Insect Venom Toxin Peptides, Its Antimicrobial Effects and Host Immune Responses: a Review

Acta Scientific MICROBIOLOGY (ISSN: 2581-3226) Volume 4 Issue 4 April 2021 Review Article

Insect Venom Toxin Peptides, its Antimicrobial Effects and Host Immune Responses: A Review

Simran Sharma and Ravi Kant Upadhyay* Received: March 01, 2021 Department of Zoology, Deen Dayal Upadhyaya Gorakhpur University, UP, India Published: March 25, 2021 *Corresponding Author: Ravi Kant Upadhyay, Department of Zoology, Deen Dayal © All rights are reserved by Simran Sharma Upadhyaya Gorakhpur University, UP, India. and Ravi Kant Upadhyay.

Abstract Present review article explains antimicrobial activity of hymenopteran insect venoms. Insects mostly bees, wasps, hornets use

Insect venom glands secret multiple toxin components which are powerful weapons secreted from venom glands. Bees, wasps, and venom toxins to defend their hive, nests and mainly colonies in territory. These insects sting very swiftly and inflict venom in its prey.

envenomation does not transmit any pathogen. Bee venom severely affects cytoskeletal system and impairs nerve cell function that hornet inflict venom for self and territorial defense and impose physiological alterations with multiple symptoms in intruders; but results in organ paralysis and deformity and even death after multiple bites. In bees severity of microbial infection is increased due

in making antiviral defense. Insects secrete antimicrobial peptides in venom which protect themselves from infection by generat- to impact of biotic and abiotic factors. Few phenolic compounds such as flavonoids mixed in honey, propolis, and royal jelly assist

venom components from honey bees, wasps and hornets can be used as templates for generation of new therapeutic agents and bio- ing immune response against pathogens. Purified venom toxins exhibit antibacterial, antifungal and antiviral defense. No doubt

synthesize diverse venom components. This overall information generated at molecular level could be used for making diagnostic pesticides for insect pest management. For this purpose venom gland genome is to be sequenced for finding regulatory genes which kits to detect effect of bee venom allergens. Keywords:

Hymenopteran Insects; Venom; Toxins; Biological and Therapeutic Effects

Abbreviations - Immunodeficiency Virus; CXCR4: Chemokine Receptor; BmNPV: MAC-1: Macropin; AMPs: Antimicrobial Peptide; AcKTSPI: Kazal- Bombyx Mori Nucleopolyhedrovirus; RFP: Red Fluorescent Pro (Polybia dimorpha); Equmenine mastoparan-EM1 and Equmenine - type Serine Protease Inhibitor; PNG-1: Panurgines, Polydim-I tein; ACPs: Anti-Cancer Peptides; Jak/STAT: Janus kinase/signal - : Transducer and Activator Of Transcription; JNK: c-Jun N-termi Polybia Spodoptera frugiperda; and Lymantria dispar mastoparan-EM2 Peptides; MP-V1: Mastoparan V1; AMG: Ante nal Kinase; MAPK: Mitogen-Activated Protein Kinases; SF-21AE paulista, - rior Main Gland; PMG: Posterior Main Gland; Polybia-CP: Introduction (IPL-Ldfbc1) Cells Melittin; PLA2: Phospholipase A2; VSV: Vesicular Stoma - Hymenopteran insects such as honey bees, wasps and hornets titis Virus; RSV: Respiratory Syncytial Virus; HSV: Herpes Simplex are highly venomous. These make hives and protect them. After Virus; JV: Junín Virus; RSV: Respiratory Syncytial Virus; VSV: Ve sicular Stomatitis Virus; TMV: Tobacco Mosaic Virus; HIV: Human

Citation: . “Insect Venom Toxin Peptides, its Antimicrobial Effects and Host Immune Responses: A Review". Acta Scientific Microbiology Simran Sharma and Ravi Kant Upadhyay 4.4 (2021): 140-156. Insect Venom Toxin Peptides, its Antimicrobial Effects and Host Immune Responses: A Review

141 feeling a little disturbance in surroundings honey bees and wasps Based on research outcomes spider venom toxins are also found attack in groups while hornets attack in group of two or three in- highly effective against various pathogens and could be used as sects. Envenomation by hornets is highly painful to human than the useful resource for drug development. These were found highly wasp stings because hornet venom contains acetylcholine 5% in effective against drug-resistant microorganisms. The primary functions of solitary wasp are protection of hive while social wasp protects every member and its progenies by developing defense amount. Various species of honey bees are major plant pollinators Due to rising pollution and depletion of foraging sites, wild bee col- and collect nectar from garden flowers and from agriculture fields. onies are decreasing at alarming rate. This local decline is going on paralyzing the prey while social wasps defend their colonies hav- against predators and pathogens. Solitary wasps use stinging for at larger scale in some of the geographical regions. For population decline in wild bees many factors like viral diseases and tempera- difference in venom components on the basis of socialization hyal- ing progenies from vertebrate predators. There occurs a significant ture variations and predators are responsible. In has been noted urinidase, phospholipase A2 and metalloendopeptidase are com- - mon venom components found in both solitary and social wasp. fecting them. After bee bite people experience multiple symptoms, Venom peptides from wasps show diverse biological activities. that positive sense strand RNA viruses are targeting bees and in but insect envenomation do not transmit the virus. Bee venom severely affect cytoskeletal system and nerve cells that results in - organ paralysis and deformity and even death after multiple bites. Solitary wasps possess more diverse bioactive components that tary wasp venom contains pompilidotoxin and dendrotoxin pep- In case of microbial infection severity is increased due to impact are used in prey inactivation by physiological manipulation. Soli of biotic and abiotic factors. Bees protect themselves from infec- tides which are neurotoxic in nature. These also contain insulin tion by using defensins and generating immune response against peptide binding proteins. Insulin peptide binding proteins is highly pathogens. - specific to solitary wasps Contrary to this, venom allergen 5 pro This article highlights antiviral defense found in bees, includ- teins; venom acid phosphatases, and various phospholipases, were ing the Western honey bee (Apis mellifera found relatively more specific to social wasp venom. (Apis cerana Bombus Antimicrobial peptides ), the Eastern honey bee wild bees maintain antiviral defense but for controlling their heavy Antimicrobial peptides are commonly found in all insect groups, ) and bumble bee species (Bees sp.). Though decline and mitigation of bee losses immune -genetic studies are to and used in making immune defense against various pathogens. be done to establish relationship between socialization of bees and These peptides were found highly active against Gram-negative immune function. Primarily eusocial wasps have an important role and Gram-positive bacteria, fungi and viruses, etc. These insect ori- in the origin of eusociality that comes after cooperative foraging and social defense. The uniqueness is that all members of a group gin AMPs show low toxicity to mammalian cells. Macropin (MAC-1) solitary bee Macropis fulvipes. It is a lecuine and lysine rich toxin get infection in maintaining socialization for which they synthesize is an antimicrobial peptide (AMPs) isolated from the venom of the defensins. These are used to make immune defense. Moreover, hu- peptide having 13 amino acids in its structure. MAC-1 shows broad man beings use antibiotics to defend themselves in response to spectrum activity against both Gram negative and Gram positive - Apis cerana counter the pathogen. Antibacterial peptides synthesized in insects viral infection; similarly, bees synthesize defense proteins to en bacteria. Similarly, a peptide isolated from bee ( ) venom active against Gram-positive bacteria [3] in response to various pathogens were found highly effective and acts as a Kazal-type serine protease inhibitor (AcKTSPI) and found could be used as broad spectrum anti-microbial agents. These also (Table 1). become new alternative of synthetic antibiotics. the venom of the wild bee Panurgus calcaratus. These peptides Panurgines are antimicrobial peptides (AMPs) isolated from Antibacterial peptides from insects can be used as therapeutic display strong antimicrobial activity against Gram-positive and agents or potential drugs which could target multidrug resistant Gram-negative bacteria and many fungal strains. These show low pathogens. Today multiple drug resistance in microbes is a big- hemolytic activities against human erythrocytes [4] gest challenge for the pharmaceutical companies and researchers. . PNG-1 is α-helical amphipathic dodecapeptide shows amino acid sequences

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Species Against Activity Peptides References

analgesic, and cardiovascular et al. Apismellifera S. typhimurium effect,Anti-inflammatory, hemolytic, antioxidant 2020 activities, catalytic activity, Jacinthe Frangieh., anti-cancerous Melittin, PLA2 digestive, neurotoxic, et al. Assassin bugs B. subtilis hemolytic, antibacterial, and Ptu1‐like peptides, S1 proteases, redulysins, 2019 cytotoxic effects hemolysins and cystatins Maike L Fischer.,

Macropis fulvipes S. typhimurium Macropin et al. 2017 Properties Anti-bacterial, Anti-Biofilm B. subtilis, Su Jin Ko., Heterometrus S. typhimurium, and P. Hadrurin, scorpine, xanthopus Umair Ahmed., et al. aeruginosa, B. subtilis, Anti-bacterial Pandinin 1, and Pandinin 2012 S. typhimurium, and P. 2 aeruginosa

Acanthoscurria Anti-tumoral Activities, Guilherme A. Câmara., et B. subtilis, cysteine-rich peptides rondoniae Anti-bacterial Short peptides and al. 2020

Anti- HBV activity, cytotoxic (CRPs) effect, Antibacterial and ion Zhengyang Zeng., et al. B. subtilis Defensin BmKDfsin4 channel–modulating 2017 Scorpion activities. Gram-positive and Anti-bacterial, hemolytic et al. Gram-negative bacteria effect 2019 Salwa Mansur Ali., Scolopendra Anti-bacterial, Lysates et al. Pardosa astrigera B. subtilis 2020 Min Kyoung Shin., Hadrurin,Lycotoxin-Pa4a scorpine, Heterometrus B. subtilis, S. typhimurium, anti-inflammatory effects UmairAhmed., et al. Anti-microbial Pandinin 1, and Pandinin xanthopus and P. aeruginosa 2012 2 Gram-negative bacteria Anti-bacterial MDAP-2 Pei Z., et al. 2018 Escherichia coli House- flies Bombyx mori Pseudomonas Anti-bacterial Gloverin2 Wang Q., et al. 2018 putida JM109 and Staphylococcus aureus, Streptococcus pyogenes, Bacillus cereus, Escherichia coli K1, Blaptica dubia antiamoebic effects et al. 2018 Salmonella enterica, Serratiamarcescens, Melittin,PLA2 Akbar N., Pseudomonas aeruginosa, Klebsiella pneumonia Antibacterial agent with Mantidis ootheca Pseudomonas aeruginosa MDAP-2 Wang WD., et al. 2018

Pseudomonas Antibacterialanti-biofilm activityactivity, Marcela Bucekova., Honey bee aeruginosa and Glucose oxidase activity et al.2 017 Staphylococcus aureus Melittin,PLA2

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Blattella Antibacterial activity, HamidrezaBasseri., et al. Micrococcus luteus Chitosan germanica antifungal 2019 Periplaneta Antibacterial activity, HamidrezaBasseri., et al. Micrococcus luteus Chitosan americana antifungal 2019 Reticuliterme A. baumannii antibiotic activity Yuan Zeng., et al. sflavipes Antibacterial activity, PLA2 2016 Bombyx mori E.coli et al. 2014 Antiviral activity Vespa orientalis Micrococcus luteus Antibacterial activity Seroin C P Singh., et al. 2018 Drosophila Micrococcus luteus Antibacterial activity AntibacterialAuNps activity, JafarJalaei., melanogaster Stenopsycheko- Bacillus subtilis, Bacillus - Antibacterial daikanalensis flexus lectin lu., et al. 2018 β-galactoside binding Bhuvaragavan Sreeramu C. quinquefas- Bacillus subtilis, Bacillus Antioxidant, larvicidal, - ciatus flexus scavenging, antibacterial et al. 2018 Balasubramani Sundara Escherichia coli, PLA2 rajan., Klebsiella pneumonia, et al. Bombyxmori Anti-pathogenic activities. Chbp gene Bacillus subtilis and 2018 G K S Manjunatha., L. Phytophthora meadii

Hermetiaillucens Staphylococcus aureus Immunomodulatory activity, et al. 2017 CSαβ peptides-DLP2 and Melipona S. aureus, Zhanzhan Li., DLP4 quadrifasciata methicillin-resistant S. Anti-oxidant, antimicrobial propolis A R Torres., et al. 2018 quadrifasciata aureus, Gram-positive (S. aureus, methicillin-resistant S. Tetragonisca aureus, Anti-oxidant, antimicrobial propolis A R Torres., et al. 2018 angustula gram-negative (E. coli and K. E. pneumonia faecalis) and Anti-infective agents effective against

Loxosceles gaucho S. aureus drug-resistant et al. 2019 microorganisms, Paula Segura-Ramírez., anti-bacterial U1-SCRTX-Lg1a Tetramoriumbi- Anti-Helicobacter pylori ., et al. Helicobacter pylori Bicarinalin carinatum Properties 2017 Jesus Guzman Potent bacteriostatic effect, ., et al. A. baumannii curing drug-resistant bacterial infections, Yongjun Wang Spider venom Lycosin-II Cysteine proteases, Group 2016 III phospholipase A2, C type lectins, lipocalins, Hemorrhagic, coagulation Ana B. G. Veiga., et al. S. aureus protease inhibitors, disorder 2005 serpins, Kazal-type Lonomiaoblique inhibitors, cystatins and trypsin inhibitor

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et al. S. aureus defensin ancestral activity 2018 Neurotoxic, Antibacterial Shangfei Zhang., Scorpion toxins apolipophorins, hemocyanins,Latrotoxins, chitinases, Latrodectus Enzymatic activity, toxicity, arginine kinase, allergen Khamtorn, Pornsawan., A. baumannii geometricus and antibacterial activity antigen 5-like protein, et al. 2020 astacin-like metalloproteases, and serine proteases. L. tredecimgut- A. baumannii Antibacterial et al. 2015 tatus Latroeggtoxin-IV QianLei., Table 1: Antibacterial venom toxins insects.

- teins with an ancestral activity [12]. These insect derived short tide was isolated from Lasioglossum laticeps antimicrobial peptides have shown better bactericidal activity LNWGAILKHIIK-NH₂. Lasiocepsin a 27-residue antimicrobial pep also exhibits antibacterial and antifungal activity [5]. Polybia-MPII against multidrug resistant M. tuberculosis than that of the conven- (wild bee) venom. It shows very high antimicrobial potential and shows comparatively tional antibiotics ethambutol, isoniazid and rifampicin [12]. Both low erythrocyte hemolysis than other peptides of this same family peptides Pin2 and Pin2 have shown much potent antimicrobial - activity and could be used as an alternative of antibiotics to treat lated from the venom of the social wasp Pseudopolybia vespiceps tuberculosis [13]. These show very low hemolytic effects [14-17]. [6]. Similar antimicrobial activity is reported in mastoparans iso against Staphylococcus aureus and Mycobacterium abscessus, Candi- Laches anatarabaevi synthesize cytolytic peptides which da albicans and Cryptococcus neoformans in vitro. These antimicrobial peptides display pore-forming ability in membrane and could Spider venom peptides to paralyze prey or deter aggressors. This is a bi- be used as antimicrobial drugs. act synergistic action when used with neurotoxins. Spiders use functional peptide which binds to bacterial membrane and found Polybia dimorpha is a neotropical wasp, secretes an antimi- - crobial peptide Polydim-I in venom [7]. This is a cationic peptide cepsin is isolated from Lasioglossum laticeps active against Gram-negative and Gram-positive bacteria. Lasio displays potent antimicrobial activity against different microor- contains 27 amino acid residues. This peptide shows antibacterial (wild bee) venom it ganisms. It disrupts cell wall and but shows no cytotoxic effects in mammalian cells [8] - and anti-fungal activity. Lasiocepsin structurally belongs to the ShK peptide isolated from the venom of the social wasp Vespula vul- brane [15] . MP-V1 (Mastoparan V1) is an antimicrobial family, it shows strong affinity with anionic phospholipids of mem . It was found active against infection - garis Salmonella typhimurium . Lasiocepsin peptide permeabilizes through membrane [9] - of Gram-negative bacteria and kills them. Lasiocepsin peptide in [9,10]. Kazal-type serine proteases found in insect venoms exhibit er depends on presence of cardiolipin that found at the poles of . Few α-helical peptides also found in Equmenine wasp venom teracts with phospholipids at N terminus site; its penetration pow thrombin, elastase, plasmin, proteinase K, or subtilisin A inhibition bacterial cells - activity. Both Equmenine mastoparan-EM1 and Equmenine mas- tor but these do not feed upon it. But spiders paralyze their prey [16]. Solitary wasps use sting to paralyze the preda toparan-EM2 peptides exhibit potent antibacterial activity [11]. and feed them to their larvae.

Vespula vulgaris secrete MP-V1 antimicrobial peptide that was spider venoms. These show potent antimicrobial activity against Antimicrobial peptides (AMPs) are also identified in scorpion and found active against Salmonella infection [17]. Polydim-I is a cationic peptide shows powerful antimicrobial activity against dif- - pathogenic bacteria. Scorpion venom contains some bi-functional ferent microorganisms [18]. Equmenine wasps Anterhynchium peptides, which could be used to synthesize/engineer new pro

145 flavor and passes through membrane of bacteria. It shows strong ac- - tion against drug resistant bacteria The wasp A. marginatum micado venom contains antimicrobial α-helical crobial, histamine-releasing, and hemolytic activities. Wasp venom baumannii MPs Agelaia-MPI and Polybia-MPII had better action peptides as the major peptide component that also showed antimi [26] (Figure 1). peptide Mastoparan-EM1 and EM2 display mast cell degranulation [27]. Anoplin and its several activity [19]. EMP-EM peptides strongly bind with bacterial and analogs showed antibacterial activity against methicillin-resistant against MDR (multidrug-resistant) mammalian cell membranes. The paper wasp Polistes dominulus Staphylococcus aureus Escherichia coli (ATCC venom was found effective against polymicrobial disease of vine- Pseudomonas aeruginosa - ATCC 33591 (MRSA), yards [20]. tant Enterococcus faecium [28] - 25922), (ATCC 27853), vancomycin-resis porin 1 and parabutoporin isolated from scorpion Opistophtalmus Wasp venoms are complex mixtures of proteinacious and non- (ATCC 700221) . Similarly, opisto carinatus inhibit growth of Gram-negative bacteria [29] proteinacious substances. Endoparasitoid wasp, Microplitis mediator secretes VRF1, a metalloprotease homolog venom protein. (Table 1) It modulates egg encapsulation in its host, the cotton bollworm, (Figure 1). Helico verpa armigera. This endoparasitoid wasp venom protein interferes with the Toll signaling pathway in the host hemocytes [21] and regulate plasmatocyte numbers. It also regulates mobilization . Similarly, another protein Edin express in the fat body of hosts of sessile hemocytes in Drosophila larvae [22]. Insect venom is a rich source of diverse peptides which could be used for drug design and innovative therapeutic discoveries [23].

Bee and wasp venom contains several biologically active bio- molecules such as peptides and enzymes. These show strong therapeutic potential against micro-organisms mainly causative agents of infectious diseases. Bee venom components also found active against different cancer cell types [24]. Insect venom toxins could be used to cure of central nervous system diseases i.e. Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis in Figure 1: - Platymeris bigutta- Showing antibacterial activity of insect venom toxins. human. The venoms from the anterior main gland (AMG) and pos tus Psytalla horrida terior main gland (PMG) of the reduviid bugs - Antifungal activity L. and Stål secretes distinct protein mixtures acterized proteins, whereas AMG venom contained hemolysins and A synthetic decapeptide antifungal activity against Penicillium possesses S1 proteases, redulysins, Ptu1-like peptides, and unchar cystatins. It shows neurotoxic, hemolytic, antibacterial, and cyto- rot of apples [30], toxic effects [25]. effect on the oncogenic channel K 10.1 [31]. A peptide analog from α-hefutoxin 1 andv analogues showed inhibitory

Antibacterial activity against Cryptococcus spp. and Paracoccidioides spp. This peptide the mastoparan wasps (MK58911) showed antifungal activity Bee and wasp venom contains several biologically active bio- could be used as a new antifungal drug to treat systemic mycoses molecules such as peptides and enzymes. These show strong thera- [32] peutic potential against micro-organisms mainly causative agents the venom of the social wasp Polybia paulista. It shows potent an- . Polybia-CP is an antimicrobial cationic peptide purified from of infectious diseases. Polybia-CP isolated from Polybia paulista tifungal activity against Candida albicans (C. albicans) and Candida shows strong antibacterial potential against both Gram-positive glabrata (C. glabrata C. glabrata, and Gram-negative bacteria. This is a membrane active peptide and could be used for development of antifungal agents. Polybia- ). Polybia-MPI, inhibits growth of

CP enhances the production of cellular reactive oxygen species wasp venom was also found effective against Candida albicans.146 It that aid to its anti-fungal activity [33]. It shows potent antifungal shows low cytotoxicity and non teratogenicity in Danio rerio [35]. activity against Candida albicans and Candida glabrata - wasp Orancistrocerus drewseni showed antifungal activity [37] 2 . Similarly, Similarly, OdVP2 and OdVP2L peptides were isolated from solitary microbial activity due to its truncation and acylation. Anoplin could anoplin (GLLKRIKTLL-NH ) isolated from wasp shows potent anti be used as promising drug candidates for drug development [34] T. (Figure 2). Polybia-CP is a much potent antifungal peptide. Similar - stigmurus [38]. antifungal peptides have been identified in the venom glands of tive decapeptide isolated from wasp venom. Its shows strong anti- (Table 2 and figure 2). Anoplin is an amphipathic, α-helical bioac A peptide Ts-FKLFKKILKVL-NH(2) (BP22), bears fungal, activities against Leptosphaeria maculans and protection of conventional antibiotic. It also shows antifungal activity against Tsortosyl group, shows an efficacy of 56% disease reduction, than Brassica napus plants from disease . Mastoparan analog from both plant-pathogenic and entomopathogenic fungi [30]

[36] (Table 2). S. No. Insect species Against Activity Peptides References

1. Candida species et al. 2018 Anti-fungal activity Anti-biofilm, Spider Cryptococcus Lycosin-I Li Tan., 2. Galleria mellonella Anti-fungal Mastoparan neoformans et al. 2019 Junya de Lacorte Haemolytic, Singulani., cytotoxic, antifungal et al. 3. Bee venoms Candida spp 2019 activities LL-III (LL-III/43) and JitkaKočendová., and anti-biofilm HAL-2 (peptide VIII) Astacin-like metalloprotease toxins, Pardosa Cryptococcus Antiviral and Kunitz-type serine 4. et al. 2018 pseudoannulata neoformans antifungal activities protease inhibitors, venom allergen 5, Lixin Huang., hyaluronidase Staphylococcus aureus and Mycobacterium abscessus subsp. Pseudo polybiave et al. 5. Massiliense, Candida Antifungal activities Mastoparans spices albicans and Juliana C Silva., Cryptococcus 2016 neoformans C. tropicalis and C. Manoela Torres-Rêgo., Tityus stigmurus TistH krusei, C. albicans activities et al. 2019 Anti-biofilm 6. et al. 7. Macropis fulvipes C. tropicalis Hemolytic activity Macropin 2014 LenkaMonincová., Bacillus subtilis, Bacillus thuringiensis, Kazal-type serine 9. Apiscerana Beauveriabassiana, and Bo Yeon Kim., et al. 2013 activities protease Fusarium Anti-biofilm graminearum Fulvia fulva and Young Moo Choo., et al. 10. Bombus ignitus Hemolytic activities Bombolitin Alternaria radicina 2010

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-theraphotoxin-Lp1a U1 (lasiotoxin-1), Candida parapsilosis Cytotoxic, and Felipe Roberto Borba 11. Lasiodora -theraphotoxin-Lp1cU -theraphotoxin- and Candida albicans hemolytic activities 3(lasiotoxin-3), Ferreira., et al . 2016 Lsp1a (LTx5), and phospholipase A2 2 ω-theraphotoxin-Asp3a,and hyaluronidase (PLA ) Peter V Dubovskii., et al. 12. Lachesanatarabaevi Candida albicans Cytotoxic, neurotoxic 2015 latarcins (Ltc) Kairong Wang., et al. 13. Polybia paulista C. tropicalis polybia-CP activities 2015 Anti-biofilm et al. 14. Panurgus calcaratus Candida albicans Cytotoxic, neurotoxic panurgines 2013 SabínaČujová., Lasioglossum et al. 15. Fulvia fulva laticeps activities 2013 Anti-biofilm LenkaMonincová., Loxosceles TAGLasiocepsin and DAG Candida parapsilosis Hemolytic activities A V Bednaski., et al. 2015 intermedia phospholipids 16. 17. Heterometrus sp. C. tropicalis et al activities Anti-biofilm κ-hefutoxin 1 Lien Moreels., . 2016 Table 2: Anti-fungal activity of animal toxins.

ectoparasitic wasp Nasoniavi tripennis involve in the release of intracellular calcium stores via the activa- causes cellular injury and tion of phospholipase C. It results in oncotic death. Wasp venom stimulates sudden release of calcium from ER compartments, it 2+ channels, and the Ca(2+ pump. Calcium is also released from some other intracellular store is distinct from RyRs, L-type Ca )-ATPase [40]

(Table 3 and figure 3). Antiviral activity - - Bee venom and its components i.e. melittin (MLT), phospholi - pase A2 (PLA2), and apamin showed inhibitory effects against im portant disease causing viruses i.e. Influenza A virus (PR8), Vesicu in vitro and in vivo [41]. Honey bee lar Stomatitis Virus (VSV), Respiratory Syncytial Virus (RSV), and peptide melittin found effective against several viruses including Figure 2: Herpes Simplex Virus (HSV) - Showing antifungal activity of insect venom toxins. coxsackievirus, enterovirus, influenza A viruses, human immuno deficiency virus (HIV), herpes simplex virus (HSV), Junín virus (JV), Anti-trypanosomal [24,42]. Mastoparan-derived respiratory syncytial virus (RSV), vesicular stomatitis virus (VSV), Mastoparan also shows anti-protozoan activity and inhibits and tobacco mosaic virus (TMV) development forms of Trypanosoma cruzi [39]. Venom from the peptide MP7-NH2 inactivates viruses and stimulate cell-mediated

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S. No. Insect Activity Peptides References 1. Ixodes ricinus Antimalarial, Antiplasmodial Defensins et al. 2018 Trypanocidal activity, Ana Maria Antonello., et al. 2. Photorhabdus luminescens Bioactive metabolite Joana Couto., parasiticidal activity 2019 Trypanocidal activity, Ana Maria Antonello., et al. 3. Xenorhabdus nematophila Bioactive metabolite parasiticidal activity 2019 Moricin-B, Moricin-C4, Anti-parasitic activity, 4. Galleria mellonella Cecropin-D and Anionic anti-leishmanial activity et al. 2018 Peptide 2 Isabel A Patiño-Márquez.,

Anti-leishmanial and antitry- - 5. Achillea fragrantissima et al. 2017 panosomal activity Sesquiterpenenol-D and chrysosple lactones,- flavonoids, chrysosple netine, alkamides Joseph Skaf.,

Table 3: Anti-protozoal activity of insect venom toxin peptides.

- shown to have strong anti-human immunodeficiency virus (HIV) activity. T22 inhibits the T cell line-tropic (T-tropic) HIV-1 infec which serves as a coreceptor for the entry of T-tropic HIV-1 strains. tion through its specific binding to a chemokine receptor CXCR4, Bee venom toxins show biological activities mainly antiviral [47]

(Table 4 and figure 4).

Figure 3:

Showing antifungal activity of insect venom toxins.

[43] antiviral defense. MP7-NH2 inactivates mainly enveloped viruses Figure 4: (Table 4 and figure 4). Scorpion-venom-derived mucroporin- M1 was found active against RNA viruses (measles viruses, SARS- Showing antiviral activity of insect venom toxins. inhibits HIV-1 replication and progression particle [44]. This is a CoV, and H5N1 and HIV-1. Kn2-7 is a scorpion venom peptide that promising candidate development of therapeutic agent against Tick saliva also contains defensins against microbes mainly vi- HIV-1 [45]. Cationic peptides showed anti-infection and anti-tu- [48]. moral activity - ruses. It plays a major role in the innate immunity of ticks [46]. T22 [Tyr5,12, Lys7]-polyphemusin II) has been T22 [Tyr5,12, Lys7]-polyphemusin II) inhibits human immuno

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S. No. Insect Biological effect Peptides References 1. Apis mellifera Cytotoxic and anti-herpetic effect Propolis et al. 2018 2. Bombyx mori Cytotoxicity et al. 2014 K Labska., 3. Calliphora vicina Cytotoxicity, antiviral activity Tridecapeptidealloferon ., et al. 2012 Seroin C P Singh., 4. Drosophila Antiviral immunity, Alfred W Bronkhorst., et al. 2019 Yejin Kim 5. Genipin glycoside et al. 2018 activity Larvacidal activities, insecticidal Anti oxidant activity and irritation Qing Xia., Apis mellifera Melittin et al. 2018 property 7.6. Apis cerana Antiviral immunity Cecropin A1 Alexander J McMenamin., et al. 2018 8. Bombus sp Antibacterial, antiviral Prodigiosin et al. 2018 Alexander J McMenamin., Antibacterial, antiviral, anti Alexander J McMenamin., 9. Apis mellifera M Viuda-Martos., et al. 2018 vasodilatory actions -inflammatory, antiallergic, and Propolis, flavonoids Catalytically-active 10. Aedesaegypti et al. 2019 anti-Zika virus, adulticidal activity Anti-flavi-viral, mosquitocidal, 2 Haemaphysalis Defensin-like peptide, ShengzhangDong., 11. Virucidal activity sPLA Melbourne Rio Talactac., et al. 2017 longicornis HEdefensin

12. Bombyx mori Prodigiosin Wei Zhou., et al

13. Lonomia obliqua AntiviralAntiviral activity againstactivity BmNPV Defensin-like peptide A C V Carmo., et al. 2016. 2012

14. Bombyx mori Antiviral, antifungal et al. 2018 (RFP Red fluorescent protein 15. Musca domestica L In vitro G KFurongWang., S Manjunatha., et al. 2013 Bombyx mori Potential antiviral factor et al. 2004 anti-influenza activity Antiviral, insecticidal, and fungicidal 17.16. Lonomia obliqua Serine protease Hiroshi Nakazawa.,et al. 2009 activities antiviral, insecticidal, and fungicidal rAVLO Katia N Greco., 18. Aedes albopictus et al. 1993 activities Ribavirin (Rbv) ribavirin H J Liao., Table 4: Anti-viral activity of insect venom(Rbv) toxin peptides.

B. mori larvae. It shows antifungal and anti- deficiency virus (HIV) activity. T22 inhibits replication of HIV-1 immune defense. Red fluorescent protein (RFP) is purified from serves as a co-receptor for the entry of T-tropic HIV-1 strains. Pro- through its specific binding to a chemokine receptor CXCR4, which the digestive juice of digiosin showed antiviral activity Bombyx mori nucleopolyhedrovi- chbp gene and it belongs to lipocalin gene family found involve in bacterial properties. N-terminal sequence of RFP analysis having in vitro, anti-pathogenic activities. RFP from the midgut of the silkworm [49]. The hemolymph of Lonomia oblique caterpillars contain an rus (BmNPV)-infected cells with specific modes of action antibacterial activity against, Klebsiella pneumonia, Bacillus subti- larvae showed antiviral activity against the BmNPV. It also shows system for expression [50]. antiviral protein. This antiviral protein needs baculovirus/Sf9 cell lis and, Phytophthora meadii [51] - The midgut mucosa and serosa and other membrane structures . PEF (protein-enriched fraction) acts as natural barrier of pathogens and assist in making innate isolated from the larvae of the housefly showed strong antiviral ac tivity against influenza virus. It stops virus entry into the cells. PEF

150 has a great potential as a resource of healthy products [52] (Table small cationic and hydrophobic peptides which show antioxidant, antimicrobial, neuroprotective or antitumor effects [52]. Rbv 4). BmSP-2 is an insect digestive enzyme that acts as an antiviral [56] (Table 4). protein is isolated from hemolymph of Lonomia oblique; it shows Anti-cancer peptides factor against BmNPV at the initial site of viral infection - Anti-cancer peptides ( es [53]. This protein function as a constitutive agent to make the peptides. Anticancer peptides much ably kill cancer cells by caus- potent antiviral activity against measles, influenza and polio virus ACPs) are small cationic and hydrophobic innate immune defense. These effects may be mediated by changes ing irreparable membrane damage and cell lysis, or by inducing in the GTP pools of treated cells [54]. apoptosis. Mastoparan induce mast cell granulation through exo- from Bombyx mori Seroins are proteins isolated used as potent candidates for development of transgene-based dis- a transition opening of a pore [57]. show strong anti-viral activity. Seroins could be cytosis (Table 5). It facilitates mitochondrial permeability through ease resistant silkworm strains [55]. Melittin and phospholipase Miscellaneous Animal venoms possess hundreds of molecules, mostly pep- A2 (PLA2) are major components of bee venom. Bees and wasps tides which display diverse biological activities mainly pharmaco- venom also contain anti-cancer peptides (ACPs), most of them are

Species Peptides Biological effects Activity References Pompilidotoxin and Antimicrobial Active against bacteria Peptide Wasps insulin-like peptide binding and fungi et al Solitory wasp and hunting dendrotoxin-like peptide), Si Hyeock Lee., ., 2016 Neurotoxic peptides Rogerio Coutinho protein) Cytotoxic effects, cell Polydim-I Anti-mycobacterial Polybia dimorpha wall disruption et al. Neotropical Social Wasp das Neves., Membrane-Active Action Antimicrobial Kairong Wang., et al. Polybia paulista Polybia-CP 2016 Mode Peptide 2012 Vespula antimicrobial et al. vulgaris Modulation peptide 2017 Social wasp Anti-Salmonella Activity Yeon Jo Ha., Mastoparan V1 (MP-V1), Marcia Perez dos

histamine-releasing Antimicrobial, and wasp Anterhynchium Eumeninemastoparan-AF . 2019 factor hemolytic et al flavoSolitary marginatum eumenine micado Santos Cabrera.,

Eumenine mastoparan-EM1 (and eumenine Moderate degranulation Katsuhiro Konno., mastoparan- activity, leishmanicidal Antibacterial activity wasp Eumenesmicado et al. 2019 Solitary eumenine EM2,mastoparan peptides, activity

peptides linear cationic α-helical

Parasitoid wasps Leptopilin Edin Cellular cytotoxicity et aboulardi degranulation Leena Mast cell (MC) al. 2015 -MaijaVanha-aho., Endoparasitoid wasp, VRF1, a metalloprotease Toll signaling pathway in Anti viral et al. 2018 Microplitis mediator homolog venom protein the host hemocytes Zhe Lin.,

151 Antifungal Hemolytic activity et al. 45 The wild bee Panurgus therapeutic, Panurgines against human calcaratus. antimicrobial erythrocytes. Čujová S., peptides Lasioglossum laticeps (wild Membrane Antibacterial and Bednaski AV., et al. -permeabilising activity antifungal activity Lasiocepsin et al. bee) Potent action against 2017 Pseudo polybiavespiceps Mastoparans, Polybia-MPII S. aureus, apoptosis and antimicrobial drugs, Juliana C Silva.,

Membrane-activeinflammation action Kairong Wang., et al. Polybia paulista Polybia-CP Antifungal activity mode 2014. Social wasp Moderate degranulation et al. OdVP1, OdVP2 and OdVP3 activity, leishmanicidal Orancistrocerusdrewseni activities 2010 Solitary wasp activity Strong antifungal JiHyeongBaek., Polybia paulista wasp Mastoparan Parasitic infection Anti trypanosomal venom Vinhote., et al. 2017 Juliana Freire Chagas The activation of Ectoparasitic wasp Nasonia phospholipase C, and David B Rivers., et al. Metalloprotease Anti trypanosomal vitripennis culminates in oncotic 2005. death

Table 5: Wasp venom peptides. logical and therapeutic [58]. Polistine wasps use venom stinging as an effective weapon against predators. It contains neurotoxin mune deficiency pathways [62] (Table 5). Apis mel- which are haemolytic, and algogenic in nature [59]. Honey, propo- lifera, shows antimicrobial activity against gram positive bacte- Mellitin, a major component isolated from bee venom, ria. Insects also synthesize variety of immune-induced molecules [59] lis, and royal jelly, contain phenolic compounds mainly flavonoids which show antibacterial and antifungal property . Cationic allergic and vasodilatory activities . Flavonoids inhibit impor- . These show anti-bacterial, antiviral, anti-inflammatory, anti- peptides are also known as alloferons. These were isolated from tant physiological activities such as lipid peroxidation, platelet [63] [60] Calliphora vicina aggregation, capillary permeability and fragility. It also inhibits cy- Nasonia vitripennis shows lethal effects. Wasps, bees and hornet clo-oxygenase and lipoxygenase enzyme activity . Honeybees blow fly (Diptera) (Table 5).Crude venom of wasp venom shows hemolytic activity to Sarcophaga peregrina prepare propolis a resinous substance that is used in traditional [60] Drosophila melanogaster Trichoplusia ni medicine against Varicella zoster virus . It shows antimicrobial, (NIH Spodoptera frugiperda SaPe4), (CRL 1963), (TN- [61] Lymantria dispar . Moreover, peptides and 368 and BTI-TN-5B1-4), (SF-21AE), and anti-inflammatory, and immune modulatory effects. - - (IPL-Ldfbc1) cells [64] cholesterolemic, vasodilative and hypotensive activities. Honey uronidase, venom dipeptidyl peptidases, conotoxin-like peptide, Royal jelly shows antibacterial, anti-inflammatory, anti-hyper proteins such as pilosulin-like peptides, phospholipase A₂s, hyal and icarapin-like peptide antimicrobial, hemolytic, and histamine- bee venom components prepare antiviral defense by using RNA autophagy. It also operates through conserved immune pathways synthesized and some of them displayed antimicrobial, hemolytic, interference (RNAi), endocytosis, melanization, encapsulation and releasing activities. Pilosulin-like peptides 1-6 were chemically and histamine-releasing activities used as important tools for the development of new therapeutic including Jak/STAT (Janus kinase/signal transducer and activator [65] (Table 5). These could be - drugs. of transcription), JNK (c-Jun N-terminal kinase), MAPK (mitogen- activated protein kinases) and the NF-kB mediated Toll and im

152 Mode of action of peptides Brefeldin A Insect toxins comprise a diverse array of chemicals ranging It interferes in Golgi apparatus endoplasmic reticulum oper- from small molecules, polyamines and peptide toxins. Many of ated functions. Mastoparan activates heterotrimeric G proteins, these venom components target nervous system and neuromuscu- promotes binding of beta-COP to Golgi membranes in vitro. It an- lar ion channels and so rapidly affect the behavior of animals to tagonizes the effect of brefeldin A on beta-COP in perforated cells - as well as in isolated Golgi membranes . brane surface of nerve cells while mastoparan shows strong cyto- which the toxin is applied or injected. Melittin, acts on the mem [68] lytic effects. Philanthotoxins found in digger wasps specially target Sifuvirtide ligand-gated ion channels. These act on nervous system and at neu- during fusion after its delivery . Sifuvirtide stops HIV-1 fusion. It interacts with lipid structures [69] romuscular junctions. Apamin isolated from bee venom acts upon Prodigiosin neuropeptides. The crude honey bee (Apis mellifera calcium-activated potassium channels, and influence release of on skeletal, smooth as well as cardiac muscles. Crude venom also Prodigiosin selectively target virus-infected cells, inhibit viral ) shows effects causes neurotoxicity and inhibits autonomic as well as neuromus- gene transcription, and virus-mediated membrane fusion. Prodigi- cular system. Honey bee venom, shows induction of apoptosis in osin found cell cytoplasm where it interact with cytoplasm factors malignant cells. It shows inhibitory, anti-invasive and cytotoxic ef- and inhibit virus replication [70]. fect on several types of cancer lines. Bee venom components melit- Conclusion tin shows showed anti-proliferative and anti-metastatic properties Insect venom toxin peptides showed diverse biological activity and apoptosis in malignant glioma cells. i.e. vasodilatory, anti-septic and cytotoxic hypotensive, antioxidant Mastoparan activity, anti-allergic, anti-hypercholesterolemic, anti-rheumatic Mastoparan destroys bilayer membranes and come across and analgesic, anticancer effects. Insect venom toxins also pos- through pores. Both low and high concentrations of mastoparan sess remarkable antibacterial, antifungal antiviral, and insecticidal affect membrane permeabilization through transition pore. G- activity. Antimicrobial peptides isolated from venoms of different protein participates in regulation of the permeability through insects could be used as useful resources for new anti-infective transition pore . Mastoparan severely affects mitochondrial agents. Due to diverse biological activity of insect venom toxins permeability through bi-functional mechanism. Polybia-MPII in- and its fast action of venom toxins make them important for the [66] duces myonecrosis and apoptosis, by involving caspases signaling from venoms of different hymenopteran insects could be used for activity. It results in mitochondrial damage, and cytokine activation pharmaceutical industry. No doubt antimicrobial peptides isolated . This peptide binds to membrane lipids due to electrostatic at- designing anti-infective therapeutic agents. These peptides could traction. It partially accumulates, neutralizes the opposite charges be used as templates for designing appropriate and more potent [66] and induces pore formation in biological membrane. Mastoparan structures by using drug design and drug delivery systems. For as an inducer of mast cell granules exocytosis has been also related are to be explored in various animal models. It is only possible after to many essential mechanisms of cell function [57]. pharmacological use of venom toxins, component specific effects - Cationic polydim-I macology and immunology. This wider knowledge on insect toxins coordinating efforts being done in the field of biochemistry, phar This peptide binds to membrane lipids due to electrostatic at- against various disease pathogens and will open new ways and in- traction. It partially accumulates, neutralizes the opposite charges will help in production of new highly potent drug molecules to fight and induces pore formation in biological membrane. It could be used against multi-drug resistant pathogens mainly bacteria in the Acknowledgementsnovations in the field of therapeutic and pharmaceutical research. hospital environment . Authors are thankful to H.O.D., Department of Zoology for re- [67] search facilities.

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Citation: . “Insect Venom Toxin Peptides, its Antimicrobial Effects and Host Immune Responses: A Review". Acta Scientific Microbiology Simran Sharma and Ravi Kant Upadhyay 4.4 (2021): 140-156.