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Insect venoms can cause severe allergic reactions, including anaphylaxis, in sensitized individuals. In this study, we aim at preventing anaphylaxis mediated by the most abundant and dominant honeybee venom allergen phospholipase A2 (Api m 1) by blocking its interaction with allergic patient IgE. Therefore, we characterize selected Api m 1-specific nanobodies and identify two high-affinity binders with non-overlapping epitopes. Crystal structures of Api m 1/nanobody complexes reveal diametrically opposed epitopes, one of which involves the active site of Api m 1. Based on this background, we develop mono- and bispecific nanobody-human IgG 1 Fc, which exhibits pronounced blocking of IgE binding and effector cell activation in blood samples from honeybee venom allergic patients and reduces systemic reactions in a mouse model of allergen-induced anaphylaxis. This work provides a rationale for using nanobody-based inhibitors to prevent Api m 1-mediated anaphylaxis in honeybee venom allergy. Insect venom can cause severe allergic reactions including anaphylaxis. Here, the authors report structural and functional evidence that nanobody-based inhibitors can limit the allergenic and toxic activity of the major honeybee venom allergen and that passive administration prevents anaphylaxis in vivo.

Envenoming resulting from Apis honeybee stings pose a neglected public health concern, with clinical complications ranging from mild local reactions to severe systemic manifestations. This review explores the mechanisms underlying envenoming by honeybee sting, discusses diagnostic approaches, and reviews current pharmacological interventions. This section explores the diverse clinical presentations of honeybee envenoming, including allergic and non-allergic reactions, emphasizing the need for accurate diagnosis to guide appropriate medical management. Mechanistic insights into the honeybee venom’s impact on physiological systems, including the immune and cardiovascular systems, are provided to enhance understanding of the complexities of honeybee sting envenoming. Additionally, the article evaluates emerging diagnostic technologies and therapeutic strategies, providing a critical analysis of their potential contributions to improved patient outcomes. This article aims to provide current knowledge for healthcare professionals to effectively manage honeybee sting envenoming, thereby improving patient care and treatment outcomes.

Social insects employ venom as an external immune defence against pathogens and parasites. Like other Hymenopterans, the venom gland of honey bee ( Apis mellifera ) serves as a reservoir of antimicrobial substances, primarily melittin. This study investigated the presence and origin of venom on honey bee body that could act as an external immune defence in honey bee workers infested by the ectoparasite mite, Varroa destructor . Using a multi-step approach, we first confirmed the presence of venom on bees’ bodies using melittin as a marker. We then examined how grooming could facilitate the distribution of venom on the bee’s body through behavioural observations. Further assays were used to compare melittin levels on the bodies of Varroa -free and Varroa -infested workers and assess the effects of bee-venom on mite activity. Our findings confirmed the occurrence of “venom bathing” in A. mellifera , excluding social components or environmental contamination, with bees likely coating their bodies with antimicrobial substances through self-grooming. Our results further suggest that infested bees spread higher amount of venom on their bodies compared to uninfested bees, and bee-venom significantly reduced mite activity, suggesting that the venom functions as an external defence. However, Varroa negatively impacted melittin production. Our study reveals a previously unknown negative effect of V. destructor : impairment of honey bees’ external immune defence through reduced melittin production.

Sensitization to cross-reactive allergens complicates identifying the culprit insect in Hymenoptera venom allergy via diagnostic tests. This study evaluates sensitization to hyaluronidases (Api m 2 from honey bee (Apis mellifera) venom, HBV; Pol d 2 from European paper wasp (Polistes dominula) venom, PDV; and Ves v 2.0101 and Ves v 2.0201 from yellow jacket (Vespula vulgaris) venom, YJV) and their cross-reactivity in allergic patients from Italy, Spain, and Germany using ImmunoCAPs, ELISA, and basophil activation tests. Sensitization rates were 45% for Api m 2 in HBV-allergic subjects, 25% for Pol d 2 in PDV-allergic individuals, and 20% and 10% for Ves v 2.0201 and Ves v 2.0101 in YJV-allergic patients, respectively. Patients primarily sensitized to Api m 2 showed minimal cross-reactivity to vespid hyaluronidases, whereas those primarily sensitized to Pol d 2 or Ves v 2.0201 exhibited IgE reactivity to Api m 2. Neither Pol d 2 nor Ves v 2.0201 triggered basophil activation. Cross-reactivity of Api m 2, Pol d 2, and Ves v 2.0201 depends on the primary sensitizing venom. Sensitization to Pol d 2 and Ves v 2.0201 remains below 25%, yet these patients may exhibit cross-reactivity to Api m 2. Conversely, HBV-allergic patients sensitized to Api m 2 show minimal reactivity to Pol d 2 or Ves v 2.0201.

Complement activation split products are signatures of many immunopathological disorders. Among the laboratory findings observed in these diseases, a reduction in the level of circulating intact complement components can be mentioned, and this change has also been detected in envenomation by multiple Africanized honeybee (Apis mellifera) stings. Although envenomation by these animals elicits diverse life-threatening reactions, the capacity of bee venom (AmV) to activate the human complement system remains elusive. By coupling immunochemical and functional approaches, it was observed that AmV strongly consumes components of the alternative pathway (AP) of the complement system in normal human serum (NHS). Additionally, AmV interfered with classical (CP) and lectin pathways (LP) activities. In parallel, a high increase in Ba fragment levels was detected, suggesting that the changes in AP activity were due to its activation. Furthermore, an increase in the level of the C1s-C1INH complex and a decrease in the physiological level of MASP1-C1INH suggested that CP and LP were also activated in the presence of AmV. Strikingly, NHS exposed to increasing AmV concentrations varying from 5 to 1000 µg/mL presented a high generation of C3a, C4a and C5a anaphylatoxins, and sC5b-9 complexes assembly, thus reinforcing that AmV triggers complement activation. These results show that AmV is a strong complement activator. This activation presents a mixed profile, with a predominance of AP activation. This suggests that complement split products can play important roles in the envenomation by Africanized honeybee, as they could induce diverse immunopathological events observed in patients and may also dictate patient clinical prognosis.

Background: Hymenoptera venom allergy is a potentially severe allergic reaction in the general population. The only preventative approach in these cases is venom immunotherapy (VIT), which follows different protocols. The recommended initial dose is 0.001–0.1 mcg of venom extract. However, few reports have declared the safety of 1 mcg venom as the starting dose. Methods: The study was conducted on Iranian patients with a history of anaphylaxis to venom. Skin tests confirmed hypersensitivity to honeybee, yellow jacket, and/or paper wasp from subfamily Polistes using Apis melifera, Vespula spp, and Polistes spp venom extracts, respectively. Subsequently, the patients were treated with the cluster protocol. Results: Twenty-two patients (17 males and 5 females, aged 28.3±11.8 years) were enrolled in the study. Skin prick tests and intradermal tests showed positive results for yellow jacket in 17 (77.3%) and 21 (95.4%) patients, honeybee in 14 (63.6%) and 17 (77.3%) patients, and wasp in 14 (63.6%) and 17 (77.3%) patients, respectively. Upon administering the initial dose of 1 mcg/mL, 40.9% (9 cases) of patients presented mild local reactions, including 7 with yellow jacket allergy, 5 with honeybee allergy, and 3 with wasp allergy. One patient with yellow jacket allergy had a mild systemic reaction. Patients with a positive skin test for wasp had significantly lower rate of reactions after the first dose of venom (p=0.026). Throughout the entire build-up phase, more than 90% (20 of 22) of patients experienced mild local reactions, followed by large local reactions (3 cases, 13.6%), mild systemic reactions (1 case at 1 mcg/mL dose), and moderate-to-severe systemic reactions (3 cases, 13.6%). Large local and moderate-to-severe systemic reactions were detected after injecting 50 mcg (each one case) and 100 mcg (each 2 cases) of venom extracts. Conclusion: This study recommends 1 mcg/mL of the venom extract as a safe starting dose for VIT. This accelerated protocol could successfully reduce the time and costs of therapy for patients undergoing out-patient cluster VIT.

Following bee stings, multiple case reports have described the onset of autoimmune-related conditions, including myasthenia gravis, nephrotic syndrome, Henoch-Schönlein purpura, myocardial infarction, cerebrovascular events, and localized alopecia, typically within a few days, indicating that bee venom may play a role in triggering autoimmunity. We report a rare case of total alopecia occurring within ten days after a bee sting. While the literature includes one prior case of total alopecia following bee sting-induced anaphylaxis, our case is distinct in that the patient developed total alopecia in the absence of any hypersensitivity reactions, suggesting a potential immunomodulatory or exacerbating effect of the bee sting on the immune system.

The globally distributed ectoparasite Varroa destructor is a vector for viral pathogens of the Western honeybee (Apis mellifera), in particular the Iflavirus Deformed Wing Virus (DWV). In the absence of Varroa low levels DWV occur, generally causing asymptomatic infections. Conversely, Varroa-infested colonies show markedly elevated virus levels, increased overwintering colony losses, with impairment of pupal development and symptomatic workers. To determine whether changes in the virus population were due Varroa amplifying and introducing virulent virus strains and/or suppressing the host immune responses, we exposed Varroa-naïve larvae to oral and Varroa-transmitted DWV. We monitored virus levels and diversity in developing pupae and associated Varroa, the resulting RNAi response and transcriptome changes in the host. Exposed pupae were stratified by Varroa association (presence/absence) and virus levels (low/high) into three groups. Varroa-free pupae all exhibited low levels of a highly diverse DWV population, with those exposed per os (group NV) exhibiting changes in the population composition. Varroa-associated pupae exhibited either low levels of a diverse DWV population (group VL) or high levels of a near-clonal virulent variant of DWV (group VH). These groups and unexposed controls (C) could be also discriminated by principal component analysis of the transcriptome changes observed, which included several genes involved in development and the immune response. All Varroa tested contained a diverse replicating DWV population implying the virulent variant present in group VH, and predominating in RNA-seq analysis of temporally and geographically separate Varroa-infested colonies, was selected upon transmission from Varroa, a conclusion supported by direct injection of pupae in vitro with mixed virus populations. Identification of a virulent variant of DWV, the role of Varroa in its transmission and the resulting host transcriptome changes furthers our understanding of this important viral pathogen of honeybees.

Previous studies have shown that rabbit IgG antibodies against Schistosoma mansoni egg antigens (SmSEA) cross-react with allergens in natural rubber latex, peanuts and grass and tree pollens. Here we describe antigenic molecules that cross-react with rabbit anti- S . mansoni IgG antibodies in extracts of the house dust mite (HDM) Dermatophagoides farinae , the Australian cockroach (ACR) Periplaneta australasiae and in the venom of the honey bee Apis mellifera (HBV). Tandem mass spectrometry identified the cross-reactive allergens as Der f 15 in HDM, two homologues of the Periplaneta americana cockroach allergen Cr-PI/Per a 3 in ACR and two isoforms of the allergen Api m 1 (phospholipase A2: PLA2) in HBV. Cross-reactive rabbit anti-SmSEA IgG antibodies eluted from the three invertebrate allergens reacted with S . mansoni egg antigens and variably with schistosome cercarial and worm antigens. Treatment of the electroblotted allergens with sodium metaperiodate abrogated most of the cross-reactivity of the rabbit anti-SmSEA antibodies, suggesting it was due to cross-reactive carbohydrate determinants (CCDs). Furthermore, analyses of the allergens’ amino acid sequences indicated that they had potential for both N- and O-linked glycosylation. A potential role for the CCDs shared by the schistosome and invertebrates in inducing an allergy-protective effect, as proposed by the hygiene hypothesis, is discussed.

The health of the honeybee and, indirectly, global crop production are threatened by several biotic and abiotic factors, which play a poorly defined role in the induction of widespread colony losses. Recent descriptive studies suggest that colony losses are often related to the interaction between pathogens and other stress factors, including parasites. Through an integrated analysis of the population and molecular changes associated with the collapse of honeybee colonies infested by the parasitic mite Varroa destructor, we show that this parasite can de-stabilise the within-host dynamics of Deformed wing virus (DWV), transforming a cryptic and vertically transmitted virus into a rapidly replicating killer, which attains lethal levels late in the season. The de-stabilisation of DWV infection is associated with an immunosuppression syndrome, characterized by a strong down-regulation of the transcription factor NF-κB. The centrality of NF-κB in host responses to a range of environmental challenges suggests that this transcription factor can act as a common currency underlying colony collapse that may be triggered by different causes. Our results offer an integrated account for the multifactorial origin of honeybee losses and a new framework for assessing, and possibly mitigating, the impact of environmental challenges on honeybee health.