Autofagosomibiogeneesi (2013 )( mitokondria, syntaxiini17 etc, starvaatio )

https://www.nature.com/articles/cr2013159#f2

• Abstract
• Introduction
• Atg proteins
• The Atg1/ULK complex
• The class III PI3K complex and the Atg2-Atg18/WIPI complex
• The Atg12 conjugation system
• The Atg8/LC3 conjugation system
• Atg9 vesicles
• Searching for the origin of the autophagosomal membrane
• Autophagosome formation on the ER
• ER-mitochondria contact sites
• ER exit sites
• The ER-Golgi intermediate compartment (ERGIC)
• The plasma membrane and recycling endosomes
• Atg9 vesicles as a membrane source
• Autophagosome formation in selective autophagy
• Concluding remarks
• References
• Acknowledgements
• Author information
• Rights and permissions
• About this article
• Further reading

Miten Legionella LCV pääse irti mitokondriasta, johon se ajautuu , ja nitistää Syntaxiinin17 ja miksi.

LCV vakuolin  tutkimuksissa on havaittu sen joutuvan mitokondriokontaktiin  hetkiseksi ja sitten irtoavan välttäen endosyyttisiä  kuljetusteitä ja liittyen  ER-Golgi retrogradiseen  kalvomateriaaliin.
 Tästä löytyy selvitys viime vuoden artikkelissa, toukokuu 2017.

Legionellan effektoriproteiini Lpg1137 katkaisee  ER- mitokondriakommunikaation pilkkomalla syntaksiini17- proteiinin. 

LÄHDE: 
 https://www.ncbi.nlm.nih.gov/pubmed/28504273

Nat Commun. 2017 May 15;8:15406. doi: 10.1038/ncomms15406.

Legionella effector Lpg1137 shuts down ER-mitochondria communication through cleavage of syntaxin 17. Arasaki K¹, Mikami Y¹, Shames SR², Inoue H¹, Wakana Y¹, Tagaya M<sup>1

Tiivistelmästä suomennosta.</sup>

Makrofagin infektoitumisen aikana patogeeninen legionella pneumophilabakteeri erittää effektoriproteiineja, jotka indusoivat  konversion  plasmakalvoperäisesta  vakuolista  endoplasmisen retikulumin kaltaiseksi replikatiiviseksi vakuoliksi. Nämä  endoplasmista  verkostoa (ER)  muistuttavat vakuolit (LCV)  lopuksi fuusioituvat endoplasmiseen verkostoon (ER), jossa patogeeni replikoituu.
Tässä työssään tutkijat osoittavat, että L. pneumophilan efsektori Lpg1137  on eräs seriiniproteaasi, jonka vaikutuskohde  on  mitokondria ja siihen assosioituneet kalvot.
 Lpg1137 sitoutuu  syntaxiin 17 ja pilkkoo sen.
  Syntaxiini 17 on eräs liukoinen N-etyylimaleimidi-sensitiiviseen faktoriin liittyvä proteiinireseptori (SNARE) -proteiini, jonka tiedetään osallistuvan  mitokondrian dynamiikan säätelyyn tekemällä interaktio mitokondrian fissiofaktorin Drp1 kanssa   ravintoa saavissa soluissa ja  autofagiaan  Atg14L:n  ja muiden SNARE-proteiinien  kanssa  nälkätilassa olevassa solussa.
 Kun  Syntaxiini 17 pilkkoutuu,  estyy  sekä autofagia että stauroporiinilla indusoituva  apoptoosi, jota Bax, Drp-1:stä riippuvalla tavalla tapahtuu.
Täten Legionella pneumophila voi tukkia  ER- mitokondria - kommunikaation pilkkomalla syntaxiini17 -proteiinin.

• During infection of macrophages, the pathogenic bacterium Legionella pneumophila secretes effector proteins that induce the conversion of the plasma membrane-derived vacuole into an endoplasmic reticulum (ER)-like replicative vacuole. These ER-like vacuoles are ultimately fused with the ER, where the pathogen replicates. Here we show that the L. pneumophila effector Lpg1137 is a serine protease that targets the mitochondria and their associated membranes. Lpg1137 binds to and cleaves syntaxin 17, a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein that is known to participate in the regulation of mitochondrial dynamics through interaction with the mitochondrial fission factor Drp1 in fed cells and in autophagy through interaction with Atg14L and other SNAREs in starved cells. Cleavage of syntaxin 17 inhibits not only autophagy but also staurosporine-induced apoptosis occurring in a Bax, Drp1-dependent manner. Thus, L. pneumophila can shut down ER-mitochondria communication through cleavage of syntaxin 17. PMID:28504273 PMCID: PMC5440676 DOI: 10.1038/ncomms15406

Free PMC Article

Sitaatti yksityiskohdasta.

Syntaxin 17 (Stx17) is a SNARE originally implicated in a vesicle-trafficking step to the smooth-surfaced tubular ER membranes that are abundant in steroidogenic cells¹⁴.

 Stx17 is unique in that it has a long hairpin-like C-terminal hydrophobic domain (CHD), followed by a cytoplasmic basic region. Stx17 participates in cellular events unrelated to membrane fusion.

 In fed cells, Stx17 promotes mitochondrial fission by defining the localization and activity of the mitochondrial fission factor Drp1 (ref. ¹⁵).

 On starvation, on the other hand, Stx17 dissociates from Drp1 and associates with Atg14L, a subunit of the phosphatidylinositol 3-kinase (PI3K)  complex. This promotes the recruitment of this kinase to the mitochondria-associated ER membrane (MAM)¹⁶, which leads to the formation of phosphatidylinositol 3-phophate (PI3P)-enriched omegasomes that are considered to represent a membrane/lipid source for autophagosomes^17,18. 

In the late stage of autophagy, Stx17 present on autophagosomes mediates the fusion of autophagosomes with lysosomes^19,20,21.

In this study, we show that Stx17 is degraded on Legionella infection. We identify the Legionella effector Lpg1137 as the responsible protein for Stx17 breakdown and show that Lpg1137 is a serine protease that localizes to the ER–mitochondria contact site, where Stx17 is located.

Ihmisen MMP entsyymit voivat aktivoitua bakteerien proteinaaseilla

http://www.jbc.org/content/272/9/6059.full.html

Activation of Human Matrix Metalloproteinases by Various Bacterial Proteinases*

Tatsuya Okamoto^‡,^§, Takaaki Akaike^‡, Moritaka Suga^§,
Sumio Tanase^¶, Hidechika Horie^‡, Seiya Miyajima^‡,
Masayuki Ando^§, Yoshio Ichinose^∥ and Hiroshi Maeda^‡**

1. From the Department of ^‡ Microbiology
2. ^§ Internal Medicine I, and
3. ^¶ Biochemistry II, Kumamoto University School of Medicine, Kumamoto 860 and the
4. ^∥ Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852, Japan

Legionellan effektoriproteiini AnkB vaatii isäntäsolulta FIH/ asparaginyylihydroksylaation

https://www.karger.com/Article/Pdf/235770


LÄHDE:
 Front Cell Infect Microbiol. 2017 Mar 6;7:54. doi: 10.3389/fcimb.2017.00054. eCollection 2017.
Host FIH-Mediated Asparaginyl Hydroxylation of Translocated Legionella pneumophila Effectors.

Price C¹, Merchant M², Jones S¹, Best A¹, Von Dwingelo J¹, Lawrenz MB³, Alam N⁴, Schueler-Furman O⁴, Kwaik YA³.

Abstraktin suomennos.

FIH-välitteinen posttranslationaalinen modifikaatio Asn--hydroxylaatiolla   merkitsee eukaryoottisille proteiiniella  proteiini-proteiini-interaktiossa olennaista seikkaa. 

Yhdestätoista Legionella pneumophilasta (siis  sen translokoituneista effektoreista)  on identifioitu  FIH-tunnistusmotiivi , yersiniasta YopM, Shigellasta IpaH4.5 ja Ricketssiasta  ankyriiniproteiini.

Massapsketromeriset analyysit L. opneumophilan AnkB ja AnkH effektoriproteiinista vahvastiaa  , että niisä on tapahtunut asparainyylihydroksylaatio. 

AnkB.effektoria  lokalisoituu  Lpn -bakteeria sisältävään LCV  vakuoliin ja  se osoittautuu FIH-modifiaation saaneeksi.  Isäntäsolun proteiineista sen kanssa interaktion tekevät  Mint2 ja MT1-MMP, joita  legionellaa sisältävä vakuoli (LCV) vaatii  Dot/Icm tyyppi IV-sekreetiosta riippuvalla tavalla. 

Jos estetään  FHI kemiallisesti  tai  RNAi-välitteisellä FHI poistogeenisyydellä , legionella pneumophilan  intravakuolaarinen replikaatio kumoutuu.  Nämä tiedot osoittavat, että   patogeenia sisältävä vakuoli hankkii isäntäkehosta FIH ja että  asparaginyylihydroksylaatio on  välttämätön  translokoituneille efektoriproteiineille , jota ne voisivat  olla funktionaalisia.

• Abstract
• FIH-mediated post-translational modification through asparaginyl hydroxylation of eukaryotic proteins impacts regulation of protein-protein interaction.   We have identified the FIH recognition motif in 11 Legionella pneumophila translocated effectors, YopM of Yersinia, IpaH4.5 of Shigella and an ankyrin protein of Rickettsia. Mass spectrometry analyses of the AnkB and AnkH effectors of L. pneumophila confirm their asparaginyl hydroxylation. Consistent with localization of the AnkB effector to the Legionella-containing vacuole (LCV) membrane and its modification by FIH, our data show that FIH and its two interacting proteins, Mint3 and MT1-MMP are acquired by the LCV in a Dot/Icm type IV secretion-dependent manner. 
  Chemical inhibition or RNAi-mediated knockdown of FIH promotes LCV-lysosomes fusion, diminishes decoration of the LCV with polyubiquitinated proteins, and abolishes intra-vacuolar replication of L. pneumophila. These data show acquisition of the host FIH by a pathogen-containing vacuole and that asparaginyl-hydroxylation of translocated effectors is indispensable for their function.KEYWORDS: AnkB; Dot/Icm; FIH; Legionella; ankyrin; asparagine hydroxylation; bacterial pathogenesis; hypoxia-inducible factor (HIF).
  
  
  

  Mikä on FIH-välitteinen posttranslationaalinen modifikaatio asn-hydroksylaatiolla?

  https://www.frontiersin.org/articles/10.3389/fcimb.2017.00054/full
  ---Citate:
  Although intracellular bacterial pathogens have been shown to exploit various host post-translational machineries, their exploitation of the host asparaginyl hydroxylation post-translational modification has never been described. The 2-oxoglutarate dioxygenase, designated as factor inhibiting HIF1 (FIH), is a key eukaryotic enzyme, which selectively hydroxylates an asparagine residue within the L(X)5[D/E]φNφ motif (φ represents aliphatic amino acids) in eukaryotic proteins (Hewitson et al., 2002; Lando et al., 2002a,b; Cockman et al., 2009). The addition of the strongly electronegative oxygen atom increases both polarity of a protein and can act as a hydrogen bond donor and acceptor. Therefore, hydroxylation can function as a “molecular switch” for protein-protein interactions (Loenarz and Schofield, 2011). FIH plays a key role in various cellular processes and in particular, it regulates the activity of hypoxia-inducible factor (HIF1), which is the master transcriptional regulator of hypoxia (Webb et al., 2009). During normoxia, HIF1 is hydroxylated by FIH on an asparagine residue and this modification acts as a molecular switch to prevent interaction with its co-activator p300/CBP, blocking transcription of hundreds of HIF1-regulated genes involved in oxygen  homeostasis, energy production and immune responses (Hewitson et al., 2002; Lando et al., 2002a,b). In addition, FIH catalyzes asparaginyl hydroxylation of approximately 20 ankyrin repeat domain-containing (ARD) proteins such as p105 and IκBα (Cockman et al., 2009). FIH-dependent hydroxylation of the ARD protein, ASPP2, is required for binding of this protein to its target Par-3 (Janke et al., 2013). Therefore, asparaginyl hydroxylation acts as a molecular switch to promote or reduce protein-protein interactions between HIF1-p300/CBP and ASPP2-Par3 (Hewitson et al., 2002; Lando et al., 2002a,b; Janke et al., 2013). Additionally, FIH hydroxylates the deubiquitinase OTUB, which appears to regulate cellular metabolism (Scholz et al., 2016). A recent study has revealed a complex FIH interactome with many proteins that may serve as substrates for FIH enzyme activity, thus greatly expanding the number of eukaryotic proteins modified by asparaginyl hydroxylation (Rodriguez et al., 2016). However, the biological consequence of asparaginyl hydroxylation of eukaryotic proteins largely remains unclear.
  
  When L. pneumophila invades amoebae or human macrophages, it evades the default endosomal-lysosomal degradation pathway and remodels its phagosome into a specialized ER-derived vacuole via intercepting ER-to-golgi vesicular traffic (Isberg et al., 2009; Al-Quadan et al., 2012; Price et al., 2014). This is achieved by the translocation of ~300 effector proteins via the Dot/Icm type IVB secretion system T4SS (de Felipe et al., 2008; Isberg et al., 2009; Zhu et al., 2011). These effectors modulate a myriad of eukaryotic processes including host signaling, vesicular trafficking, protein synthesis, apoptosis, prenylation, ubiquitination, and proteasomal degradation (Al-Quadan et al., 2012; Price et al., 2014). Surprisingly, very few of these effectors are essential for intracellular replication of L. pneumophila, suggesting specific requirements for different effectors in different environmental hosts.
  
  The AnkB translocated effector is essential for proliferation of L. pneumophila within the two evolutionarily-distant hosts, mammalian and protozoan cells, and for intrapulmonary bacterial proliferation and manifestation of pulmonary disease in the mouse model (Al-Khodor et al., 2008; Price et al., 2009, 2010a,b, 2011; Lomma et al., 2010). Recent characterization of the crystal structure of AnkB has confirmed that it is a non-canonical F-box protein with three ankyrins repeats domain (Price et al., 2009; Lomma et al., 2010; Wong et al., 2017). The crystal structure has also confirmed that the F-box domain of AnkB interacts with the host SCF1 ubiquitin ligase, which explains show AnkB functions as a platform for the docking of polyubiquitinated proteins to the Legionella-containing vacuolar (LCV) membrane within macrophages and amoebae (Price et al., 2009; Lomma et al., 2010; Wong et al., 2017). The AnkB-assembled polyubiquitinated proteins are predominately Lys48-linked that are ultimately degraded by the host proteasome machinery, which generates higher levels of cellular amino acids that are the main sources of carbon and energy to power replication of L. pneumophila (Price et al., 2011). This enables intracellular bacteria to overcome host limitation of essential nutrients and favorable sources of carbon and energy, such as amino acids (Price et al., 2011; Abu Kwaik and Bumann, 2013).
  
  

  • ( Tässä johdetaan solussa  hajoitettavaksi tuomitut eli K48 polyubikitinoidut jäteproteiinit LCV vakuoliin, jossa  Legionella käyttää niiden aineksen  replikaatioon tarvittavana ravintona- asiaa ei  solu varmaan pysty "huomaamaan").

  
  Here we show that 11 L. pneumophila type IVB-translocated effectors including, AnkB and AnkH, harbor the recognition motif for FIH-dependent asparaginyl-hydroxylation. Furthermore, the FIH recognition motif is found in translocated effectors from other intracellular microbial pathogens including YopM from Yersinia pestis, IpaH4.5 of Shigella flexneri and a putative translocated ARD-protein of Rickettsia felis. We show that the AnkH and AnkB effectors are modified by asparaginyl hydroxylation. The LCV recruits FIH, which is indispensable for intra-vacuolar proliferation of L. pneumophila and plays a partial role in the ability of the LCV to evade lysosomal fusion and is needed for AnkB-dependent assembly of polyubiquitinated proteins on the LCV. This is the first example of an injected microbial effectors post-translationally modified by asparaginyl hydroxylation.
  
  

  Acquisition of FIH, Mint3, and MT1-MMP by the LCV

  The AnkB effector is localized to the LCV membrane through host-mediated farnesylation (Price et al., 2010b). In addition, the effectors LepB, SdeC, and SdcA which are potential candidates for FIH-mediated asparaginyl hydroxylation are also LCV-localized (Chen et al., 2004, 2007; Luo and Isberg, 2004; Bardill et al., 2005; Ingmundson et al., 2007; Tan et al., 2011). Since FIH is a cytosolic enzyme that can be sequestered to membranous structures such as the Golgi apparatus through interaction with Mint3 and MT1-MMP in macrophages (Sakamoto and Seiki, 2009, 2010) and the LCV intercepts ER-Golgi vesicular traffic (Isberg et al., 2009; Al-Quadan et al., 2012; Price et al., 2014), we determined if FIH and its two interacting partners (Mint3 and MT1-MMP) were recruited to the LCV within hMDMs. 

  The data showed that by 2 h of infection, 75, 65, and 56% of the LCVs harboring wild type bacteria co-localized with FIH, Mint3, and MT1-MMP, respectively (Figures 2A–D). In contrast, only 27, 18.2, and 0% of the LCVs harboring the dotA translocation-deficient mutant co-localized with FIH, Mint3, and MT1-MMP, respectively (Figures 2A–D) and this was significantly reduced relative to co-localization observed for wild type LCVs (unpaired t-test, p < 0.01). This indicates recruitment of these proteins to the LCV is dependent on the Dot/Icm T4SS apparatus.

  
  

  •  Jotta tämä F1H funktio saataisiin pyydystettyä LCV vakuoleihin,   legionella  T5SS systeemin on rekrytoitava myös Mint3 ja MT1-MMP, koska F1H on sytosolinen  entsyymi ja  näiden toisten tekijöiden avulla se saadaan saostumaan kalvoihin kuten ER-Golgi, jolloin  se on legionellan tarpeisiin saatavissa ja sijoitettavissa LCV vakuoleihin.
  • 
    

  ---- Some citates from the article : 
  AnkB plays a central role for L. pneumophila by promoting the degradation of polyubiquitinated proteins which allows this organism to access essential amino acids that are used for both energy and a carbon source (Price et al., 2009, 2011). Substitution of the three hydroxylated asparagine residues significantly impacts the ability of AnkB to recruit polyubiquitinated proteins to the LCV and concomitantly fails to restore intra-vacuolar replication of an ankB mutant strain of L. pneumophila.
  -----
  Furthermore, blocking host FIH activity results in a similar phenotype to the AnkB substitutions, and taken together suggests that asparaginyl hydroxylation of AnkB contributes to the function of this effector.
   Blocking FIH activity results in a dose-dependent inhibition of intra-vacuolar replication of L. pneumophila. Interestingly however, only ~55% of LCVs trafficked to a lysosomal compartment, indicating that the FIH-mediated block in intra-vacuolar replication of L. pneumophila has both lysosomal evasion-independent and -dependent mechanisms.

  -----
  Both AnkB and AnkH are needed for intra-vacuolar proliferation of L. pneumophila but neither impacts the normal trafficking and biogenesis of the LCV (Al-Khodor et al., 2008; Habyarimana et al., 2008, 2010; Price et al., 2009, 2010a,b, 2011; Lomma et al., 2010).
  ------
   The lysosomal evasion-dependent mechanism may involve both injected effectors, though no single injected effector to date has been shown to be required for the ability of the LCV to evade the lysosomes (de Felipe et al., 2008; Isberg et al., 2009; Zhu et al., 2011).
  -----
  Mint3
    In macrophages, membrane-associated FIH is inactive, at least in terms of HIF1 hydroxylation activity, but through its binding to Mint3 it enables HIF1 to promote transcription of glycolytic genes that are needed by the macrophage to generate ATP (Sakamoto and Seiki, 2009, 2010).
   ------
   L. pneumophila uses host amino acids as the primary source of carbon and energy by AnkB-dependent proteasomal degradation, but exogenous pyruvate alone can compensate for proteasomal degradation to enable intra-vacuolar replication of L. pneumophila (Price et al., 2011). This indicates that host pyruvate is an additional metabolite scavenged by intra-vacuolar L. pneumophila. Therefore, a consequence of FIH recruitment to the LCV may be increased HIF1 activity, which will ultimately increase availability of pyruvate that the bacteria can scavenge from the intracellular environment to use as an energy source and building block of macromolecules.
   ---
  
  

  Original Research ARTICLE

  Front. Cell. Infect. Microbiol., 06 March 2017 | https://doi.org/10.3389/fcimb.2017.00054

  
  

Ruotsin Kolmården Tropicarium esittää myös mamboja

http://www.tropicarium.se/visa_djur/?id=189
Jos mamboja on eläintarhasas, lie lähistössä (Tukholmasssa)  aina saatavilla  vastaseerumia mahdollisille  käärmeenpuremille, joita voi työtapaturmana tulla, arvelen.  

Katsauksia mamban pureman biologiasta ja hoidosta

 1996
https://www.wemjournal.org/article/S1080-6032(96)71002-5/pdf

2017 Sveitsi,  A case report
https://www.hindawi.com/journals/cricc/2017/5021924/
 Abstract

Mambas (genus Dendroaspis) are among the most feared venomous African snakes. Without medical treatment, mamba bites are frequently fatal. First-aid treatment includes lymphatic retardation with the pressure immobilization technique. Medical management comprises continuous monitoring, securing patency of the airway, ensuring adequate ventilation, symptomatic measures, and administration of specific antivenin. We report an unusual case of a snake breeder bitten by a black mamba in Switzerland, report the clinical course, and review the lifesaving emergency management of mamba bites. This case highlights the importance of early antivenin administration and suggests that emergency and critical care physicians as well as first responders all around the world should be familiar with clinical toxinology of exotic snake bites as well as with the logistics to most rapidly make the specific antivenin available.

“The snake bites the tamer first.”
Romanian Proverb.
 1. Introduction

Dendroaspis polylepis (black mamba) is one of the most dangerous snakes worldwide. Without medical treatment, mamba bites are frequently fatal [1]. As mamba bites are rare in Europe [2–5] treatment can be challenging, particularly if rapid administration of antivenin fails [6]. We report the case of a Swiss snake breeder who was bitten by a black mamba, report the typical clinical course, and review the management of neurotoxic snake bites.
2. Case Presentation

Written informed consent for publication was obtained from the patient.

While feeding a 5-year-old male black mamba, a 34-year-old snake breeder suddenly noticed a tiny bloody mark on his forearm and, at the same time, a slight tingling of his lips. He immediately realized that he had been bitten and called a befriended snake expert to seek advice. The patient was thus able to provide the first responders with detailed information about the snake and on where to obtain the corresponding antivenin. He instructed his wife to apply a pressure bandage to the forearm. Within the next five minutes, chest tightness, generalized paresthesia, and fasciculation occurred. Upon arrival of the ambulance, the patient was unable to walk, was tachypneic, and had prominent dysarthria. Assuming a concomitant allergic reaction, the paramedics administered methylprednisolone, clemastine, and adrenaline before transferring the patient to the nearest hospital. In the meantime, the Swiss helicopter ambulance collected the antivenin from one of the 8 national antivenin depots.

Forty minutes after the bite, the patient arrived in the emergency department, complaining of worsening fasciculations and paresthesia affecting the extremities and the face. On physical examination, he was fully conscious with a heart rate of 105/min and a blood pressure of 165/80 mmHg. He was tachypneic at 30/min. Pulse oximetry revealed an oxygen saturation of 95% on room air. There were two tiny puncture wounds with local swelling and redness on the left forearm. Motor function was normal, except for mild ptosis. Seventy minutes after the bite, the patient was given 2 vials (20 ml) of “SAMIR Polyvalent Snake Antivenin” together with 2.5 mg of IV midazolam for ongoing hyperventilation. Thereafter, the patient was transferred to our tertiary intensive care unit for further treatment.

Upon arrival in our ICU, the patient was hemodynamically stable but still tachycardic and tachypneic. Fasciculations, dysarthria, and ptosis had slightly improved. ECG showed a grade 1 atrioventricular block without any other abnormalities. Initial laboratory tests were unremarkable, apart from moderate respiratory alkalosis. Over the next few hours, sweating, chills, and difficulty with swallowing as well as nausea occurred. However, the airway was never compromised, coughing reflex was intact, and respiratory failure did not occur. Therefore, and because of initial concerns about a possible allergic reaction, we decided against further antivenin administration. On the next day, symptoms of envenomation had improved, but the patient developed cellulitis of the bitten forearm and rhabdomyolysis, with a peak serum creatine kinase level of 16,049 U/L. Upon treatment with intravenous fluids and amoxicillin/sulbactam, his condition gradually improved. After four days in the hospital, he was discharged home with muscular pain as the only residual symptom. A few weeks later, the patient had fully recovered.
3. Discussion

Snake bites by Dendroaspis are rare in Europe. In 1987 Markwalder and Koller [2] described two cases of bites by Dendroaspis viridis (the green mamba). In France, one victim survived a green mamba bite although administration of antivenin failed [6]. Bites by black mambas have been reported in Germany [3] and in the Czech Republic [4]. To our knowledge, our case is the third registered black mamba bite in Switzerland and the first to be published.

The venom of black mambas is highly neurotoxic and contains a combination of α-neurotoxins, which induce postsynaptic blockade of the neuromuscular junctions, and dendrotoxins, which inhibit the voltage-dependent potassium channels, enhancing the release of acetylcholine at the neuromuscular junction, thus producing a neuromuscular block similar to a depolarizing block [7, 8]. In contrast, fasciculins act as acetylcholinesterase inhibitors, thus increasing the availability of acetylcholine at the neuromuscular junction and producing generalized, long-lasting fasciculations [9]. Calciseptine, another venom component, inhibits smooth muscle contraction and cardiac function by blocking L-type calcium channels [10]. The venom does not usually cause tissue destruction and necrosis [11, 12] as it lacks significant protease activity [13], although it does contain low percentages of other proteins, such as metalloproteinases (MMPs) , hyaluronidase, prokineticin, nerve growth factor (NGF), vascular endothelial growth factor (VEGF), phospholipase A2 (PLA2) , 5′-nucleotidase, and phosphodiesterase (PDE) [7].

After a mamba bite, symptoms can occur as quickly as within 10 minutes [13]. A tingling sensation at the site of the bite may be the only initial sign of envenomation [14]. Other neurological symptoms include miosis, ptosis, blurred vision, bulbar symptoms, paresthesia, fasciculations, ataxia, and loss of consciousness. General signs of envenomation may include local pain, nausea, cough, and profuse sweating from asympthetic overstimulation. In severe cases, intubation, mechanical ventilation, and circulatory support may be necessary [4].

First-aid management includes reassuring the patient, removing constricting jewelry, and lymphatic retardation with pressure immobilization technique. Multiple bites are common, as mambas can strike repeatedly. A bandage is wrapped starting proximal to the bite site, just above the fingers or toes, and should cover the entire limb. Subsequent immobilization by a splint is recommended [15]. The bandage is not removed until administration of antivenin [16]. A tourniquet is not recommended.

The cornerstone of medical management is ensuring patent airway and adequate ventilation, providing circulatory support when necessary, and intravenous administration of specific antivenin [17]. Antivenin treatment should be considered whenever mamba envenomation is diagnosed by the presence of the systemic or neurological signs described above. Absence of fang marks does not preclude envenomation. On the other hand, presence of fang (myrkkyhammas) marks does not confirm it, since dry bites may occur. The recommended initial dose of SAIMR polyvalent antiserum is 20 ml (2 vials) [18]. Additional antivenin (up to five times the initial dose) should be titrated against the signs and symptoms of envenomation. Antivenin treatment is effective even when neurotoxic effects have become quite pronounced [19]. Therefore, there is no upper time limit for antivenin administration [20].

Antivenin therapy is not without risks. IgE-mediated allergic reactions including frank anaphylaxis can occur either to the antivenin or to the venom itself [21]. Delayed reactions (within 6–21 days after exposure) do occur, such as urticaria and serum sickness disease [22]. However, given the poor prognosis of an untreated mamba bite, even an anaphylactic response does not represent a contraindication to antivenin administration. In such cases, antivenin infusion should be temporarily discontinued and the patient should be stabilized before the antivenin infusion is resumed at a slower rate. An intravenous test dose of 1 ml diluted in 9 ml normal saline may be used in patients at high risk of allergic reactions. Limited evidence supports the use of prophylactic epinephrine prior to the administration of antivenins [23, 24]. There is no evidence for pretreatment with either antihistamines or corticosteroids [25, 26].

In our patient, fasciculation, muscle contractions, bulbar paralysis, and rhabdomyolysis were the main clinical symptoms. Respiratory failure did not occur for three possible reasons. First reason is the patient’s immediate recognition of the bite and exemplary first-aid response, including pressure bandage and physical rest. Second, although the venom metering hypothesis is controversial [27] the amount of venom injected was probably submaximal as the bite was most likely defensive. Third, the rapid availability of antivenin prevented further deterioration, especially respiratory failure. However, the clinical course probably would have been more severe, if the patient himself had not reacted so swiftly. Our report highlights the importance of early antivenin administration. Emergency and critical care physicians as well as first responders around the world should, therefore, be familiar with clinical toxinology of snake bites and with the logistics to most rapidly make the specific antivenin available.
Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.
References

P. A. Christensen, “Snakebite and the use of antivenom in southern Africa,” South African medical journal, vol. 59, no. 26, pp. 934–938, 1981. View at Google Scholar


    K. Markwalder and M. Koller, “Mamba bites. 2 case reports and observations on the therapy of neurotoxic poisonous snake bites,” Schweizerische Rundschau fur Medizin Praxis, vol. 76, no. 46, pp. 1281–1284, 1987. View at Google Scholar
    M. Schutzbach, S. Vonderhagen, and M. Jäger, “Antivenom therapy after a black mamba snakebite,” Unfallchirurg, vol. 119, no. 12, pp. 1053–1056, 2016. View at Publisher · View at Google Scholar · View at Scopus
    J. Závada, J. Valenta, O. Kopecký, Z. Stach, and P. Leden, “Black mamba dendroaspis polylepis bite: a case report,” Prague Medical Report, vol. 112, no. 4, pp. 298–304, 2011. View at Google Scholar · View at Scopus
    M. Stadelmann, M. Ionescu, M. Chilcott, J.-L. Berney, and L. Gétaz, “Exotic snake bites in Switzerland,” Revue Medicale Suisse, vol. 6, no. 248, pp. 969–972, 2010. View at Google Scholar · View at Scopus
    T. Leclerc, B. Debien, J.-P. Perez, M.-P. Petit, and B. Lenoir, “Mamba envenomation in mainland France: management of exotic envenomations needs rethinking,” Annales Francaises d'Anesthesie et de Reanimation, vol. 27, no. 4, pp. 323–325, 2008. View at Publisher · View at Google Scholar · View at Scopus
    A. H. Laustsen, B. Lomonte, B. Lohse, J. Fernández, and J. M. Gutiérrez, “Unveiling the nature of black mamba (Dendroaspis polylepis) venom through venomics and antivenom immunoprofiling: identification of key toxin targets for antivenom development,” Journal of Proteomics, vol. 119, pp. 126–142, 2015. View at Publisher · View at Google Scholar · View at Scopus
    D. Petras, P. Heiss, R. A. Harrison, R. D. Süssmuth, and J. J. Calvete, “Top-down venomics of the East African green mamba, Dendroaspis angusticeps, and the black mamba, Dendroaspis polylepis, highlight the complexity of their toxin arsenals,” Journal of Proteomics, vol. 146, pp. 148–164, 2016. View at Publisher · View at Google Scholar · View at Scopus
    U. K. Ranawaka, D. G. Lalloo, H. J. de Silva, and J. White, “Neurotoxicity in snakebite—the limits of our knowledge,” PLoS Neglected Tropical Diseases, vol. 7, no. 10, Article ID e2302, 2013. View at Publisher · View at Google Scholar
    J. R. De Weille, H. Schweitz, P. Maes, A. Tartar, and M. Lazdunski, “Calciseptine, a peptide isolated from black mamba venom, is a specific blocker of the L-type calcium channel,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 6, pp. 2437–2440, 1991. View at Publisher · View at Google Scholar · View at Scopus
    R. Hilligan, “Black mamba bites: report of 2 cases,” South African Medical Journal, vol. 72, no. 3, pp. 220-221, 1987. View at Google Scholar · View at Scopus
    H. M. Strover, “Report on a death from black mamba bite (Dendroaspis polylepis),” Central African Journal of Medicine, vol. 13, no. 8, pp. 185-186, 1967. View at Google Scholar · View at Scopus
    N.-H. Tan, A. Arunmozhiarasi, and G. Ponnudurai, “A comparative study of the biological properties of Dendroaspis (mamba) snake venoms,” Comparative Biochemistry and Physiology. Part C, Comparative, vol. 99, no. 3, pp. 463–466, 1991. View at Publisher · View at Google Scholar · View at Scopus
    Chapman D. S., “The symptomatology, pathology, and treatment of the bites of venomous snakes of central and southern Africa,” in Venomous Animals and their Venoms, pp. 463–527, Academic Press, New York, NY, USA, 1968. View at Google Scholar
    S. K. Sutherland, Australian Animal Toxins, Oxford University Press, Melbourne, Australia, 1983.
    P. S. Hodgson and T. M. Davidson, “Biology and treatment of the mamba snakebite,” Wilderness and Environmental Medicine, vol. 7, no. 2, pp. 133–145, 1996. View at Publisher · View at Google Scholar · View at Scopus
    WHO, Guidelines for the Prevention and Clinical Management of Snakebite in Africa, WHO, 2010, http://apps.who.int/iris/handle/10665/204458.
    N. F. Moran, W. J. Newman, R. G. Theakston, D. A. Warrell, and D. Wilkinson, “High incidence of early anaphylactoid reaction to SAIMR polyvalent snake antivenom,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 92, no. 1, pp. 69-70, 1998. View at Publisher · View at Google Scholar
    S. K. Sutherland, “Antivenoms: better late than never,” Medical Journal of Australia, vol. 2, no. 24, p. 813, 1977. View at Google Scholar · View at Scopus
    S. Dwivedi, S. Sheshadri, and C. D'Souza, “Time limit for anti-snake venom administration,” The Lancet, vol. 334, no. 8663, p. 622, 1989. View at Publisher · View at Google Scholar · View at Scopus
    P. Malasit, D. A. Warrell, P. Chanthavanich et al., “Prediction, prevention, and mechanism of early (anaphylactic) antivenom reactions in victims of snake bites,” British Medical Journal, vol. 292, no. 6512, pp. 17–20, 1986. View at Publisher · View at Google Scholar · View at Scopus
    J. E. Erffmeyer, “Serum sickness,” Annals of Allergy, vol. 56, no. 2, pp. 105–110, 1986. View at Google Scholar · View at Scopus
    J. Tibballs, “Premedication for snake antivenom,” Medical Journal of Australia, vol. 160, no. 1, pp. 4–7, 1994. View at Google Scholar · View at Scopus
    A. P. Premawardhena, C. E. De Silva, M. M. D. Fonseka, S. B. Gunatilake, and H. J. De Silva, “Low dose subcutaneous adrenaline to prevent acute adverse reactions to antivenom serum in people bitten by snakes: randomised, placebo controlled trial,” British Medical Journal, vol. 318, no. 7190, pp. 1041–1043, 1999. View at Publisher · View at Google Scholar · View at Scopus
    H. W. Fan, L. F. Marcopito, J. L. C. Cardoso et al., “Sequential randomised and double blind trial of promethazine prophylaxis against early anaphylactic reactions to antivenom for bothrops snake bites,” British Medical Journal, vol. 318, no. 7196, pp. 1451–1453, 1999. View at Publisher · View at Google Scholar · View at Scopus
    I. B. Gawarammana, S. A. Kularatne, W. P. Dissanayake, R. P. V. Kumarasiri, N. Senanayake, and H. Ariyasena, “Parallel infusion of hydrocortisone ± chlorpheniramine bolus injection to prevent acute adverse reactions to antivenom for snakebites: a randomised, double-blind, placebo-controlled study,” Medical Journal of Australia, vol. 180, no. 1, pp. 20–23, 2004. View at Google Scholar · View at Scopus

B. A. Young, C. E. Lee, and K. M. Daley, “Do snakes meter venom?” BioScience, vol. 52, no. 12, pp. 1121–1126, 2002. View at Publisher · View at Google Scholar · View at Scopus

 

Vihreä tai musta mamba purrut Landvetterissä miestä

Vastamyrkkyä ei Sahlgrensskassa juuri tätä kärmelajia kothaan, joten  sitä kiikutettiin Tukholmasta.
Green mamba venom
PubMed

Best matches for Green mamba venom:

Peptides with in vitro anti-tumor activity from the venom of the Eastern green mamba, Dendroaspis angusticeps (Elapidae). Conlon JM et al. J Venom Res. (2014)

Top-down venomics of the East African green mamba, Dendroaspis angusticeps, and the black mamba, Dendroaspis polylepis, highlight the complexity of their toxin arsenals. Petras D et al. J Proteomics. (2016)

Crystallization of recombinant green mamba ρ-Da1a toxin during a lyophilization procedure and its structure determination. Maïga A et al. Acta Crystallogr Sect F Struct Biol Cryst Commun. (2013)

Search results

Items: 1 to 20 of 312

<< First< Prev

Page of 16

Next >Last >>

Select item 299905301.

Rapid ligand fishing for identification of acetylcholinesterase-binding peptides in snake venom reveals new properties of dendrotoxins.

Vanzolini KL, Ainsworth S, Bruyneel B, Herzig V, Seraus MGL, Somsen GW, Casewell NR, Cass QB, Kool J.

Toxicon. 2018 Jul 7;152:1-8. doi: 10.1016/j.toxicon.2018.06.080. [Epub ahead of print]

PMID:

29990530

Free Article

Similar articles

Select item 296262992.

Short-chain consensus alpha-neurotoxin: a synthetic 60-mer peptide with generic traits and enhanced immunogenic properties.

de la Rosa G, Corrales-García LL, Rodriguez-Ruiz X, López-Vera E, Corzo G.

Amino Acids. 2018 Jul;50(7):885-895. doi: 10.1007/s00726-018-2556-0. Epub 2018 Apr 6.

PMID:

29626299

Similar articles

Select item 292686913.

Mambalgins, the Venom-origin Peptides as a Potentially Novel Group of Analgesics: Mini Review.

Brzezicki MA, Zakowicz PT.

CNS Neurol Disord Drug Targets. 2018;17(2):87-97. doi: 10.2174/1871527317666171221110419.

PMID:

29268691

Similar articles

Select item 291565864.

In-Depth Glyco-Peptidomics Approach Reveals Unexpected Diversity of Glycosylated Peptides and Atypical Post-Translational Modifications in Dendroaspis angusticeps Snake Venom.

Degueldre M, Echterbille J, Smargiasso N, Damblon C, Gouin C, Mourier G, Gilles N, De Pauw E, Quinton L.

Int J Mol Sci. 2017 Nov 18;18(11). pii: E2453. doi: 10.3390/ijms18112453.

PMID:

29156586

Free PMC Article

Similar articles

Select item 288870465.

Effect of amino acids near the RGD sequence on binding activities between αIIbβ3 integrin and fibrinogen in the presence of RGD-containing synthetic peptides from elegantin and angustatin.

Oyama E, Takahashi H, Ishii K.

Peptides. 2017 Oct;96:31-37. doi: 10.1016/j.peptides.2017.09.004. Epub 2017 Sep 5.

PMID:

28887046

Similar articles

Select item 288676636.

High-density peptide microarray exploration of the antibody response in a rabbit immunized with a neurotoxic venom fraction.

Engmark M, Jespersen MC, Lomonte B, Lund O, Laustsen AH.

Toxicon. 2017 Nov;138:151-158. doi: 10.1016/j.toxicon.2017.08.028. Epub 2017 Sep 1.

PMID:

28867663

Similar articles

Select item 288435327.

The medical threat of mamba envenoming in sub-Saharan Africa revealed by genus-wide analysis of venom composition, toxicity and antivenomics profiling of available antivenoms.

Ainsworth S, Petras D, Engmark M, Süssmuth RD, Whiteley G, Albulescu LO, Kazandjian TD, Wagstaff SC, Rowley P, Wüster W, Dorrestein PC, Arias AS, Gutiérrez JM, Harrison RA, Casewell NR, Calvete JJ.

J Proteomics. 2018 Feb 10;172:173-189. doi: 10.1016/j.jprot.2017.08.016. Epub 2017 Aug 24.

PMID:

28843532

Similar articles

Select item 288026478.

Pharmacological modulation of Acid-Sensing Ion Channels 1a and 3 by amiloride and 2-guanidine-4-methylquinazoline (GMQ).

Besson T, Lingueglia E, Salinas M.

Neuropharmacology. 2017 Oct;125:429-440. doi: 10.1016/j.neuropharm.2017.08.004. Epub 2017 Aug 9.

PMID:

28802647

Similar articles

Select item 286302899.

Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease.

Ciolek J, Reinfrank H, Quinton L, Viengchareun S, Stura EA, Vera L, Sigismeau S, Mouillac B, Orcel H, Peigneur S, Tytgat J, Droctové L, Beau F, Nevoux J, Lombès M, Mourier G, De Pauw E, Servent D, Mendre C, Witzgall R, Gilles N.

Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):7154-7159. doi: 10.1073/pnas.1620454114. Epub 2017 Jun 19.

PMID:

28630289

Free PMC Article

Similar articles

Select item 2789077510.

Expanding the neutralization scope of the EchiTAb-plus-ICP antivenom to include venoms of elapids from Southern Africa.

Sánchez A, Segura Á, Vargas M, Herrera M, Villalta M, Estrada R, Wu F, Litschka-Koen T, Perry MA, Alape-Girón A, León G.

Toxicon. 2017 Jan;125:59-64. doi: 10.1016/j.toxicon.2016.11.259. Epub 2016 Nov 24.

PMID:

27890775

Similar articles

Select item 2782413311.

High-throughput immuno-profiling of mamba (Dendroaspis) venom toxin epitopes using high-density peptide microarrays.

Engmark M, Andersen MR, Laustsen AH, Patel J, Sullivan E, de Masi F, Hansen CS, Kringelum JV, Lomonte B, Gutiérrez JM, Lund O.

Sci Rep. 2016 Nov 8;6:36629. doi: 10.1038/srep36629.

PMID:

27824133

Free PMC Article

Similar articles

Select item 2734055712.

Cenderitide: structural requirements for the creation of a novel dual particulate guanylyl cyclase receptor agonist with renal-enhancing in vivo and ex vivo actions.

Lee CY, Huntley BK, McCormick DJ, Ichiki T, Sangaralingham SJ, Lisy O, Burnett JC Jr.

Eur Heart J Cardiovasc Pharmacother. 2016 Apr;2(2):98-105. doi: 10.1093/ehjcvp/pvv040. Epub 2015 Dec 10.

PMID:

27340557

Free PMC Article

Similar articles

Select item 2731817613.

Top-down venomics of the East African green mamba, Dendroaspis angusticeps, and the black mamba, Dendroaspis polylepis, highlight the complexity of their toxin arsenals.

Petras D, Heiss P, Harrison RA, Süssmuth RD, Calvete JJ.

J Proteomics. 2016 Sep 2;146:148-64. doi: 10.1016/j.jprot.2016.06.018. Epub 2016 Jun 16.

PMID:

27318176

Similar articles

Select item 2704498314.

Discovery and characterisation of a novel toxin from Dendroaspis angusticeps, named Tx7335, that activates the potassium channel KcsA.

Rivera-Torres IO, Jin TB, Cadene M, Chait BT, Poget SF.

Sci Rep. 2016 Apr 5;6:23904. doi: 10.1038/srep23904.

PMID:

27044983

Free PMC Article

Similar articles

Select item 2687718415.

Toxicovenomics and antivenom profiling of the Eastern green mamba snake (Dendroaspis angusticeps).

Lauridsen LP, Laustsen AH, Lomonte B, Gutiérrez JM.

J Proteomics. 2016 Mar 16;136:248-61. doi: 10.1016/j.jprot.2016.02.003. Epub 2016 Feb 12.

PMID:

26877184

Similar articles

Select item 2673070916.

Development of Equine IgG Antivenoms against Major Snake Groups in Mozambique.

Guidolin FR, Caricati CP, Marcelino JR, da Silva WD.

PLoS Negl Trop Dis. 2016 Jan 5;10(1):e0004325. doi: 10.1371/journal.pntd.0004325. eCollection 2016 Jan.

PMID:

26730709

Free PMC Article

Similar articles

Select item 2668000117.

Mambalgin-1 Pain-relieving Peptide, Stepwise Solid-phase Synthesis, Crystal Structure, and Functional Domain for Acid-sensing Ion Channel 1a Inhibition.

Mourier G, Salinas M, Kessler P, Stura EA, Leblanc M, Tepshi L, Besson T, Diochot S, Baron A, Douguet D, Lingueglia E, Servent D.

J Biol Chem. 2016 Feb 5;291(6):2616-29. doi: 10.1074/jbc.M115.702373. Epub 2015 Dec 17.

PMID:

26680001

Free PMC Article

Similar articles

Select item 2649252718.

Analgesic effects of mambalgin peptide inhibitors of acid-sensing ion channels in inflammatory and neuropathic pain.

Diochot S, Alloui A, Rodrigues P, Dauvois M, Friend V, Aissouni Y, Eschalier A, Lingueglia E, Baron A.

Pain. 2016 Mar;157(3):552-9. doi: 10.1097/j.pain.0000000000000397.

PMID:

26492527

Similar articles

Select item 2631450919.

α-Dendrotoxin inhibits the ASIC current in dorsal root ganglion neurons from rat.

Báez A, Salceda E, Fló M, Graña M, Fernández C, Vega R, Soto E.

Neurosci Lett. 2015 Oct 8;606:42-7. doi: 10.1016/j.neulet.2015.08.034. Epub 2015 Aug 24.

PMID:

26314509

Similar articles

Select item 2630944420.

Snakes and snakebite envenoming in Northern Tanzania: a neglected tropical health problem.

Kipanyula MJ, Kimaro WH.

J Venom Anim Toxins Incl Trop Dis. 2015 Aug 26;21:32. doi: 10.1186/s40409-015-0033-8. eCollection 2015.

PMID:

26309444