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The ability of parasitic wasps to manipulate a host's metabolism is under active investigation. Components of venom play a major role in this process. In the present work, we studied the effect of the venom of the ectoparasitic wasp Habrobracon hebetor on the metabolism of the greater wax moth host (Galleria mellonella). We identified and quantified 45 metabolites in the lymph (cell-free hemolymph) of wax moth larvae on the second day after H. hebetor venom injection, using NMR spectroscopy and liquid chromatography coupled with mass spectrometry. These metabolites included 22 amino acids, nine products of lipid metabolism (sugars, amines and alcohols) and four metabolic intermediates related to nitrogenous bases, nucleotides and nucleosides. An analysis of the larvae metabolome suggested that the venom causes suppression of the tricarboxylic acid cycle, an increase in the number of free amino acids in the lymph, an increase in the concentration of trehalose in the lymph simultaneously with a decrease in the amount of glucose, and destructive processes in the fat body tissue. Thus, this parasitoid venom not only immobilizes the prey but also modulates its metabolism, thereby providing optimal conditions for the development of larvae., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Ethnopharmacological Relevance: Rheumatoid arthritis (RA) is a chronic inflammatory disease that is related to the aberrant proliferation of fibroblast-like synoviocytes (FLS). Wasp venom (WV, Vespa magnifica, Smith), an insect secretion, has been used to treat RA in Chinese Jingpo national minority's ancient prescription. However, the potential mechanisms haven't been clarified., Aim of the Study: The purposes of this paper were two-fold. First, to investigate which was the best anti-RA effective part of WV-I (molecular weight less than 3 kDa), WV-II (molecular weight 3-10 kDa) and WV-III (molecular weight more than 10 kDa) that were separated from WV. Second, to explore the underlying molecular mechanism of WV and WV-II that was best effective part in RA., Materials and Methods: The wasps were electrically stimulated and the secretions were collected. WV-I, WV-II and WV-III were acquired by ultracentrifuge method according to molecular weight. Next, WV, WV-I, WV-II and WV-III were identified by HPLC. Functional annotation and pathway analysis of WV used to bioinformatics analysis. RNA-seq analyses were constructed to identify differentially expressed genes (DEGs). GO and KEGG pathway analyses were performed by Metascape database. STRING was used to analyze the PPI network from DEGs. Next, PPI network was visualized using Cytoscape that based on MCODE. The pivotal genes of PPI network and MCODE analysis were verified by qRT-PCR. Subsequently, MH7A cells were performed by MTT assay to evaluate the ability of inhibiting cell proliferation. Luciferase activity assay was conducted in HepG2/STAT1 or HepG2/STAT3 cells to assess STAT1/3 sensitivity of WV, WV-I, WV-II and WV-III. Additionally, interleukin (IL)-1β and IL-6 expression levels were detected by ELISA kits. Intracellular thioredoxin reductase (TrxR) enzyme was evaluated by TrxR activity assay kit. ROS levels, lipid ROS levels and Mitochondrial membrane potential (MMP) were assessed by fluorescence probe. Cell apoptosis and MMP were measured by using flow cytometry. Furthermore, the key proteins of JAK/STAT signaling pathway, protein levels of TrxR and glutathione peroxidase 4 axis (GPX4) were examined by Western blotting assay., Results: RNA-sequencing analysis of WV displayed be related to oxidation-reduction, inflammation and apoptosis. The data displayed that WV, WV-II and WV-III inhibited significantly cells proliferation in human MH7A cell line compared to WV-I treatment group, but WV-III had no significant suppressive effect on luciferase activity of STAT3 compared with IL-6-induced group. Combined with earlier reports that WV-III contained major allergens, we selected WV and WV-II further to study the mechanism of anti-RA. In addition, WV and WV-II decreased the level of IL-1β and IL-6 in TNF-α-induced MH7A cells via inactivating of JAK/STAT signaling pathway. On the other hand, WV and WV-II down-regulated the TrxR activity to produce ROS and induce cell apoptosis. Furthermore, WV and WV-II could accumulate lipid ROS to induce GPX4-mediated ferroptosis., Conclusions: Taken together, the experimental results revealed that WV and WV-II were potential therapeutic agents for RA through modulating JAK/STAT signaling pathways, redox homeostasis and ferroptosis in MH7A cells. Of note, WV-II was an effective part and the predominant active monomer in WV-II will be further explored in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Polybia paulista is a neotropical social wasp related to severe accidents and allergic reactions cases, including anaphylaxis, in southeastern Brazil. Antigen 5 (Poly p 5) is a major allergenic protein from its venom with potential use for component-resolved diagnostic. Therefore, the previous characterization of the immune response profile triggered by Poly p 5 should be evaluated. Recombinant Poly p 5 (rPoly p 5) was used to sensitize BALB/c mice with six weekly intradermal doses, and the specific antibody production and the functional profile of CD4 + T cells were assessed. rPoly p 5 induced the production of specific immunoglobulins (sIg) sIgE, sIgG1 and sIgG2a, which could recognize natural Poly p 5 presented in the venom of four different wasp species. rPoly p 5 stimulated in vitro the CD4 + T cells from immunized mice, which showed a significant proliferative response. These antigen-specific CD4 + T cells produced IFN-γ and IL-17A cytokines and increased ROR-γT transcription factor expression. No differences between the control group and sensitized mice were found in IL-4 production and GATA-3 and T-bet expression. Interestingly, increased CD25 + FoxP3 + regulatory T cells (Tregs) frequency was observed in the splenocyte cell cultures from rPoly p 5 immunized mice after the in vitro stimulation with both P. paulista venom extract and rPoly p 5. Here we showed that rPoly p 5 induces antigen-specific antibodies capable of recognizing Antigen 5 in the venom of four wasp species and modulates antigen-specific CD4 + T cells to IFN-γ production response associated with a Th17 profile in sensitized mice. These findings emphasize the potential use of rPoly p 5 as an essential source of a major wasp allergen with significant immunological properties., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: Recent evidence suggests a key role of the inflammatory responses in wasp venom-induced acute kidney injury (AKI). However, the potential regulatory mechanisms underlying the inflammatory responses in wasp venom-induced AKI remain unclear. STING reportedly plays a critical role in other AKI types and is associated with inflammatory responses and diseases. We aimed to investigate the involvement of STING in inflammatory responses associated with wasp venom-induced AKI., Methods: The role of the STING signaling pathway in wasp venom-induced AKI was studied in vivo using a mouse model of wasp venom-induced AKI with STING knockout or pharmacological inhibition and in vitro using human HK2 cells with STING knockdown., Results: STING deficiency or pharmacological inhibition markedly ameliorated renal dysfunction, inflammatory responses, necroptosis, and apoptosis in wasp venom-induced AKI in mice. Moreover, STING knockdown in cultured HK2 cells attenuated the inflammatory response, necroptosis, and apoptosis induced by myoglobin, the major pathogenic factor in wasp venom-induced AKI. Urinary mitochondrial DNA upregulation has also been observed in patients with wasp venom-induced AKI., Conclusions: STING activation mediates the inflammatory response in wasp venom-induced AKI. This may offer a potential therapeutic target for the management of wasp venom-induced AKI., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Endoparasitoid wasps introduce venom into their host insects during the egg-laying stage. Venom proteins play various roles in the host physiology, development, immunity, and behavior manipulation and regulation. In this study, we identified a venom protein, MmRho1, a small guanine nucleotide-binding protein derived from ovary in the endoparasitoid wasp Microplitis mediator and found that knockdown of its expression by RNA interference caused down-regulation of vitellogenin and juvenile hormone, egg production, and cocoons formation in the female wasps. We demonstrated that MmRho1 entered the cotton bollworm's (host) hemocytes and suppressed cellular immune responses after parasitism using immunofluorescence staining. Furthermore, wasp MmRho1 interacted with the cotton bollworm's actin cytoskeleton rearrangement regulator diaphanous by yeast 2-hybrid and glutathione s-transferase pull-down. In conclusion, this study indicates that MmRho1 plays dual roles in wasp development and the suppression of the host insect cellular immune responses., (© 2022 Institute of Zoology, Chinese Academy of Sciences.)

Endoparasitoid wasps inject venom proteins into the hemocoel of host insects to ensure survival, growth, and development of their progenies by blocking host immunity. We previously identified ten serine protease inhibitors of the serpin superfamily in venom of the endoparasitoid wasp, Microplitis mediator, but it is unclear how these inhibitors may interact with host immune serine proteases. In this study, we investigated the functions of two serpins, MmvSPN-1 and MmvSPN-2, in the regulation of humoral immune responses in two hosts, the oriental armyworm Pseudaletia separate and the cotton bollworm Helicoverpa armigera, by dsRNA knockdown and biochemical assays using recombinant proteins. Knockdown of the two serpins resulted in increases in prophenoloxidase (PPO) activation and antimicrobial peptide (AMP) production in the hosts. After injection into the host hemocoel, the recombinant serpins inhibited PPO activation and AMP transcription. Mass spectrometry analysis of the pull-downs and in vitro reconstitution experiments revealed that HacSP29, a clip-domain serine protease in H. armigera, is the target of these two serpins. Therefore, these two inhibitors in the wasp venom may protect eggs from attacks by melanization and AMPs in the host insects., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

To achieve successful development, female parasitoids, while laying eggs, introduce various virulence factors, mainly venoms, into host insects to manipulate their physiology. Although numerous studies have been conducted to characterize the components of venoms that regulate host immune responses, few systematic investigations have been conducted on the roles of venom proteins in host metabolic regulation. In this investigation, we characterized a novel venom protein in Pachycrepoideus vindemiae called glucose-6-phosphate dehydrogenase (PvG6PDH) and showed it has a vital role in regulating host carbohydrate metabolism. PvG6PDH encodes 510 amino acids and features a signal peptide and two conserved "G6PDH" domains. Multiple sequence alignment showed it has high amino acid identity with G6PDH from other pteromalids, and quantitative polymerase chain reaction analysis and immunofluorescent staining demonstrated a significantly higher expression of PvG6PDH in the venom apparatus compared with the carcass. We report that PvG6PDH contributes to parasitism by inhibiting the glucose-6-phosphate (G6P) metabolism of host Drosophila melanogaster, as demonstrated by PvG6PDH injection and RNA interference analysis. Further tests revealed that the accumulation of host G6P was caused by the transcriptional inhibition of G6P-metabolism-related genes. These findings greatly contribute to our understanding of venom-mediated host metabolic regulation, further laying the foundation for the development of venom proteins as biological agents for pest control., (© 2021 Institute of Zoology, Chinese Academy of Sciences.)

To explore and compare the expression patterns of venom components depending on post-capture periods, venom gland-specific transcriptome and proteome analyses were conducted for five model hymenopteran species at a series of time points after capture. Venom gland-specific genes with signal sequences were considered as putative venom component genes. Expression patterns of venom gland-specific genes in all the social wasps and bees examined varied considerably depending on the post-capture period. Higher numbers of venom genes exhibited a decreasing expression pattern than an increasing pattern as the capture period increased. For example, genes encoding most of the allergens (dipeptidyl peptidase 4, endocuticle structural glycoprotein, odorant-binding protein, phospholipase A1, A2, B1, serine protease, serine protease inhibitor and venom allergen 5), pain-producing factor (mast cell degranulating peptide), and paralyzing factor (neprilysin) commonly exhibited decreasing expression patterns in all of the hymenopteran species tested, except for some of the major venom genes in Apis mellifera and Bombus ignitus, which showed an increasing pattern. These findings indicate species- or group-specific variations in the expression patterns of major venom genes. Taken together, flash freezing in liquid nitrogen immediately after capture was determined to be the best way to obtain the most natural expression profiles of venom components in social wasp species, thus, enabling a better understanding of the toxic potential of venom in wasp sting accidents. This study provides guidance for establishing optimal protocols for venom gland isolation and venom extraction from wasps and bees that can ensure the most naturally represented venom composition., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Uncertainties remain about the molecular mechanisms governing clonal mast cell disorders (CMCD) and anaphylaxis., Objective: This study aims at comparing the burden, phenotype and behavior of mast cells (MCs) and basophils in patients with CMCD with wasp venom anaphylaxis (CMCD/WVA + ), CMCD patients without anaphylaxis (CMCD/ANA - ), patients with an elevated baseline serum tryptase (EBST), patients with wasp venom anaphylaxis without CMCD (WVA + ) and patients with a non-mast cell haematological pathology (NMHP)., Methods: This study included 20 patients with CMCD/WVA + , 24 with CMCD/ANA - , 19 with WVA + , 6 with EBST and 5 with NMHP. We immunophenotyped MCs and basophils and compared baseline serum tryptase (bST) and both total and venom specific IgE in the different groups. For basophil studies, 13 healthy controls were also included., Results: Higher levels of bST were found in CMCD patients with wasp venom anaphylaxis, CMCD patients without anaphylaxis and EBST patients. Total IgE levels were highest in patients with wasp venom anaphylaxis with and without CMCD. Bone marrow MCs of patients with CMCD showed lower CD117 expression and higher expression of CD45, CD203c, CD63, CD300a and FcεRI. Within the CMCD population, patients with wasp venom anaphylaxis showed a higher expression of FcεRI as compared to patients without anaphylaxis. Expression of MRGPRX2 on MCs did not differ between the study populations. Basophils are phenotypically and functionally comparable between the different patient populations., Conclusion: Patients with CMCD show an elevated burden of aberrant activated MCs with a significant overexpression of FcεRI in patients with a wasp venom anaphylaxis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer RMC declared a past co-authorship with the authors DE, MF, AG, MMH, CB, ID, and VS to the handling Editor., (Copyright © 2022 Elst, De Puysseleyr, Ebo, Faber, Van Gasse, van der Poorten, Decuyper, Bridts, Mertens, Van Houdt, Hagendorens, De Clerck, Verlinden, Vermeulen, Maes, Berneman, Valent and Sabato.)

Vespa velutina has been rapidly expanding throughout Galicia since 2012. It is causing human health risks and well-known losses in the beekeeping sector. Control methods are scarce, unspecific, and ineffective. Semiochemicals are insect-derived chemicals that play a role in communication and they could be used an integrated pest management tool alternative to conventional pesticides. A previous determination of the organic chemical profile should be the first step in the study of these semiochemicals. HS-SPME in living individuals and the sting apparatus extraction followed by GC-MS spectrometry were combined to extract a possible profile of these compounds in 43 hornets from Galicia. The identified compounds were hydrocarbons, ketones, terpenes, and fatty acid, and fatty acid esters. Nonanal aldehyde appeared in important concentrations in living individuals. While pentadecane, 8-hexyl- and ethyl oleate were mainly extracted from the venom apparatus. Ketones 2-nonanone, 2-undecanone and 7-nonen-2-one, 4,8-dimethyl- were identified by both procedures, as was 1,7-Nonadiene, 4,8-dimethyl-. Some compounds were detected for the first time in V. velutina such as naphthalene, 1,6-dimethyl-4-(1-methylethyl). The chemical profile by caste was also characterized.

Parasitoid wasps represent the plurality of venomous animals, but have received extremely little research in proportion to this taxonomic diversity. The lion's share of investigation into insect venoms has focused on eusocial hymenopterans, but even this small sampling shows great promise for the development of new active substances. The family Pompilidae is known as the spider wasps because of their reproductive habits which include hunting for spiders, delivering a paralyzing sting, and entombing them in burrows with one of the wasp's eggs to serve as food for the developing larva. The largest members of this family, especially the tarantula hawks of the genus Pepsis , have attained notoriety for their large size, dramatic coloration, long-term paralysis of their prey, and incredibly painful defensive stings. In this paper we review the existing research regarding the composition and function of pompilid venoms, discuss parallels from other venom literatures, identify possible avenues for the adaptation of pompilid toxins towards human purposes, and future directions of inquiry for the field.