Cobra Venom: Comparison
View Latest Version
Please note this is a comparison between Version 1 by Bhargab Kalita and Version 2 by Beatrix Zheng.

Cobras (genus Naja) are widely distributed over Asia and Africa, and cobra envenomation is responsible for a large number of mortality and morbidity on these continents. Like other elapid venoms, cobra venoms are neurotoxic in nature; however, they also exhibit local cytotoxic effects at the envenomed site, and the extent of cytotoxicity may vary from species to species. Cobra venoms are predominated by the non-enzymatic three-finger toxin family which constitutes about 60-75% of the total venom. Cytotoxins (CTXs), an essential class of the non-enzymatic three-finger toxin family, are ubiquitously present in cobra venoms. These low-molecular-mass toxins, contributing to about 40 to 60% of the cobra venom proteome, play a significant role in cobra venom-induced toxicity, more prominently in dermonecrosis (local effects).

  • membrane perturbations
  • necrosis
  • cobra venom
  • antivenom neutralization

1. Epidemiology of Cobra Bites in the World

Snake envenoming is a devastating health issue that affects millions of individuals across the globe, particularly in the developing countries of tropical and subtropical regions. Global epidemiological data suggest 81,000–138,000 snakebite-associated deaths from 1.8–2.7 million cases of envenoming yearly, thereby highlighting the urgency of research into this neglected public health concern [1][2][1,2]. Moreover, region-wise distribution of snakebite data suggests most of the cases of snake envenoming are concentrated in the rural areas of South Asia, Southeast Asia, and East Sub-Saharan African countries [3].
The majority of the medically critical venomous species of snakes belong to the Viperidae (340 species), Elapidae (360 species), and Atractaspidae (69 species) families [4]. Accordingly, the World Health Organization (WHO) has recognized venomous snakes under categories 1 and 2 depending upon their distribution, venom lethality, and incidences of envenoming and deaths. Category 1 medically essential species are of the highest medical importance, and the WHO has recognized at least 109 species under this category. Furthermore, it has been observed that most medically relevant species are represented by only a few genera. For instance, about 25 Category 1 medically important snake species in Africa belong to only five genera—Naja, Dendroaspis, Echis, Bitis, and Cerastes [5].
Cobras, represented by the genus Naja (nāgá, meaning ‘snake’ in Sanskrit), belong to the Elapidae family of snakes, and most of their species are classified under Category 1 by the WHO. There are nearly 30 species of cobra (Naja) (Table 1) that are widely distributed in Africa and Asia [6][7][6,7], and they are responsible for a considerable number of snake envenoming cases on these continents. For various reasons, most global epidemiological studies have not discretely recorded the exact estimates of cobra envenoming in Africa and Asia. While neurotoxicity is one of the vital clinical manifestations to distinguish cobra envenomation, other elapid snakes, for example, mambas (Dendroaspis sp.), kraits (Bungarus sp.), or even some viperids, for example, berg adders (Bitis atropos) [8], and Russell’s vipers (Daboia russelii) from southern India and Sri Lanka [9][10][11] [9,10,11] have also been reported to inflict neurological disorders in patients. Therefore, identifying the inflicting species based solely on clinical manifestations might not always be accurate.
Table 1. Geographical distribution of different Naja species and their WHO medical importance category. Data presented in this table were retrieved from snakebite information and the data platform maintained by the World Health Organization (https://www.who.int/teams/control-of-neglected-tropical-diseases/snakebite-envenoming/snakebite-information-and-data-platform/overview#tab=tab_1). The data were accessed on 5 October 2022.
Snake Species Common Name Medical Importance/

Category		 Region of Distribution Number of Countries Human Population (2020) in This Species’ Range
N. anchietae Anchieta’s cobra Highest, Secondary Africa 6 19,008,230
N. annulata Banded water cobra Highest, Secondary Africa 10 114,642,902
N. annulifera Snouted cobra Highest Africa 8 70,731,878
N. ashei Ashe’s spitting cobra Highest Africa 6 32,513,269
N. atra Chinese cobra Highest Asia and Australasia 5 570,266,425
N. christyi Christy’s water cobra Secondary Africa 3 15,111,896
N. guineensis Black forest cobra Highest, Secondary Africa 7 55,106,930
N. haje Egyptian cobra Highest, Secondary Africa 21 443,884,351
N. kaouthia Monocled cobra, Thai cobra Highest, Secondary Asia 11 976,884,863
N. katiensis Mali cobra, West Africa brown spitting cobra Highest, Secondary Africa 12 123,542,818
N. mandalayensis Mandalay spitting cobra Highest Asia and Australasia 1 14,774,047
N. melanoleuca Black and white cobra, Forest cobra Highest, Secondary Africa 11 244,375,176
N. mossambica Mozambique spitting cobra Highest, Secondary Africa 10 130,049,980
N. naja Indian cobra, Spectacled cobra Highest, Secondary Asia and Australasia 5 1,656,817,409
N. nigricincta Western barred spitting cobra, Zebra cobra Highest, Secondary Africa 4 11,381,021
N. nigricollis Black-necked spitting cobra Highest, Secondary Africa 33 727,256,279
N. nivea Cape cobra Highest Africa 4 17,651,152
N. nubiae Nubian spitting cobra Secondary Africa 5 39,843,095
N. oxiana Central Asian cobra, Transcaspian cobra Highest, Secondary Asia and Australasia, Middle East 8 242,127,307
N. pallida Red spitting cobra Secondary Africa 6 59,847,176
N. peroescobari Sao Tome cobra Highest Africa 1 189,185
N. philippinesis Northern Philippine cobra Highest Asia and Australasia 1 592,982,107
N. sagittifera Andaman cobra Secondary Asia and Australasia 1 373,959
N. samarensis Southern Philippine cobra, Visayan cobra Highest Asia and Australasia 1 30,350,207
N. savannula West African banded cobra Highest, Secondary Africa 16 151,894,138
N. senegalensis Senegalese cobra Highest, Secondary Africa 13 84,781,768
N. siamensis Indochinese spitting cobra, Siamese spitting cobra Highest, Secondary Asia and Australasia 5 119,240,121
N. sputatrix Southern Indonesian spitting cobra Highest, Secondary Asia and Australasia 2 167,089,984
N. subfulva Brown forest cobra Highest, Secondary Africa 22 377,545,129
N. sumatrana Equatorial spitting cobra Highest, Secondary Asia and Australasia 6 124,654,470
Moreover, except for Australia, no other countries currently employ snake venom detection kits to identify the encountered snake species [12]. Therefore, keeping track of exact numbers of envenomation by a particular snake species becomes quite challenging to identify the inflicting species taxonomically. In addition, discrepancies in epidemiological data on snake envenomation, either due to the absence of a cohesive and systematic analysis of snakebite cases or because many envenomation cases, are not reported to hospitals, may not be ruled out [13]. Nevertheless, given the wide distribution of cobras and their lethal venoms, it is reasonable to believe that these elapids contribute significantly to the morbidity and mortality associated with snake envenomation in Africa and Asia. Furthermore, evidence from a few isolated studies from some Asian and African countries indicates that the frequency of cobra (genus Naja) envenomation largely varies between 8–30% of the total envenoming cases [14][15][16][17][18][14,15,16,17,18].
Compositionally, cobra venoms are predominated by low-molecular-mass (<20 kDa) enzymatic and non-enzymatic toxins (see Section 2 for details). In addition, among the non-enzymatic class, the three-finger toxin (3FTX) is the prominent protein (toxin) family that significantly contributes to cobra venom-induced pathophysiology and toxicity [10][19][20][21][22][23][24][25][26][10,19,20,21,22,23,24,25,26]. Notably, among the various sub-classes of 3FTXs, the proportion of cytotoxins (CTX) and post-synaptic neurotoxins (NTX) dictates the lethality of cobra venoms [24][27][24,27].
 

2. Composition of Cobra Venom: A Summary

Biochemical and pharmacological analyses of crude Naja venom and their purified toxins are crucial in highlighting the variation in venom composition owing to the different geographical locations of these species [28][29][28,29]. However, these conventional methods are not apt for the characterization of non-enzymatic proteins, and with cobra venoms being primarily dominated by non-enzymatic toxins, a comprehensive cobra venom composition has yet to be unraveled. Recent developments in mass spectrometry-based snake venom toxin profiling have enabled thorough analysis of cobra venom composition. Proteomic findings have suggested that cobra venoms are predominated by enzymatic phospholipase A2 (PLA2) (~13–15 kDa) and non-enzymatic 3FTXs (~6–9 kDa); together, they constitute about 90% of the total cobra venom. Other enzymatic proteins in cobra venoms include L-amino acid oxidase, serine proteases, metalloproteases, phosphodiesterases, 5′-nucleotidases, cholinesterases, phospholipase B, hyaluronidases, and aminopeptidases. In addition, the minor non-enzymatic classes of toxins in cobra venoms include Cobra venom factors, Kunitz-type serine protease inhibitors, nerve growth factors, cystatin, natriuretic peptides, cysteine-rich secretory proteins, ohanin-like proteins or vespryns, vascular endothelial growth factors, and C-type lectins or snaclecs (reviewed by [4][30][31][4,30,31]).
Notably, the proportion of cobra venom CTXs was found to vary dramatically across different Naja species; it was ~13% in Taiwanese N. kaouthia venom, while it constitutes ~73% of N. nigricollis venom (Figure 1). In general, venoms from African spitting cobras have a higher proportion of CTXs than the Asiatic cobra ones, indicating geographical variation in snake venom composition. Interestingly, while the abundance of neurotoxins corresponds well to the severity of neurotoxicity in envenomed patients, the extent of local tissue-damaging effects of cobra venom do not correlate well with the proportions of CTXs, thereby suggesting variable cytotoxicity of the toxin isoforms as well as a contribution by other cobra venom toxins that can inflict local effects on their own or in complex with CTXs [32].
 
Figure 1
Figure 1. Proteomics analyses determined the relative abundance of CTXs in cobra venoms from diverse geographical locations (Source Kalita et al [33]). The mean relative abundance of CTX in African cobra venoms (61.1 ± 12.6%) is significantly higher as compared to Asian cobra venoms (38.8 ± 17.2%); p-value = 0.001.

References

  1. Gutierrez, J.M.; Calvete, J.J.; Habib, A.G.; Harrison, R.A.; Williams, D.J.; Warrell, D.A. Snakebite envenoming. Nature Reviews. Disease Primers 2017, 3, 17079, doi:10.1038/nrdp.2017.79.
  2. Feola, A.; Marella, G.L.; Carfora, A.; Della Pietra, B.; Zangani, P.; Campobasso, C.P. Snakebite envenoming a challenging diagnosis for the forensic pathologist: A systematic review. Toxins 2020, 12, 699. doi:10.3390/toxins12110699.
  3. Kasturiratne, A.; Wickremasinghe, A.R.; de Silva, N.; Gunawardena, N.K.; Pathmeswaran, A.; Premaratna, R.; Savioli, L.; Lalloo, D.G.; de Silva, H.J. The global burden of snakebite: a literature analysis and modelling based on regional estimates of envenoming and deaths. PLoS Medicine 2008, 5, e218, doi:10.1371/journal.pmed.0050218.
  4. Tasoulis, T.; Isbister, G.K. A review and database of snake venom proteomes. Toxins 2017, 9, 290. doi:10.3390/toxins9090290.
  5. Organization, W.H. Snakebite envenoming: a strategy for prevention and control. 2019.
  6. Wallach, V.; Wuester, W.; Broadley, D.G. In praise of subgenera: taxonomic status of cobras of the genus Naja Laurenti (Serpentes: Elapidae). Zootaxa 2009, 2236, 26–36-26–36.
  7. Wuster, W. Taxonomic changes and toxinology: systematic revisions of the Asiatic cobras (Naja naja species complex). Toxicon 1996, 34, 399-406, doi:10.1016/0041-0101(95)00139-5.
  8. Warrell, D.A. Snake bite. Lancet 2010, 375, 77-88, doi:10.1016/S0140-6736(09)61754-2.
  9. Suchithra, N.; Pappachan, J.M.; Sujathan, P. Snakebite envenoming in Kerala, South India: clinical profile and factors involved in adverse outcomes. Emergency Medicine Journal 2008, 25, 200-204, doi:10.1136/emj.2007.051136.
  10. Tan, N.H.; Fung, S.Y.; Tan, K.Y.; Yap, M.K.; Gnanathasan, C.A.; Tan, C.H. Functional venomics of the Sri Lankan Russell's viper (Daboia russelii) and its toxinological correlations. Journal of Proteomics 2015, 128, 403-423, doi:10.1016/j.jprot.2015.08.017.
  11. Kalita, B.; Singh, S.; Patra, A.; Mukherjee, A.K. Quantitative proteomic analysis and antivenom study revealing that neurotoxic phospholipase A2 enzymes, the major toxin class of Russell's viper venom from southern India, shows the least immuno-recognition and neutralization by commercial polyvalent antivenom. International Journal of Biological Macromolecules 2018, 118, 375-385, doi:10.1016/j.ijbiomac.2018.06.083.
  12. Puzari, U.; Mukherjee, A.K. Recent developments in diagnostic tools and bioanalytical methods for analysis of snake venom: A critical review. Analytica Chimica Acta 2020, 1137, 208-224, doi:10.1016/j.aca.2020.07.054.
  13. Mukherjee, A.K.; Mackessy, S.P. Prevention and improvement of clinical management of snakebite in Southern Asian countries: A proposed road map. Toxicon 2021, 200, 140-152, doi:10.1016/j.toxicon.2021.07.008.
  14. Mao, Y.C.; Liu, P.Y.; Chiang, L.C.; Lai, C.S.; Lai, K.L.; Ho, C.H.; Wang, T.H.; Yang, C.C. Naja atra snakebite in Taiwan. Clinical Toxicology 2018, 56, 273-280, doi:10.1080/15563650.2017.1366502.
  15. Kularatne, S.A.; Budagoda, B.D.; Gawarammana, I.B.; Kularatne, W.K. Epidemiology, clinical profile and management issues of cobra (Naja naja) bites in Sri Lanka: first authenticated case series. Transactions of the Royal Society of Tropical Medicine and Hygiene 2009, 103, 924-930, doi:10.1016/j.trstmh.2009.04.002.
  16. Wang, W.; Chen, Q.F.; Yin, R.X.; Zhu, J.J.; Li, Q.B.; Chang, H.H.; Wu, Y.B.; Michelson, E. Clinical features and treatment experience: a review of 292 Chinese cobra snakebites. Environmental Toxicology and Pharmacology 2014, 37, 648-655, doi:10.1016/j.etap.2013.12.018.
  17. Bawaskar, H.S.; Bawaskar, P.H. Envenoming by the common krait (Bungarus caeruleus) and Asian cobra (Naja naja): clinical manifestations and their management in a rural setting. Wilderness & Environmental Medicine 2004, 15, 257-266.
  18. Faiz, M.A.; Ahsan, M.F.; Ghose, A.; Rahman, M.R.; Amin, R.; Hossain, M.; Tareq, M.N.U.; Jalil, M.A.; Kuch, U.; Theakston, R.D.G.; et al. Bites by the Monocled Cobra, Naja kaouthia, in Chittagong Division, Bangladesh: Epidemiology, clinical features of envenoming and management of 70 identified cases. The American Journal of Tropical Medicine and Hygiene 2017, 96, 876-884, doi:10.4269/ajtmh.16-0842.
  19. Utkin, Y.N. Last decade update for three-finger toxins: Newly emerging structures and biological activities. World Journal of Biological Chemistry 2019, 10, 17-27, doi:10.4331/wjbc.v10.i1.17.
  20. Utkin, Y.N. Three-finger toxins, a deadly weapon of elapid venom--milestones of discovery. Toxicon 2013, 62, 50-55, doi:10.1016/j.toxicon.2012.09.007.
  21. Dutta, S.; Chanda, A.; Kalita, B.; Islam, T.; Patra, A.; Mukherjee, A.K. Proteomic analysis to unravel the complex venom proteome of eastern India Naja naja: Correlation of venom composition with its biochemical and pharmacological properties. Journal of Proteomics 2017, 156, 29-39, doi:10.1016/j.jprot.2016.12.018.
  22. Chanda, A.; Kalita, B.; Patra, A.; Senevirathne, W.; Mukherjee, A.K. Proteomic analysis and antivenomics study of Western India Naja naja venom: correlation between venom composition and clinical manifestations of cobra bite in this region. Expert Review of Proteomics 2019, 16, 171-184, doi:10.1080/14789450.2019.1559735.
  23. Chanda, A.; Patra, A.; Kalita, B.; Mukherjee, A.K. Proteomics analysis to compare the venom composition between Naja naja and Naja kaouthia from the same geographical location of eastern India: Correlation with pathophysiology of envenomation and immunological cross-reactivity towards commercial polyantivenom. Expert Review of Proteomics 2018, 15, 949-961, doi:10.1080/14789450.2018.1538799.
  24. Chanda, A.; Mukherjee, A.K. Quantitative proteomics to reveal the composition of Southern India spectacled cobra (Naja naja) venom and its immunological cross-reactivity towards commercial antivenom. International Journal of Biological Macromolecules 2020, 160, 224-232, doi:10.1016/j.ijbiomac.2020.05.106.
  25. Petras, D.; Sanz, L.; Segura, A.; Herrera, M.; Villalta, M.; Solano, D.; Vargas, M.; Leon, G.; Warrell, D.A.; Theakston, R.D.; et al. Snake venomics of African spitting cobras: toxin composition and assessment of congeneric cross-reactivity of the pan-African EchiTAb-Plus-ICP antivenom by antivenomics and neutralization approaches. Journal of Proteome Research 2011, 10, 1266-1280, doi:10.1021/pr101040f.
  26. Kakati, H.; Patra, A.; Kalita, B.; Chanda, A.; Rapole, S.; Mukherjee, A.K. A comparison of two different analytical workflows to determine the venom proteome composition of Naja kaouthia from North-East India and immunological profiling of venom against commercial antivenoms. International Journal of Biological Macromolecules 2022, 208, 275-287, doi:10.1016/j.ijbiomac.2022.03.095.
  27. Tan, C.H.; Wong, K.Y.; Chong, H.P.; Tan, N.H.; Tan, K.Y. Proteomic insights into short neurotoxin-driven, highly neurotoxic venom of Philippine cobra (Naja philippinensis) and toxicity correlation of cobra envenomation in Asia. Journal of Proteomics 2019, 206, 103418.
  28. Mukherjee, A.K.; Maity, C.R. The composition of Naja naja venom samples from three districts of West Bengal, India. Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology 1998, 119, 621-627, doi:10.1016/s1095-6433(97)00475-3.
  29. Shashidharamurthy, R.; Jagadeesha, D.K.; Girish, K.S.; Kemparaju, K. Variations in biochemical and pharmacological properties of Indian cobra (Naja naja naja) venom due to geographical distribution. Molecular and Cellular Biochemistry 2002, 229, 93-101, doi:10.1023/a:1017972511272.
  30. Tasoulis, T.; Pukala, T.L.; Isbister, G.K. Investigating toxin diversity and abundance in snake venom proteomes. Frontiers in Pharmacology 2021, 12, 768015, doi:10.3389/fphar.2021.768015.
  31. Chanda, A.; Mukherjee, A.K. Mass spectrometric analysis to unravel the venom proteome composition of Indian snakes: opening new avenues in clinical research. Expert Review of Proteomics 2020, 17, 411-423, doi:10.1080/14789450.2020.1778471.
  32. Panagides, N.; Jackson, T.N.; Ikonomopoulou, M.P.; Arbuckle, K.; Pretzler, R.; Yang, D.C.; Ali, S.A.; Koludarov, I.; Dobson, J.; Sanker, B.; et al. How the cobra got its flesh-eating venom: Cytotoxicity as a defensive innovation and its co-evolution with hooding, aposematic marking, and spitting. Toxins 2017, 9, 103, doi:10.3390/toxins9030103.
  33. Kalita, B., Utkin, Y.N. and Mukherjee, A.K. Current Insights in the Mechanisms of Cobra Venom Cytotoxins and Their Complexes in Inducing Toxicity: Implications in Antivenom Therapy. Toxins 2022, 14(12), 839, doi:10.3390/toxins14120839
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
ScholarVision Creations
Feedback