Host Survival Research Articles

Small molecules restore azole activity against drug-tolerant and drug-resistant Candida isolates.

Each year, fungi cause more than 1.5 billion infections worldwide and have a devastating impact on human health, particularly in immunocompromised individuals or patients in intensive care units. The limited antifungal arsenal and emerging multidrug-resistant species necessitate the development of new therapies. One strategy for combating drug-resistant pathogens is the administration of molecules that restore fungal susceptibility to approved drugs. Accordingly, we carried out a screen to identify small molecules that could restore the susceptibility of pathogenic Candida species to azole antifungals. This screening effort led to the discovery of novel 1,4-benzodiazepines that restore fluconazole susceptibility in resistant isolates of Candida albicans, as evidenced by 100-1,000-fold potentiation of fluconazole activity. This potentiation effect was also observed in azole-tolerant strains of C. albicans and in other pathogenic Candida species. The 1,4-benzodiazepines selectively potentiated different azoles, but not other approved antifungals. A remarkable feature of the potentiation was that the combination of the compounds with fluconazole was fungicidal, whereas fluconazole alone is fungistatic. Interestingly, the potentiators were not toxic to C. albicans in the absence of fluconazole, but inhibited virulence-associated filamentation of the fungus. We found that the combination of the potentiators and fluconazole significantly enhanced host survival in a Galleria mellonella model of systemic fungal infection. Taken together, these observations validate a strategy wherein small molecules can restore the activity of highly used anti-infectives that have lost potency. IMPORTANCE In the last decade, we have been witnessing a higher incidence of fungal infections, due to an expansion of the fungal species capable of causing disease (e.g., Candida auris), as well as increased antifungal drug resistance. Among human fungal pathogens, Candida species are a leading cause of invasive infections and are associated with high mortality rates. Infections by these pathogens are commonly treated with azole antifungals, yet the expansion of drug-resistant isolates has reduced their clinical utility. In this work, we describe the discovery and characterization of small molecules that potentiate fluconazole and restore the susceptibility of azole-resistant and azole-tolerant Candida isolates. Interestingly, the potentiating 1,4-benzodiazepines were not toxic to fungal cells but inhibited their virulence-associated filamentous growth. Furthermore, combinations of the potentiators and fluconazole decreased fungal burdens and enhanced host survival in a Galleria mellonella model of systemic fungal infections. Accordingly, we propose the use of novel antifungal potentiators as a powerful strategy for addressing the growing resistance of fungi to clinically approved drugs.

Asymptomatic viral infection is associated with lower host reproductive output in wild mink populations

Many endemic viruses circulate in populations without hosts showing visible signs of disease, while still having the potential to alter host survival or reproduction. Aleutian Mink Disease Virus (AMDV) circulates in many American mink (Neogale vison) populations in its native and introduced ranges. In this study, we analysed how AMDV infection in female American mink affects the reproduction of a feral population. Females infected with AMDV delivered significantly smaller litters (5.8 pups) than uninfected females (6.3 pups), meaning their litter size was reduced by 8%. Larger females and yearling females had larger litters than smaller and older females. There were no significant differences in whole litter survival between infected and uninfected females; however, offspring survival until September or October within litters of infected females was 14% lower than that within those of uninfected females. This negative link between infection and reproductive output means that Aleutian disease could seriously affect the wild mink population. This study increases our understanding of the threats posed by the spread of viruses to wildlife from farm animals or humans, highlighting that viruses circulating in wildlife, even in the absence of clinical manifestation, can be important drivers of population dynamics in wildlife.

A mathematic equation derived from host-pathogen interactions elucidates the significance of integrating modern medicine with traditional Chinese medicine to treat infectious diseases

The prognosis of infectious diseases is determined by host-pathogen interactions. Control of pathogens has been the central dogma of treating infectious diseases in modern medicine, but the pathogen-directed medicine is facing significant challenges, including a lack of effective antimicrobials for newly emerging pathogens, pathogen drug resistance, and drug side effects. Here, a mathematic equation (termed equation of host-pathogen interactions, HPI-Equation) is developed to dissect the key variables of host-pathogen interactions. It shows that control of pathogens does not necessarily lead to host recovery. Instead, a combination of promoting a host's power of self-healing and balancing immune responses provides the best benefit for host. Moreover, the HPI-Equation elucidates the scientific basis of traditional Chinese medicine (TCM), a host-based medicine that treats infectious diseases by promoting self-healing power and balancing immune responses. The importance of self-healing power elucidated in the HPI-Equation is confirmed by recent studies that the tolerance mechanism, which is discovered in plants and animals and conceptually similar to self-healing power, improves host survival without directly attacking pathogens. In summary, the HPI-Equation describes host-pathogen interactions with mathematical logic and precision; it translates the ancient wisdoms of TCM into apprehensible modern sciences and opens a new venue for integrating TCM and modern medicine for a future medicine.Sun J. A mathematic equation derived from host-pathogen interactions elucidates the significance of integrating modern medicine with traditional Chinese medicine to treat infectious diseases. J Integr Med. 2023; 21(4):324–331.

Behavioral thermoregulation of caterpillars is altered by temperature, but not parasitism: An empirical field study

AbstractLaboratory assays show that parasites often have lower heat tolerance than their hosts. But how physiological tolerances and behavioral responses of hosts and parasites combine to affect their ecological interactions in heterogeneous field environments is largely unknown. We addressed this challenge using the model insect system of the braconid wasp parasitoid, Cotesia congregata, and its caterpillar host, Manduca sexta. We used experimental manipulations of microclimate in the field to determine how elevated daytime temperatures altered the behavior, performance, and survival of host and parasite. Our experimental manipulation increased daily maximum temperatures on host plants, but had negligible effects on overall mean temperature. These increased maximum temperatures resulted in subtle, biologically relevant, changes in physiology and behavior of the host and parasitoid. We found that parasitism by the wasp did not significantly alter caterpillar thermoregulatory behavior, while experimentally increased daily maximum temperatures resulted in both parasitized and unparasitized caterpillars to be found more frequently in cooler microhabitats. Overall, we did not observe the complete parasitoid mortality seen at extreme temperatures in laboratory studies, but gained insight into the sublethal effects of increased daily maximum temperatures on host and parasitoid behavior and physiology. Climate change will alter both the biotic and abiotic environments that organisms face, and we show here that empirical experiments in the field are important for understanding organismal response to these new environments.

Consequences of microsporidian prior exposure for virus infection outcomes and bumble bee host health.

Host-parasite interactions do not occur in a vacuum, but in connected multi-parasite networks that can result in co-exposures and coinfections of individual hosts. These can affect host health and disease ecology, including disease outbreaks. However, many host-parasite studies examine pairwise interactions, meaning we still lack a general understanding of the influence of co-exposures and coinfections. Using the bumble bee Bombus impatiens, we study the effects of larval exposure to a microsporidian Nosema bombi, implicated in bumble bee declines, and adult exposure to Israeli Acute Paralysis Virus (IAPV), an emerging infectious disease from honey bee parasite spillover. We hypothesize that infection outcomes will be modified by co-exposure or coinfection. Nosema bombi is a potentially severe, larval-infecting parasite, and we predict that prior exposure will result in decreased host resistance to adult IAPV infection. We predict double parasite exposure will also reduce host tolerance of infection, as measured by host survival. Although our larval Nosema exposure mostly did not result in viable infections, it partially reduced resistance to adult IAPV infection. Nosema exposure also negatively affected survival, potentially due to a cost of immunity in resisting the exposure. There was a significant negative effect of IAPV exposure on survivorship, but prior Nosema exposure did not alter this survival outcome, suggesting increased tolerance given the higher IAPV infections in the bees previously exposed to Nosema. These results again demonstrate that infection outcomes can be non-independentwhen multiple parasites are present, even when exposure to one parasite does not result in a substantial infection.

Extracellular protein homeostasis: The dawning of a new age for human disease therapies?

Extracellular protein homeostasis: The dawning of a new age for human disease therapies?

The core mangrove microbiome reveals shared taxa potentially involved in nutrient cycling and promoting host survival

BackgroundMicrobes have fundamental roles underpinning the functioning of our planet, they are involved in global carbon and nutrient cycling, and support the existence of multicellular life. The mangrove ecosystem is nutrient limited and if not for microbial cycling of nutrients, life in this harsh environment would likely not exist. The mangroves of Southeast Asia are the oldest and most biodiverse on the planet, and serve vital roles helping to prevent shoreline erosion, act as nursery grounds for many marine species and sequester carbon. Despite these recognised benefits and the importance of microbes in these ecosystems, studies examining the mangrove microbiome in Southeast Asia are scarce.cxsResultsHere we examine the microbiome of Avicenia alba and Sonneratia alba and identify a core microbiome of 81 taxa. A further eight taxa (Pleurocapsa, Tunicatimonas, Halomonas, Marinomonas, Rubrivirga, Altererythrobacte, Lewinella, and Erythrobacter) were found to be significantly enriched in mangrove tree compartments suggesting key roles in this microbiome. The majority of those identified are involved in nutrient cycling or have roles in the production of compounds that promote host survival.ConclusionThe identification of a core microbiome furthers our understanding of mangrove microbial biodiversity, particularly in Southeast Asia where studies such as this are rare. The identification of significantly different microbial communities between sampling sites suggests environmental filtering is occurring, with hosts selecting for a microbial consortia most suitable for survival in their immediate environment. As climate change advances, many of these microbial communities are predicted to change, however, without knowing what is currently there, it is impossible to determine the magnitude of any deviations. This work provides an important baseline against which change in microbial community can be measured.

PI3K/Akt/Nrf2 mediated cellular signaling and virus-host interactions: latest updates on the potential therapeutic management of SARS-CoV-2 infection.

The emergence and re-emergence of viral diseases, which cause significant global mortality and morbidity, are the major concerns of this decade. Of these, current research is focused majorly on the etiological agent of the COVID-19 pandemic, SARS-CoV-2. Understanding the host response and metabolic changes during viral infection may provide better therapeutic targets for the proper management of pathophysiological conditions associated with SARS-CoV-2 infection. We have achieved control over most emerging viral diseases; however, a lack of understanding of the underlying molecular events prevents us from exploring novel therapeutic targets, leaving us forced to witness re-emerging viral infections. SARS-CoV-2 infection is usually accompanied by oxidative stress, which leads to an overactive immune response, the release of inflammatory cytokines, increasing lipid production, and also alterations in the endothelial and mitochondrial functions. PI3K/Akt signaling pathway confers protection against oxidative injury by various cell survival mechanisms including Nrf2-ARE mediated antioxidant transcriptional response. SARS-CoV-2 is also reported to hijack this pathway for its survival within host and few studies have suggested the role of antioxidants in modulating the Nrf2 pathway to manage disease severity. This review highlights the interrelated pathophysiological conditions associated with SARS-CoV-2 infection and the host survival mechanisms mediated by PI3K/Akt/Nrf2 signaling pathways that can help ameliorate the severity of the disease and provide effective antiviral targets against SARS-CoV-2.

Evaluation of Legume-Rhizobial Symbiotic Interactions Beyond Nitrogen Fixation That Help the Host Survival and Diversification in Hostile Environments.

Plants often experience unfavorable conditions during their life cycle that impact their growth and sometimes their survival. A temporary phase of such stress, which can result from heavy metals, drought, salinity, or extremes of temperature or pH, can cause mild to enormous damage to the plant depending on its duration and intensity. Besides environmental stress, plants are the target of many microbial pathogens, causing diseases of varying severity. In plants that harbor mutualistic bacteria, stress can affect the symbiotic interaction and its outcome. To achieve the full potential of a symbiotic relationship between the host and rhizobia, it is important that the host plant maintains good growth characteristics and stay healthy under challenging environmental conditions. The host plant cannot provide good accommodation for the symbiont if it is infested with diseases and prone to other predators. Because the bacterium relies on metabolites for survival and multiplication, it is in its best interests to keep the host plant as stress-free as possible and to keep the supply stable. Although plants have developed many mitigation strategies to cope with stress, the symbiotic bacterium has developed the capability to augment the plant's defense mechanisms against environmental stress. They also provide the host with protection against certain diseases. The protective features of rhizobial-host interaction along with nitrogen fixation appear to have played a significant role in legume diversification. When considering a legume-rhizobial symbiosis, extra benefits to the host are sometimes overlooked in favor of the symbionts' nitrogen fixation efficiency. This review examines all of those additional considerations of a symbiotic interaction that enable the host to withstand a wide range of stresses, enabling plant survival under hostile regimes. In addition, the review focuses on the rhizosphere microbiome, which has emerged as a strong pillar of evolutionary reserve to equip the symbiotic interaction in the interests of both the rhizobia and host. The evaluation would draw the researchers' attention to the symbiotic relationship as being advantageous to the host plant as a whole and the role it plays in the plant's adaptation to unfavorable environmental conditions.

Amphid sensory neurons of Caenorhabditis elegans orchestrate its survival from infection with broad classes of pathogens.

The survival of a host during infection relies on its ability to rapidly sense the invading pathogen and mount an appropriate response. The bacterivorous nematode Caenorhabditis elegans lacks most of the traditional pattern recognition mechanisms. In this study, we hypothesized that the 12 pairs of amphid sensory neurons in the heads of worms provide sensing capability and thus affect survival during infection. We tested animals lacking amphid neurons to three major classes of pathogens, namely-a Gram-negative bacterium Pseudomonas aeruginosa, a Gram-positive bacterium Enterococcus faecalis, and a pathogenic yeast Cryptococcus neoformans By using individual neuronal ablation lines or mutants lacking specific neurons, we demonstrate that some neurons broadly suppress the survival of the host and colonization of all pathogens, whereas other amphid neurons differentially regulate host survival during infection. We also show that the roles of some of these neurons are pathogen-specific, as seen with the AWB odor sensory neurons that promote survival only during infections with P aeruginosa Overall, our study reveals broad and specific roles for amphid neurons during infections.

IgA Determines Bacterial Composition in the Gut.

Classically, IgA in the gut prevents the invasion of microorganisms to systemic organs through the process of neutralization and immune exclusion. Interestingly, recent reports suggest that IgA might help in biofilm formation and promote bacterial growth inside the intestine. In this study, we used flow cytometry, ELISA, and chemical models of colitis to test whether the quality and quantity of IgA can select for bacterial persistence in the gut. We found that members of Proteobacteria, such as γ-Proteobacteria and SFB, are preferentially coated by IgA in WT mice. In the partial absence of either T-dependent or -independent IgA responses, there are no significant differences in the frequency of bacteria coated with IgA in mice. However, Rag-/- mice that lack all antibodies had a severe reduction in Proteobacteria and were resistant to DSS-induced colitis, suggesting that secretory IgA might be essential for differential retention of these taxa in the mouse gut. Rag-/- littermates in the F2 generation generated from (B6 × Rag-/-) F1 mice acquired the underrepresented bacteria taxa such as γ-Proteobacteria through vertical transmission of flora. They died soon after weaning, possibly due to the acquired flora. Additionally, continued exposure of Rag-/- mice to B6 flora by cohousing mice led to the acquisition of γ-Proteobacteria and mortality. Together, our results indicate that host survival in the complete absence of an IgA response necessitates the exclusion of specific bacterial taxa from the gut microbiome.

Variation in CD8 T cell IFNγ differentiation to strains of Toxoplasma gondii is characterized by small effect QTLs with contribution from ROP16.

Toxoplasma gondii induces a strong CD8 T cell response characterized by the secretion of IFNγ that promotes host survival during infection. The initiation of CD8 T cell IFNγ responses in vitro differs widely between clonal lineage strains of T. gondii, in which type I strains are low inducers, while types II and III strains are high inducers. We hypothesized this phenotype is due to a polymorphic "Regulator Of CD8 T cell Response" (ROCTR). Therefore, we screened F1 progeny from genetic crosses between the clonal lineage strains to identify ROCTR. Naïve antigen-specific CD8 T cells (T57) isolated from transnuclear mice, which are specific for the endogenous and vacuolar TGD057 antigen, were measured for their ability to become activated, transcribe Ifng and produce IFNγ in response to T. gondii infected macrophages. Genetic mapping returned four non-interacting quantitative trait loci (QTL) with small effect on T. gondii chromosomes (chr) VIIb-VIII, X and XII. These loci encompass multiple gene candidates highlighted by ROP16 (chrVIIb-VIII), GRA35 (chrX), TgNSM (chrX), and a pair of uncharacterized NTPases (chrXII), whose locus we report to be significantly truncated in the type I RH background. Although none of the chromosome X and XII candidates bore evidence for regulating CD8 T cell IFNγ responses, type I variants of ROP16 lowered Ifng transcription early after T cell activation. During our search for ROCTR, we also noted the parasitophorous vacuole membrane (PVM) targeting factor for dense granules (GRAs), GRA43, repressed the response suggesting PVM-associated GRAs are important for CD8 T cell activation. Furthermore, RIPK3 expression in macrophages was an absolute requirement for CD8 T cell IFNγ differentiation implicating the necroptosis pathway in T cell immunity to T. gondii. Collectively, our data suggest that while CD8 T cell IFNγ production to T. gondii strains vary dramatically, it is not controlled by a single polymorphism with strong effect. However, early in the differentiation process, polymorphisms in ROP16 can regulate commitment of responding CD8 T cells to IFNγ production which may have bearing on immunity to T. gondii.

C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection

Systemic candidiasis is a common, high-mortality, nosocomial fungal infection. Unexpectedly, it has emerged as a complication of anti-complement C5-targeted monoclonal antibody treatment, indicating a critical niche for C5 in antifungal immunity. We identified transcription of complement system genes as the top biological pathway induced in candidemic patients and as predictive of candidemia. Mechanistically, C5a-C5aR1 promoted fungal clearance and host survival in a mouse model of systemic candidiasis by stimulating phagocyte effector function and ERK- and AKT-dependent survival in infected tissues. C5ar1 ablation rewired macrophage metabolism downstream of mTOR, promoting their apoptosis and enhancing mortality through kidney injury. Besides hepatocyte-derived C5, local C5 produced intrinsically by phagocytes provided a key substrate for antifungal protection. Lower serum C5a concentrations or a C5 polymorphism that decreases leukocyte C5 expression correlated independently with poor patient outcomes. Thus, local, phagocyte-derived C5 production licenses phagocyte antimicrobial function and confers innate protection during systemic fungal infection.

Cysteine synthase: multiple structures of a key enzyme in cysteine synthesis and a potential drug target for Chagas disease and leishmaniasis.

Chagas disease is a neglected tropical disease (NTD) caused by Trypanosoma cruzi, whilst leishmaniasis, which is caused by over 20 species of Leishmania, represents a group of NTDs endemic to most countries in the tropical and subtropical belt of the planet. These diseases remain a significant health problem both in endemic countries and globally. These parasites and other trypanosomatids, including T. theileri, a bovine pathogen, rely on cysteine biosynthesis for the production of trypanothione, which is essential for parasite survival in hosts. The de novo pathway of cysteine biosynthesis requires the conversion of O-acetyl-L-serine into L-cysteine, which is catalysed by cysteine synthase (CS). These enzymes present potential for drug development against T.cruzi, Leishmania spp. and T. theileri. To enable these possibilities, biochemical and crystallographic studies of CS from T. cruzi (TcCS), L.infantum (LiCS) and T.theileri (TthCS) were conducted. Crystal structures of the three enzymes were determined at resolutions of 1.80 Å for TcCS, 1.75 Å for LiCS and 2.75 Å for TthCS. These three homodimeric structures show the same overall fold and demonstrate that the active-site geometry is conserved, supporting a common reaction mechanism. Detailed structural analysis revealed reaction intermediates of the de novo pathway ranging from an apo structure of LiCS and holo structures of both TcCS and TthCS to the substrate-bound structure of TcCS. These structures will allow exploration of the active site for the design of novel inhibitors. Additionally, unexpected binding sites discovered at the dimer interface represent new potential for the development of protein-protein inhibitors.

Dynamics of co-infection in fish: A review of pathogen-host interaction and clinical outcome

Co-infections can affect the transmission of a pathogen within a population and the pathogen's virulence, ultimately affecting the disease's dynamics. In addition, co-infections can potentially affect the host's immunological responses, clinical outcomes, survival, and disease control efficacy. Co-infections significantly impact fish production and can change several fish diseases’ progression and severity. However, the effect of co-infection has only recently garnered limited attention in aquatic animals such as fish, and there is currently a dearth of studies on this topic. This study, therefore, presents an in-depth summary of the dynamics of co-infection in fish. This study reviewed the co-infection of fish pathogens, the interaction of pathogens and fish, clinical outcomes and impacts on fish immune responses, and fish survival. Most studies described the prevalence of co-infections in fish, with various parameters influencing their outcomes. Bacterial co-infection increased fish mortality, ulcerative dermatitis, and intestinal haemorrhage. Viral co-infection resulted in osmoregulatory effects, increased mortality and cytopathic effect (CPE). More severe histological alterations and clinical symptoms were related to the co-infection of fish than in single-infected fish. In parasitic co-infection, there was increased mortality, high kidney swelling index, and severe necrotic alterations in the kidney, liver, and spleen. In other cases, there were more severe kidney lesions, cartilage destruction and displacement. There was a dearth of information on mitigating co-infections in fish. Therefore, further studies on the mitigation strategies of co-infections in fish will provide valuable insights into this research area. Also, more research on the immunology of co-infection specific to each fish pathogen class (bacteria, viruses, fungi, and parasites) is imperative. The findings from such studies would provide valuable information on the relationship between fish immune systems and targeted responses.

Bats (Mammalia, Chiroptera) and bat flies (Diptera, Streblidae) found in the largest sandstone cave of Brazil

Abstract Bats provide essential ecosystem services and some are cave dependent. Caves favour the association of bats with ectoparasite Diptera, however, they are poorly sampled in the Amazon biome. Here we present the first description of a community of bats and bat flies from the largest sandstone cave in Brazil, the Planaltina cave, located in the municipality of Brasil Novo, state of Pará. Diptera were removed from captured bats and taken to the laboratory for identification. From nine species of bats belonging to four families we recorded 17 species of Diptera, 13 were monoxenous. A possible explanation for the monoxenous parasites collected is that flies have poor survival in unusual hosts. These results are an indicator that the Streblid species are host-specific since even if the hosts take refuge in the same cave, they will not share their parasites. Therefore, the present study provides important information on the parasite-host dynamics in a cave, thus highlighting the importance of cave as are essential shelters for bat species and, despite reported cases of cohabitation, mixed colonies are unlikely to form.

Glioma immunotherapy enhancement and CD8-specific sialic acid cleavage by isocitrate dehydrogenase (IDH)-1

The promise of adaptive cancer immunotherapy in treating highly malignant tumors such as glioblastoma multiforme (GBM) can only be realized through expanding its benefits to more patients. Alleviating various modes of immune suppression has so far failed to achieve such expansion, but exploiting endogenous immune enhancers among mutated cancer genes could represent a more direct approach to immunotherapy improvement. We found that Isocitrate Dehydrogenase-1 (IDH1), which is commonly mutated in gliomas, enhances glioma vaccine efficacy in mice and discerns long from short survivors after vaccine therapy in GBM patients. Extracellular IDH1 directly enhanced T cell responses to multiple tumor antigens, and prolonged experimental glioma cell lysis. Moreover, IDH1 specifically bound to and exhibited sialidase activity against CD8. By contrast, mutant IDH1R132H lacked sialidase activity, delayed killing in glioma cells, and decreased host survival after immunotherapy. Overall, our findings identify IDH1 as an immunotherapeutic enhancer that mediates the known T cell-enhancing reaction of CD8 desialylation. This uncovers a new axis for immunotherapeutic improvement in GBM and other cancers, reveals novel physiological and molecular functions of IDH1, and hints at an unexpectedly direct link between lytic T cell function and metabolic activity in target cells.

Long non-coding RNAs are essential for Schistosoma mansoni pairing-dependent adult worm homeostasis and fertility

The trematode parasite Schistosoma mansoni causes schistosomiasis, which affects over 200 million people worldwide. Schistosomes are dioecious, with egg laying depending on the females' obligatory pairing with males. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides with low or no protein-coding potential that have been involved in other species with reproduction, stem cell maintenance, and drug resistance. In S. mansoni, we recently showed that the knockdown of one lncRNA affects the pairing status of these parasites. Here, we re-analyzed public RNA-Seq data from paired and unpaired adult male and female worms and their gonads, obtained from mixed-sex or single-sex cercariae infections, and found thousands of differentially expressed pairing-dependent lncRNAs among the 23 biological samples that were compared. The expression levels of selected lncRNAs were validated by RT-qPCR using an in vitro unpairing model. In addition, the in vitro silencing of three selected lncRNAs showed that knockdown of these pairing-dependent lncRNAs reduced cell proliferation in adult worms and their gonads, and are essential for female vitellaria maintenance, reproduction, and/or egg development. Remarkably, in vivo silencing of each of the three selected lncRNAs significantly reduced worm burden in infected mice by 26 to 35%. Whole mount in situ hybridization experiments showed that these pairing-dependent lncRNAs are expressed in reproductive tissues. These results show that lncRNAs are key components intervening in S. mansoni adult worm homeostasis, which affects pairing status and survival in the mammalian host, thus presenting great potential as new therapeutic target candidates.

Clusterin Neutralizes the Inflammatory and Cytotoxic Properties of Extracellular Histones in Sepsis.

Rationale: Extracellular histones, released into the surrounding environment during extensive cell death, promote inflammation and cell death, and these deleterious roles have been well documented in sepsis. Clusterin (CLU) is a ubiquitous extracellular protein that chaperones misfolded proteins and promotes their removal. Objectives: We investigated whether CLU could protect against the deleterious properties of histones. Methods: We assessed CLU and histone expression in patients with sepsis and evaluated the protective role of CLU against histones in invitro assays and invivo models of experimental sepsis. Measurements and Main Results: We show that CLU binds to circulating histones and reduces their inflammatory, thrombotic, and cytotoxic properties. We observed that plasma CLU levels decreased in patients with sepsis and that the decrease was greater and more durable in nonsurvivors than in survivors. Accordingly, CLU deficiency was associated with increased mortality in mouse models of sepsis and endotoxemia. Finally, CLU supplementation improved mouse survival in a sepsis model. Conclusions: This study identifies CLU as a central endogenous histone-neutralizing molecule and suggests that, in pathologies with extensive cell death, CLU supplementation may improve disease tolerance and host survival.

Investigating the Role of Bacterial Long-Chain Polyphosphates in Macrophages during Legionella pneumophilaInfection

Abstract Up to 10% of community-acquired pneumonia cases are identified as Legionnaires’ Disease, caused by the pathogen Legionella pneumophila. L. pneumophila naturally resides in freshwater systems and becomes pathogenic when man-made plumbing systems grow biofilm and amoeba if not maintained. Hosts are accidentally infected by L. pneumophilavia aerosol inhalation into the respiratory system. L. pneumophila primarily reside in human alveolar macrophages, entering and replicating via the Legionella-containing vacuole. This vacuole will also release and recruit hundreds of effector molecules to prevent itself from being phagocytosed and disguise itself as a host cellular component. Polyphosphates are highly conserved molecules found in essentially every cell performing essential functions. Long-chain polyphosphates, containing hundreds of phosphate units, are produced by bacteria to perform functions critical to their survival in hosts. We have previously found that long-chain polyphosphates produced by E. coli interfere with the host innate response against infection. Here, we show that the infection of L. pneumophila and synthetic long-chain bacterial polyphosphates interfere with the inflammatory response in macrophages. We utilized a mouse model for in vitro infection of L. pneumophila in bone-marrow-derived macrophages, showing a modulated inflammatory cytokine response and cell death. Additionally, the addition of S. cerevisiae derived exopolyphosphatase, which degrades long-chain polyphosphates, decreases inflammation in vitro.