How the Cobra Got Its Flesh-Eating Venom: Cytotoxicity as a Defensive Innovation and Its Co-Evolution with Hooding, Aposematic Marking, and Spitting
by
Nadya Panagides 1,†, Timothy N.W. Jackson 1,†, Maria P. Ikonomopoulou 2,3,†, 
Kevin Arbuckle 4,†
, Rudolf Pretzler 1,†, Daryl C. Yang 5,†, Syed A. Ali 1,6, Ivan Koludarov 1, James Dobson 1, Brittany Sanker 1, Angelique Asselin 1, Renan C. Santana 1, Iwan Hendrikx 1, Harold Van der Ploeg 7, Jeremie Tai-A-Pin 8, Romilly Van den Bergh 9, Harald M.I. Kerkkamp 10, Freek J. Vonk 9, Arno Naude 11, Morné A. Strydom 12,13, Louis Jacobsz 14, Nathan Dunstan 15, Marc Jaeger 16, Wayne C. Hodgson 5, John Miles 2,3,17,‡ and Bryan G. Fry 1,*,‡
Nadya Panagides 1,†, Timothy N.W. Jackson 1,†, Maria P. Ikonomopoulou 2,3,†, Kevin Arbuckle 4,†, Rudolf Pretzler 1,†, Daryl C. Yang 5,†, Syed A. Ali 1,6, Ivan Koludarov 1, James Dobson 1, Brittany Sanker 1, Angelique Asselin 1, Renan C. Santana 1, Iwan Hendrikx 1, Harold Van der Ploeg 7, Jeremie Tai-A-Pin 8, Romilly Van den Bergh 9, Harald M.I. Kerkkamp 10, Freek J. Vonk 9, Arno Naude 11, Morné A. Strydom 12,13, Louis Jacobsz 14, Nathan Dunstan 15, Marc Jaeger 16, Wayne C. Hodgson 5, John Miles 2,3,17,‡ and Bryan G. Fry 1,*,‡
1
Venom Evolution Lab, School of Biological Sciences, University of Queensland, St. Lucia, QLD 4072, Australia
2
QIMR Berghofer Institute of Medical Research, Herston, QLD 4049, Australia
3
School of Medicine, The University of Queensland, Herston, QLD 4002, Australia
4
Department of Biosciences, College of Science, Swansea University, Swansea SA2 8PP, UK
5
Monash Venom Group, Department of Pharmacology, Monash University, Clayton VIC 3800, Australia
6
HEJ Research Institute of Chemistry, International Centre for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi 75270, Pakistan
7
Working Group Adder Research Netherlands, RAVON, 6525 ED Nijmegen, The Netherlands
8
Working Group Venomous Bites Netherlands, RAVON, 6525 ED Nijmegen, The Netherlands
9
Naturalis Biodiversity Center, 2333 CR Leiden, The Netherlands
10
Institute of Biology Leiden (IBL), Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands
11
Snakebite Assist, Pretoria ZA-0001, South Africa
12
Department Pharmacology, University of Pretoria, Pretoria ZA-0001, South Africa
13
SYNEXUS Clinical Research SA Pty Ltd., Pretoria ZA-0001, South Africa
14
Zoology Department, University of Pretoria, Pretoria ZA-0001, South Africa
15
Venom Supplies, Tanunda, South Australia 5352, Australia
16
Planet Exotica, 5 Avenue des Fleurs de la Paix, 17204 Royan, France
17
Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4878, Australia
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
Joint-senior authors on this work.
Academic Editor: Stuart M. Brierley
Toxins 2017, 9(3), 103; https://doi.org/10.3390/toxins9030103
Received: 23 January 2017 / Revised: 19 February 2017 / Accepted: 5 March 2017 / Published: 13 March 2017
(This article belongs to the Special Issue Animal Venoms and Pain)
The cytotoxicity of the venom of 25 species of Old World elapid snake was tested and compared with the morphological and behavioural adaptations of hooding and spitting. We determined that, contrary to previous assumptions, the venoms of spitting species are not consistently more cytotoxic than those of closely related non-spitting species. While this correlation between spitting and non-spitting was found among African cobras, it was not present among Asian cobras. On the other hand, a consistent positive correlation was observed between cytotoxicity and utilisation of the defensive hooding display that cobras are famous for. Hooding and spitting are widely regarded as defensive adaptations, but it has hitherto been uncertain whether cytotoxicity serves a defensive purpose or is somehow useful in prey subjugation. The results of this study suggest that cytotoxicity evolved primarily as a defensive innovation and that it has co-evolved twice alongside hooding behavior: once in the Hemachatus + Naja and again independently in the king cobras (Ophiophagus). There was a significant increase of cytotoxicity in the Asian Naja linked to the evolution of bold aposematic hood markings, reinforcing the link between hooding and the evolution of defensive cytotoxic venoms. In parallel, lineages with increased cytotoxicity but lacking bold hood patterns evolved aposematic markers in the form of high contrast body banding. The results also indicate that, secondary to the evolution of venom rich in cytotoxins, spitting has evolved three times independently: once within the African Naja, once within the Asian Naja, and once in the Hemachatus genus. The evolution of cytotoxic venom thus appears to facilitate the evolution of defensive spitting behaviour. In contrast, a secondary loss of cytotoxicity and reduction of the hood occurred in the water cobra Naja annulata, which possesses streamlined neurotoxic venom similar to that of other aquatic elapid snakes (e.g., hydrophiine sea snakes). The results of this study make an important contribution to our growing understanding of the selection pressures shaping the evolution of snake venom and its constituent toxins. The data also aid in elucidating the relationship between these selection pressures and the medical impact of human snakebite in the developing world, as cytotoxic cobras cause considerable morbidity including loss-of-function injuries that result in economic and social burdens in the tropics of Asia and sub-Saharan Africa.
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Keywords:
cytotoxin; cobra; Hemachatus; Naja; Ophiophagus; Elapidae; evolution; antipredator defense
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MDPI and ACS Style
Panagides, N.; Jackson, T.N.; Ikonomopoulou, M.P.; Arbuckle, K.; Pretzler, R.; Yang, D.C.; Ali, S.A.; Koludarov, I.; Dobson, J.; Sanker, B.; Asselin, A.; Santana, R.C.; Hendrikx, I.; Van der Ploeg, H.; Tai-A-Pin, J.; Van den Bergh, R.; Kerkkamp, H.M.; Vonk, F.J.; Naude, A.; Strydom, M.A.; Jacobsz, L.; Dunstan, N.; Jaeger, M.; Hodgson, W.C.; Miles, J.; Fry, B.G. 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.
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