanding of the biology of eukaryotes, bacteria and viruses. However, it is generally little known that their very first description, as well as the foundational work on G4s, was performed on protozoans: unicellular life forms that are often parasitic. In this review, we provide a historical perspective on the discovery of G4s, intertwined with their biological significance across the protozoan kingdom. This is a history in three parts: first, a period of discovery including the first characterisation of a G4 motif at the DNA level in ciliates (environmental protozoa); second, a period less dense in publications concerning protozoa, during which DNA G4s were discovered in both humans and viruses; and third, a period of renewed interest in protozoa, including more mechanistic work in ciliates but also in pathogenic protozoa. This last period has opened an exciting prospect of finding new anti-parasitic drugs to interfere with parasite biology, thus adding new compounds to the therapeutic arsenal.

Oncogenic spiral by infectious pathogens: Cooperation of multiple factors in cancer development.

Chronic infection is one of the major causes of cancer, and there are several mechanisms for infection-mediated oncogenesis. Some pathogens encode gene products that behave like oncogenic factors, hijacking cellular pathways to promote the survival and proliferation of infected cells in vivo. Some of these viral oncoproteins trigger a cellular damage defense response leading to senescence; however, other viral factors hinder this suppressive effect, suggesting that cooperation of those viral factors is important for malignant transformation. Coinfection with multiple agents is known to accelerate cancer development in certain cases. For example, parasitic or bacterial infection is a risk factor for adult T-cell leukemia-lymphoma induced by human T-cell leukemia virus type 1, and Epstein-Barr virus and malaria are closely associated with endemic Burkitt lymphoma. Human immunodeficiency virus type 1 infection is accompanied by various types of infection-related cancer. These findings indicate that these oncogenic pathogens can cooperate to overcome host barriers against cancer development. In this review, the authors focus on the collaborative strategies of pathogens for oncogenesis from two different points of view: (i) the cooperation of two or more different factors encoded by a single pathogen; and (ii) the acceleration of oncogenesis by coinfection with multiple agents.

ALBA4 modulates its stage-specific interactions and specific mRNA fates during Plasmodium yoelii growth and transmission.

Transmission of the malaria parasite occurs in an unpredictable moment, when a mosquito takes a blood meal. Plasmodium has therefore evolved strategies to prepare for transmission, including translationally repressing and protecting mRNAs needed to establish the infection. However, mechanisms underlying these critical controls are not well understood, including whether Plasmodium changes its translationally repressive complexes and mRNA targets in different stages. Efforts to understand this have been stymied by severe technical limitations due to substantial mosquito contamination of samples. Here using P. yoelii, for the first time we provide a proteomic comparison of a protein complex across asexual blood, sexual and sporozoite stages, along with a transcriptomic comparison of the mRNAs that are affected in these stages. We find that the Apicomplexan-specific ALBA4 RNA-binding protein acts to regulate development of the parasite's transmission stages, and that ALBA4 associates with both stage-specific and stage-independent partners to produce opposing mRNA fates. These efforts expand our understanding and ability to interrogate both sexual and sporozoite transmission stages and the molecular preparations they evolved to perpetuate their infectious cycle.

Association mapping reveals candidate loci for resistance and anaemic response to an emerging temperature-driven parasitic disease in a wild salmonid fish.

Even though parasitic infections are often costly or deadly for the host, we know very little which genes influence parasite susceptibility and disease severity. Proliferative kidney disease is an emerging and, at elevated water temperatures, potentially deadly disease of salmonid fishes that is caused by the myxozoan parasite Tetracapsuloides bryosalmonae. By screening >7.6 K SNPs in 255 wild brown trout (Salmo trutta) and combining association mapping and Random Forest approaches, we identified several candidate genes for both the parasite resistance (inverse of relative parasite load; RPL) and the severe anaemic response to the parasite. The strongest RPL-associated SNP mapped to a noncoding region of the congeneric Atlantic salmon (S. salar) chromosome 10, whereas the second strongest RPL-associated SNP mapped to an intronic region of PRICKLE2 gene, which is a part of the planar cell polarity signalling pathway involved in kidney development. The top SNP associated with anaemia mapped to the intron of the putative PRKAG2 gene. The human ortholog of this gene has been associated with haematocrit and other blood-related traits, making it a prime candidate influencing parasite-triggered anaemia in brown trout. Our findings demonstrate the power of association mapping to pinpoint genomic regions and potential causative genes underlying climate change-driven parasitic disease resistance and severity. Furthermore, this work illustrates the first steps towards dissecting genotype-phenotype links in a wild fish population using closely related genome information.

Apolipoprotein E4 is associated with improved cognitive function in Amazonian forager-horticulturalists with a high parasite burden.

The apolipoprotein E4 (E4) allele is present worldwide, despite its associations with higher risk of cardiovascular morbidity, accelerated cognitive decline during aging, and Alzheimer's disease (AD). The E4 allele is especially prevalent in some tropical regions with a high parasite burden. Equatorial populations also face a potential dual burden of high E4 prevalence combined with parasitic infections that can also reduce cognitive performance. We examined the interactions of E4, parasite burden, and cognitive performance in a traditional, nonindustrialized population of Amazonian forager-horticulturalists (N = 372) to test whether E4 protects against cognitive decline in environments with a heavy pathogen burden. Contrary to observations in industrial populations, older adult E4 carriers with high parasite burdens either maintained or showed slight improvements in cognitive performance, whereas non-E4 carriers with a high parasite burden showed reduced cognitive performance. Being an E4 carrier is the strongest risk factor to date of AD and cognitive decline in industrial populations; it is associated with greater cognitive performance in individuals facing a high parasite and pathogen load, suggesting advantages to the E4 allele under certain environmental conditions. The current mismatch between postindustrial hygienic lifestyles and active parasite-rich environs may be critical for understanding genetic risk for cognitive aging.-Trumble, B. C., Stieglitz, J., Blackwell, A. D., Allayee, H., Beheim, B., Finch, C. E., Gurven, M., Kaplan, H. Apolipoprotein E4 is associated with improved cognitive function in Amazonian forager-horticulturalists with a high parasite burden.

Derivation of the economic value of R0 for macroparasitic diseases and application to sea lice in salmon.

BACKGROUND: Macroparasites, such as ticks, lice, and helminths, are a concern in livestock and aquaculture production, and can be controlled by genetic improvement of the host population. Genetic improvement should aim at reducing the rate at which parasites spread across the farmed population. This rate is determined by the basic reproduction ratio, i.e. [Formula: see text], which is the appropriate breeding goal trait. This study aims at providing a method to derive the economic value of [Formula: see text]. METHODS: Costs of a disease are the sum of production losses and expenditures on disease control. Genetic improvement of [Formula: see text] lowers the loss-expenditure frontier. Its economic effect depends on whether the management strategy is optimized or not. The economic value may be derived either from the reduction in losses with constant expenditures or from the reduction in expenditures with constant losses. RESULTS: When [Formula: see text] ≤ 1, the economic value of a further reduction is zero because there is no risk of a major epidemic. When [Formula: see text] > 1 and management is optimized, the economic value increases with decreasing values of [Formula: see text], because both the mean number of parasites per host and frequency of treatments decrease at an increasing rate when [Formula: see text] decreases. When [Formula: see text] > 1 and management is not optimized, the economic value depends on whether genetic improvement is used for reducing expenditures or losses. For sea lice in salmon, the economic value depends on a reduction in expenditures with constant losses, and is estimated to be 0.065€/unit [Formula: see text]/kg production. DISCUSSION: Response to selection for measures of disease prevalence cannot be predicted from quantitative genetic theory alone. Moreover, many studies fail to address the issue of whether genetic improvement results in reduced losses or expenditures. Using [Formula: see text] as the breeding goal trait, weighed by its appropriate economic value, avoids these issues. CONCLUSION: When management is optimized, the economic value increases with decreasing values of [Formula: see text] (until the threshold of [Formula: see text], where it drops to zero). When management is not optimized, the economic value depends on whether genetic improvement is used for reduced expenditures or production losses. For sea lice in salmon, the economic value is estimated to be 0.065 €/unit [Formula: see text]/kg production.

Evolutionary rescue of a parasite population by mutation rate evolution.

The risk of antibiotic resistance evolution in parasites is a major problem for public health. Identifying factors which promote antibiotic resistance evolution is thus a priority in evolutionary medicine. The rate at which new mutations enter the parasite population is one important predictor; however, mutation rate is not necessarily a fixed quantity, as is often assumed, but can itself evolve. Here we explore the possible impacts of mutation rate evolution on the fate of a disease circulating in a host population, which is being treated with drugs, the use of which varies over time. Using an evolutionary rescue framework, we find that mutation rate evolution provides a dramatic increase in the probability that a parasite population survives treatment in only a limited region, while providing little or no advantage in other regions. Both epidemiological features, such as the virulence of infection, and population genetic parameters, such as recombination rate, play important roles in determining the probability of evolutionary rescue and whether mutation rate evolution enhances the probability of evolutionary rescue or not. While efforts to curtail mutation rate evolution in parasites may be worthwhile under some circumstances, our results suggest that this need not always be the case.

Coevolutionary feedback elevates constitutive immune defence: a protein network model.

BACKGROUND: Organisms have evolved a variety of defence mechanisms against natural enemies, which are typically used at the expense of other life history components. Induced defence mechanisms impose minor costs when pathogens are absent, but mounting an induced response can be time-consuming. Therefore, to ensure timely protection, organisms may partly rely on constitutive defence despite its sustained cost that renders it less economical. Existing theoretical models addressing the optimal combination of constitutive versus induced defence focus solely on host adaptation and ignore the fact that the efficacy of protection depends on genotype-specific host-parasite interactions. Here, we develop a signal-transduction network model inspired by the invertebrate innate immune system, in order to address the effect of parasite coevolution on the optimal combination of constitutive and induced defence. RESULTS: Our analysis reveals that coevolution of parasites with specific immune components shifts the host's optimal allocation from induced towards constitutive immunity. This effect is dependent upon whether receptors (for detection) or effectors (for elimination) are subjected to parasite counter-evolution. A parasite population subjected to a specific immune receptor can evolve heightened genetic diversity, which makes parasite detection more difficult for the hosts. We show that this coevolutionary feedback renders the induced immune response less efficient, forcing the hosts to invest more heavily in constitutive immunity. Parasites diversify to escape elimination by a specific effector too. However, this diversification does not alter the optimal balance between constitutive and induced defence: the reliance on constitutive defence is promoted by the receptor's inability to detect, but not the effectors' inability to eliminate parasites. If effectors are useless, hosts simply adapt to tolerate, rather than to invest in any defence against parasites. These contrasting results indicate that evolutionary feedback between host and parasite populations is a key factor shaping the selection regime for immune networks facing antagonistic coevolution. CONCLUSION: Parasite coevolution against specific immune defence alters the prediction of the optimal use of defence, and the effect of parasite coevolution varies between different immune components.

Host-parasite coevolutionary dynamics with generalized success/failure infection genetics.

Host-parasite infection genetics can be more complex than envisioned by classic models such as the gene-for-gene or matching-allele models. By means of a mathematical model, I investigate the coevolutionary dynamics arising from a large set of generalized models of infection genetics in which hosts are either fully resistant or fully susceptible to a parasite, depending on the genotype of both individuals. With a single diploid interaction locus in the hosts, many of the infection genetic models produce stable or neutrally stable genotype polymorphisms. However, only a few models, which are all different versions of the matching-allele model, lead to sustained cycles of genotype frequency fluctuations in both interacting species ("Red Queen" dynamics). By contrast, with two diploid interaction loci in the hosts, many infection genetics models that cannot be classified as one of the standard infection genetics models produce Red Queen dynamics. Sexual versus asexual reproduction and, in the former case, the rate of recombination between the interaction loci have a large impact on whether Red Queen dynamics arise from a given infection genetics model. This may have interesting but as yet unexplored implications with respect to the Red Queen hypothesis for the evolution of sex.

The evolutionary ecology of complex lifecycle parasites: linking phenomena with mechanisms.

Many parasitic infections, including those of humans, are caused by complex lifecycle parasites (CLPs): parasites that sequentially infect different hosts over the course of their lifecycle. CLPs come from a wide range of taxonomic groups-from single-celled bacteria to multicellular flatworms-yet share many common features in their life histories. Theory tells us when CLPs should be favoured by selection, but more empirical studies are required in order to quantify the costs and benefits of having a complex lifecycle, especially in parasites that facultatively vary their lifecycle complexity. In this article, we identify ecological conditions that favour CLPs over their simple lifecycle counterparts and highlight how a complex lifecycle can alter transmission rate and trade-offs between growth and reproduction. We show that CLPs participate in dynamic host-parasite coevolution, as more mobile hosts can fuel CLP adaptation to less mobile hosts. Then, we argue that a more general understanding of the evolutionary ecology of CLPs is essential for the development of effective frameworks to manage the many diseases they cause. More research is needed identifying the genetics of infection mechanisms used by CLPs, particularly into the role of gene duplication and neofunctionalisation in lifecycle evolution. We propose that testing for signatures of selection in infection genes will reveal much about how and when complex lifecycles evolved, and will help quantify complex patterns of coevolution between CLPs and their various hosts. Finally, we emphasise four key areas where new research approaches will provide fertile opportunities to advance this field.

Optimal immunity meets natural variation: the evolutionary biology of host defence.

This editorial introduces the seven articles that comprise the Parasite Immunology special issue on the Evolutionary Biology of Host Defence. The rationale for an evolutionary approach to immunoparasitology is briefly outlined, and then the articles are placed in that broader context. A central aim of each article is to explain the generation and maintenance of immunological heterogeneity among hosts in nature. The authors describe new tools and approaches that enable unprecedented insight into evolutionary and immunological processes in both the laboratory and the wild. The examples discussed include insects, birds and mammals (as hosts) and trypanosomes, apicomplexans and nematodes (as parasites).

microRNAs in parasites and parasite infection.

miRNAs, a subclass of small regulatory RNAs, are present from ancient unicellular protozoans to parasitic helminths and parasitic arthropods. The miRNA-silencing mechanism appears, however, to be absent in a number of protozoan parasites. Protozoan miRNAs and components of their silencing machinery possess features different from other eukaryotes, providing some clues on the evolution of the RNA-induced silencing machinery. miRNA functions possibly associate with neoblast biology, development, physiology, infection and immunity of parasites. Parasite infection can alter host miRNA expression that can favor both parasite clearance and infection. miRNA pathways are, thus, a potential target for the therapeutic control of parasitic diseases.

G-Quadruplex DNAzyme-Substrated CRISPR/Cas12 Assay for Label-Free Detection of Single-Celled Parasitic Infection.

Early diagnosis of parasitic diseases can dramatically alleviate medical, economic, and social burdens. Herein, we report a sensitive and label-free assay for diagnosing single-celled parasitic infections using G-quadruplex (G4) DNAzyme as a reporter for CRISPR/Cas12. The substitution of a fluorescent DNA reporter with G4 DNAzyme increased the sensitivity for detecting Leishmania donovani (L. donovani) by 5 times and obviated the need for using chemically labeled DNA probes. The G4 DNAzyme-substrated CRISPR/Cas12 (GsubCas12) assay yielded a limit of detection of 3.1 parasites in the detection of cultured L. donovani and was further applied to analyze L. donovani in infected mice. The results showed that the GsubCas12 assay could positively detect L. donovani in spleen samples from infected mice about 2 weeks after low-dose inoculation, nearly 2 weeks earlier than that of parasitological analysis. GsubCas12 assay is promising as a diagnostic tool for parasitic infection in resource-limited regions.