Neuronal NPR-15 modulates molecular and behavioral immune responses via the amphid sensory neuron-intestinal axis in C. elegans.

The survival of hosts during infections relies on their ability to mount effective molecular and behavioral immune responses. Despite extensive research on these defense strategies in various species, including the model organism Caenorhabditis elegans, the neural mechanisms underlying their interaction remain poorly understood. Previous studies have highlighted the role of neural G-protein-coupled receptors (GPCRs) in regulating both immunity and pathogen avoidance, which is particularly dependent on aerotaxis. To address this knowledge gap, we conducted a screen of mutants in neuropeptide receptor family genes. We found that loss-of-function mutations in npr-15 activated immunity while suppressing pathogen avoidance behavior. Through further analysis, NPR-15 was found to regulate immunity by modulating the activity of key transcription factors, namely GATA/ELT-2 and TFEB/HLH-30. Surprisingly, the lack of pathogen avoidance of npr-15 mutant animals was not influenced by oxygen levels. Moreover, our studies revealed that the amphid sensory neuron ASJ is involved in mediating the immune and behavioral responses orchestrated by NPR-15. Additionally, NPR-15 was found to regulate avoidance behavior via the TRPM (transient receptor potential melastatin) gene, GON-2, which may sense the intestinal distension caused by bacterial colonization to elicit pathogen avoidance. Our study contributes to a broader understanding of host defense strategies and mechanisms underlining the interaction between molecular and behavioral immune responses.

Neuronal NPR-15 modulates molecular and behavioral immune responses via the amphid sensory neuron-intestinal axis in C. elegans.

The survival of hosts during infections relies on their ability to mount effective molecular and behavioral immune responses. Despite extensive research on these defense strategies in various species, including the model organism Caenorhabditis elegans, the neural mechanisms underlying their interaction remain poorly understood. Previous studies have highlighted the role of neural G protein-coupled receptors (GPCRs) in regulating both immunity and pathogen avoidance, which is particularly dependent on aerotaxis. To address this knowledge gap, we conducted a screen of mutants in neuropeptide receptor family genes. We found that loss-of-function mutations in npr-15 activated immunity while suppressing pathogen avoidance behavior. Through further analysis, NPR-15 was found to regulate immunity by modulating the activity of key transcription factors, namely GATA/ELT-2 and TFEB/HLH-30. Surprisingly, the lack of pathogen avoidance of npr-15 mutant animals was not influenced by oxygen levels. Moreover, our studies revealed that the amphid sensory neuron ASJ is involved in mediating the immune and behavioral responses orchestrated by NPR-15. Additionally, NPR-15 was found to regulate avoidance behavior via the TRPM gene, GON-2, which may sense the intestinal distension caused by bacterial colonization to elicit pathogen avoidance. Our study contributes to a broader understanding of host defense strategies and mechanisms underlining the interaction between molecular and behavioral immune responses.

Natural Perylenequinone Compounds as Potent Inhibitors of Schistosoma mansoni Glutathione S-Transferase.

The existing treatment strategy for Schistosomiasis centers on praziquantel, a single drug, but its effectiveness is limited due to resistance and lack of preventive benefits. Thus, there is an urgent need for novel antischistosomal agents. Schistosoma glutathione S-transferase (GST) is an essential parasite enzyme, with a high potential for targeted drug discovery. In this study, we conducted a screening of compounds possessing antihelminth properties, focusing on their interaction with the Schistosoma mansoni glutathione S-transferase (SmGST) protein. We demonstrated the unique nature of SmGST in comparison to human GST. Evolutionary analysis indicated its close relationship with other parasitic worms, setting it apart from free-living worms such as C. elegans. Through an assessment of binding pockets and subsequent protein-ligand docking, we identified Scutiaquinone A and Scutiaquinone B, both naturally derived Perylenequinones, as robust binders to SmGST. These compounds have exhibited effectiveness against similar parasites and offer promising potential as antischistosomal agents.

Computational Screening of Approved Drugs for Inhibition of the Antibiotic Resistance Gene mecA in Methicillin-Resistant Staphylococcus aureus (MRSA) Strains.

Antibiotic resistance is a critical problem that results in a high morbidity and mortality rate. The process of discovering new chemotherapy and antibiotics is challenging, expensive, and time-consuming, with only a few getting approved for clinical use. Therefore, screening already-approved drugs to combat pathogens such as bacteria that cause serious infections in humans and animals is highly encouraged. In this work, we aim to identify approved antibiotics that can inhibit the mecA antibiotic resistance gene found in methicillin-resistant Staphylococcus aureus (MRSA) strains. The MecA protein sequence was utilized to perform a BLAST search against a drug database containing 4302 approved drugs. The results revealed that 50 medications, including known antibiotics for other bacterial strains, targeted the mecA antibiotic resistance gene. In addition, a structural similarity approach was employed to identify existing antibiotics for S. aureus, followed by molecular docking. The results of the docking experiment indicated that six drugs had a high binding affinity to the mecA antibiotic resistance gene. Furthermore, using the structural similarity strategy, it was discovered that afamelanotide, an approved drug with unclear antibiotic activity, had a strong binding affinity to the MRSA-MecA protein. These findings suggest that certain already-approved drugs have potential in chemotherapy against drug-resistant pathogenic bacteria, such as MRSA.

Erratum: Cholesterol Regulates Innate Immunity via Nuclear Hormone Receptor NHR-8.

[This corrects the article DOI: 10.1016/j.isci.2020.101068.].

Insights from the shotgun-based proteomics analysis of Biomphalaria glabrata.

Biomphalaria glabrata is an important host in the transmission of human schistosomiasis in the Caribbean and South America. Therefore, it is of interest to analyse the proteome data of Biomphalaria glabrata hemolymph to identify immunity related proteins in host-pathogen relationship. We used shotgun proteomic and bioinformatic analyses of the non-depleted and depleted [0.5 and 0.75% Trifluoroacetic acid (TFA) depletion] hemolymph of B. glabrata (LE strain). Analysis showed 148 proteins from the hemolymph. 148 were obtained from the 0.5% TFA-depleted sample. 62 proteins follow this from the 0.75% TFA-depleted sample. However, only 59 were found from non-depleted hemolymph. A number of proteins were identified from the hemolymph of this schistosomiasis snail vector linked to immunity related functions. This provides insights to the understanding of schistosome-snail interaction.

Immunity-longevity tradeoff neurally controlled by GABAergic transcription factor PITX1/UNC-30.

A body of evidence indicates that metazoan immune and aging pathways are largely interconnected, but the mechanisms involved in their homeostatic control remain unclear. In this study, we find that the PITX (paired-like homeodomain) transcription factor UNC-30 controls the tradeoff between immunity and longevity from the nervous system in Caenorhabditis elegans. PITX/UNC-30 functional loss enhances immunity in a GATA/ELT-2- and p38 MAPK/PMK-1-dependent manner and reduced longevity by activating MXD/MDL-1 and the C2H2-type zinc finger transcription factor PQM-1. The immune inhibitory and longevity stimulatory functions of PITX/UNC-30 require the sensory neuron ASG and a signaling pathway controlled by NPR-1, which is a G protein-coupled receptor related to mammalian neuropeptide Y receptors. Our findings uncover a suppressive role of GABAergic signaling in the neural control of a biological tradeoff where energy is allocated toward immunity at the expense of longevity.

Cholesterol Regulates Innate Immunity via Nuclear Hormone Receptor NHR-8.

Cholesterol is an essential nutrient for the function of diverse biological processes and for steroid biosynthesis across metazoans. However, the role of cholesterol in immune function remains understudied. Using the nematode Caenorhabditis elegans, which depends on the external environment for cholesterol, we studied the relationship between cholesterol and innate immunity. We found that the transporter CHUP-1 is required for the effect of cholesterol in the development of innate immunity and that the cholesterol-mediated immune response requires the nuclear hormone receptor NHR-8. Cholesterol acts through NHR-8 to transcriptionally regulate immune genes that are controlled by conserved immune pathways, including a p38/PMK-1 MAPK pathway, a DAF-2/DAF-16 insulin pathway, and an Nrf/SKN-1 pathway. Our results indicate that cholesterol plays a key role in the activation of conserved microbicidal pathways that are essential for survival against bacterial infections.

Comparative Functional Study of Thioester-containing Related Proteins in the Recently Sequenced Genome of Biomphalaria glabrata.

BACKGROUND: There is paucity of information on functional relationship and characterization of Biomphalaria glabrata thioester-containing proteins (BgTEP) to other well-annotated homologues. We performed functional characterization studies of BgTEP to homologues in Anopheles gambiae and in disparate invertebrates. METHODS: Genomic sequences of TEPs were retrieved after annotation of the B. glabrata genome. In addition, TEP sequences deposited in NCBI protein database were also retrieved and utilized for sequence analysis. BgTEP relatedness to its other homologues as well as functional domain and protein-protein interaction analysis was performed. RESULTS: Our analysis resulted in the identification of TEPs in a number of organisms including, B. glabrata, A. gambiae, and Chlamys farreri. In addition, we identified 19 TEP sequences spread across 10 animal species. The B. glabrata genome contains 14190 unannotated proteins after filtration with about 85% of its proteome annotated. The phylogenetics, functional domain and protein-protein interaction analyses suggest an immunological role for BgTEP in B. glabrata. CONCLUSION: The predicted role of thioester-containing proteins to be involved in immunological role in B. glabrata may have a strong effect on resistance to infection.

Analysis of antibiotics resistant genes in different strains of Staphylococcus aureus.

The control of Staphylococcus aureus infection is being hampered by methicillin and other resistant strains. The identification of the unique antibiotic resistant genes from the genomes of various strains of S. aureus is of interest. We analyzed 11 S. aureus genomes sequences for Antibiotics Resistance Genes (ARGs) using CARD 2017 platform. We identified 32 ARGs across 11 S. aureus strains. Tet(38), norB, lmrB, mepA and mepR were present across genomes except for S. aureus strain UTSW MRSA 55. The mepA and mepR were found across 11 different genomes. However, FosB3, vgaALC, mphC and SAT-4 were found in UTSW MRSA 55, S.a. strain ISU935 and S.a. strain FDAARGOS_159. The prevalent mode of mechanism of antibiotics resistant was efflux pump complex or subunit conferring antibiotic resistance as well as protein(s). Analysis of norB, ImrB, norA, ImrB, tet (38), sav1866 and mecA have 12 to 14 TMHs. The results help in the understanding of Staphylococcus aureus pathogenesis in the context of antibiotic resistance.

Identification and characterization of sodium and chloride-dependent gamma-aminobutyric acid (GABA) transporters from eukaryotic pathogens as a potential drug target.

We explored 285 completed eukaryotic pathogen genomes for GABA transporter proteins as effective chemotherapy targets. We identified 8 GABA proteins that spread across 4 phyla with 5 different pathogen species; Eimeria mitis Houghton, Neospora caninum Liverpool, S. mansoni, S. haematobium and Trichinella spiralis. Sub-cellular localization prediction revealed that these proteins are integral membrane and are mostly insoluble. It is found that about 81% of these proteins are non-crystallizable and 15% are crystallizable. Transmembrane helices predictions show that the GABA transporters have 10, 11, 12 and 14 TMHs with 15, 23, 31 and 11%, respectively. It is further observed that most of these GABA transporters are from several parasites`genomes.