25 MAY 2010 USPHS Annual Conference Stephanie Venn-Watson, DVM, MPH

1. Finding crossroads in marine mammal medicine and public health: An overview of research at the Navy Marine Mammal Program 25 MAY 2010 USPHS Annual Conference Stephanie Venn-Watson, DVM, MPH National Marine Mammal Foundation

2. Circle of Public Health…

3. Overview of Navy Marine Mammal Program • Space and Naval Warfare Systems Center Pacific • 50 year history • 100 animals • Bottlenose dolphins (Tursiopstruncatus) • California sea lions (Zalophuscalifornianus) • Serve the Fleet • Underwater object recovery • Swimmer detection • Mine detection • Broader national interests • Marine biosensors • Comparative medicine models

4. National Marine Mammal Foundation Mission: To improve marine mammal and human health through research; to serve our nation; and, by sharing our discoveries, to inspire creative thinking and a commitment to ocean conservation in future generations. Vision: To enrich life for marine mammals and humans through scientific innovation, education, and national and humanitarian service.

5. Talk Overview • What are the highest priority marine mammal pathogens? • Which pathogens are of the greatest interest to public health? • What is the state of marine mammal zoonosis education? • One Health…why marine mammals, why you?

6. Prioritizing Marine Mammal Pathogens • Risk scoring system conducted by subject matter experts (SME) • Likelihood of exposure + morbidity + mortality + epizootic • Confidence scores to characterize SME confidence in data • Highest possible risk rating = 12 • Marine mammal categories • Large cetaceans (whales) • Small cetaceans (dolphin, porpoise) • Otariids (sea lions) • Phocids (seals)

7. Large Cetaceans (whales) • 19 pathogens • Not enough information to assess risk

8. Small Cetaceans: 40 pathogens

9. Otariids: 40 pathogens

10. Phocids: 53 pathogens

11. Public Health Implications • 76 pathogens reported in marine mammals • At least 27 (36%) are zoonoses of high importance • 12 (16%) are reportable human diseases in U.S. • 20 (26%) are associated with emerging / re-emerging human diseases in U.S. • Both reportable and emerging human diseases: • Listeria monocytogenes • Mycobacterium tuberculosis • Salmonella spp. • Shigella spp. • Group B Streptococcus • Vibrio cholera • Cryptococcus spp. • Rhabdovirus • West Nile Virus

12. Talk Overview • What are the highest priority marine mammal pathogens? • Which pathogens are of the greatest interest to public health? • What is the state of marine mammal zoonosis education? • One Health…why marine mammals, why you?

13. Leptospira interrogans serovars • Mass mortality events among California sea lions along NW coast • Same serovars as those that infect humans (primarily pomona) • Renal failure, abortions • Adults,subadults > pups, juveniles • Seropositive prevalence highest during autumn months • Phasic epizootics: Every 3 years, latent > active infections Gulland et al. (1996) Leptospirosis in California sea lions stranded along the central California coast, 1981-1994 J Wldlf Dis 32:572-580 Colagross-Schoten et al. (2002) Diagnosis and seroprevalence of leptospirosis in California sea lions from coastal California J Wldlf Dis 38:7-17

14. Morbillivirus • Emerging paramyxovirus • Mass mortality events in phocids (seals) and bottlenose dolphins • U.S. East coast, Europe • Dolphin morbillivirus ≈ human measles; phocine distemper virus ≈ CDV • Infection > immune suppression > secondary infection • Encephalitis, pneumonia Hall (1995) Morbilliviruses in marine mammals. Trends in Microbiology 3:4-9

15. Brucella spp. • High, global seroprevalence among cetaceans and pinnipeds • Abortion, pulmonary abscess, vertebral osteomyelitis • Marine Brucella species isolated from brain lesions in two humans Cloeckaert et al. (2001) Classification of Brucella spp. Isolated from marine mammals... Microbes and Infection 3:729-738 Sohn et al. (2003) Human neurobrucellosis with intracerebral granuloma caused by a marine mammal Brucella spp. Emerg Infect Dis 9.

16. Cryptococcus gattii • Emerging pathogen • British Columbia – 45 lab-confirmed animal cases, 50 human cases • Six cetaceans (Dall’s porpoise, harbor porpoise) • Current spread southward along NW U.S. coast (Washington and Oregon State) Stephen et al. (2002) Multispecies outbreak of cryptococcosis on southern Vancouver Island, BC Can Vet J 43:792-794

17. Calicivirus / Norovirus • San Miguel sea lion virus, evidence of infection in humans • Novel norovirus, picobirnavirus, and Toxin A producing Clostridum difficile associated with event • Vomiting, diarrhea, and pharyngeal lesions • Sea lions (100% attack rate), dolphins (2), human trainers (8/30), trainers’ dogs (3) Smith et al. (1998) Calicivirus emergence from ocean reservoirs: zoonotic interspecies movements. Emerg Infect Dis 4:13-20

18. Toxoplasma gondii • High mortality among sea otters off California coast (52% seroprevalence among dead sea lions); also infects sea lions, dolphins, seals • Encephalitis, disseminated disease • Exposure may be due to mussel concentration of Toxoplasma oocysts from land runoff • Type X strain Conrad et al. (1998) Transmission of Toxoplasma: clues from the study of sea otters as sentinels of Toxoplasma gondii flow into the marine environment. Int J Parsitol 35:1155-1168

19. Emerging Pathogen? Coxiella burnetii • CDC select agent • Phocids in Pacific Northwest*, sea lion in San Diego** • Handler in NW with + titer • Investigation on hold due to sample handling concerns *POC=Stephen Raverty; **POC=Judy St. Leger

20. Human and sea lion virus recombination: Astrovirus • Evidence of recombination of sea lion and human astrovirus • Implications regarding ocean as potential for emerging infectious diseases in humans Rivera et al .(2010) Characterization of phylogenetically diverse astroviruses of marine mammals J Gen Virol 91:166-173

21. Zoonosis Survey of Marine Mammal Handlers & Vets • Anecdotal • Vesicles on hands following contact with sea lion vesicles caused by calicivirus (San Miguel sea lion virus) • Campylobacteriosis following contact with sea lions with Campy + diarrhea • Abdominal rashes, throat lesions, vomiting and diarrhea • MRSA (suspected human > animal transmission) • Overall risk is low • Biggest risk = animal bites • Most common lesions = skin lesions • Marine Brucella serosurvey = 0% positive www.vetmed.ucdavis.edu/whc/mmz/

22. Talk Overview • What are the highest priority marine mammal pathogens? • Which pathogens are of the greatest interest to public health? • What is the state of marine mammal zoonosis education? • One Health…why marine mammals, why you?

23. Marine Mammal Zoonoses Education & Outreach • Marine mammal handler with clinical signs or pregnant handler • Marine mammals with clinical signs • Physician • Says, ‘Marine mammals are no risk’ • No diagnostic testing • No communication with veterinarians • Need for formal guidance and materials for potential disease exposures • Need for more diagnostic testing of humans • Role of NASPHV for education and consultation? • Role of CDC for diagnostics?

24. Talk Overview • What are the highest priority marine mammal pathogens? • Which pathogens are of the greatest interest to public health? • What is the state of marine mammal zoonosis education? • One Health…why marine mammals, why you?

25. One Health • Pathogen surveillance among animals – agriculture, wildlife • Comparative medicine – rodents, pigs, dogs, natural models • Pathogens move readily from land to ocean, ocean to land • Marine mammals can be reservoirs for emerging disease • Marine mammals have evolved terrestrial mechanisms to live in the ocean

26. Why Bottlenose Dolphins? • Order = Cetacea, Family = Delphinidae • Diverged from terrestrial species 55 million years ago • Closest relatives = pigs, camels, ruminants (artiodactyl)

27. Odd goings on: Relationships between humans and bottlenose dolphins Of all other animal groups, only cetaceans and primates have: • Big brains with high blood glucose demands • Red blood cells among adults that are extremely permeable to glucose Encephalization Quotients (EQ) HUMAN = 7.4 BOTTLENOSE DOLPHIN = 5.3 CHIMPANZEE = 2.4 MOUSE = 0.5 *Craik et al. (1998) GLUT-1 mediation of rapid glucose transport in dolphin red blood cells. Am J Physiol 274:R112-R119.

28. Odd goings on: Relationships between humans and bottlenose dolphins ‘Remarkable functional similarity in the glucose transport properties of red blood cells from adult dolphins and humans…implies that the extraordinarily high glucose permeability of…[RBCs] from adult humans and apes….is not a quirk peculiar to the primate lineage’ – Craik et al., 1998

29. Odd goings on: Relationships between humans and bottlenose dolphins Infectious Diseases Lobomycosis (Lacazia loboi): Only two species ever known to have lobomycosis = bottlenose dolphins and humans Morbillivirus: Dolphin morbillivirus most closely related to human measles Papillomavirus: Concurrent, multiple species infections found only in two species = bottlenose dolphins and humans

30. Comparative Medicine: Type II Diabetes • Type II diabetes (adult-onset, insulin resistant) • Dolphins exhibit diabetes-like changes after overnight fasting, but revert back to non-diabetic-like state upon daily feeding • Potential for genetic fasting switch that turns diabetes on and off • Why? • Insulin resistance may be beneficial for large-brained mammals with high glucose demands and low carbohydrate intake • Normal in dolphins with fish diet • Pathologic in humans with high carbohydrate diet • Next steps – Partnership with Salk Institute, Kansas State University • Determine gene and protein-based mechanisms for glucose metabolism in dolphins • “Dolphinize” a mouse liver Venn-Watson and Ridgway (2007) Big Brains and Blood Glucose: Common Ground for Diabetes Mellitus in Humans and Healthy Dolphins. Comp Med 57:390-395

31. What happens when a dolphin eats sugar? Six healthy, adult dolphins were fed either 1-3L 10% dextrose with ionosol or 4.5-5.5 kg mackerel SUGAR MEAL normal high FISH MEAL

32. Comparative Medicine: Hemochromatosis • Hemochromatosis (iron overload) in dolphins associated with insulin resistance and hypertriglyceridemia • Hemochromatosis also associated with insulin resistance in humans • Johnson et al., 2009 Use of phlebotomy treatment in Atlantic bottlenose dolphins with iron overload. J Am Vet Med Assoc 235: 194-200 • Venn-Watson et al., 2008 Assessment of increased serum aminotransferases in a managed Atlantic bottlenose dolphin population. 44: 318-330. • Wrede et al. 2006. Association between serum ferritin and the insulin resistance syndrome in a representative population. Eur J Endocrin 154:333-340.

33. Comparative Medicine: Urate Nephrolithiasis • Pure urate nephrolithiasis (kidney stones) in dolphins • Associated with hypocitraturia • Hypocitraturia and pure urate nephrolithiasis associated with insulin resistance in humans • Venn-Watson et al., Clinical relevance of uratenephrolithiasis in bottlenose dolphins (Tursiopstruncatus), Dis Aqua Org In press • Venn-Watson et al., Hypocitraturia in Atlantic bottlenose dolphins (Tursiopstiruncatus): Assessing a potential risk factor for uratenephrolithiasis. In press • Sakhaee et al. 2002. Pathophysiologic basis for normouricosuric uric acid nephrolithiasis. Kidney Intern 62:971-979.

34. Comparative Medicine: Treating sleep disorders and improving vigilance • Dolphins have a small corpus callosum with little cross-talk • Can experience half-brain sleep • Enables rest while maintaining constant vigilance • Ridgway et al. (2009) Dolphins maintain cognitive performance during 72 to 120 hours of continuous auditory vigilance J Exp Biol 212:1519-1527

35. Comparative Medicine: Combating dehydration in a liquid desert • Dolphins have little access to fresh water • Have some urine concentration capability, but not like desert rat • How do they remain hydrated? Hypotheses: • Absorb water across skin • Drink seawater • Generate metabolic water

36. Comparative Medicine: Healing wounds in a microbial-rich environment • Wild marine mammals sustain remarkable injuries from shark bites, human interaction (propellers, nets, etc) • Many heal injuries in contaminated environments without medical intervention • Collaboration with Vet-Stem • Researching properties of regenerative/stem cells in adult adipose tissues Dr Ingrid Visser

37. California sea lions: domoic acid and epilepsy • Marine algae (Pseudonitzschia) produces domoic acid • Domoic acid toxicosis associated with mass mortalities in sea lions • Seizures, abortions • Early evidence that one exposure could lead to epilepsy • National Oceanographic and Atmospheric Administration

38. 5-Year Investment Strategy for Clinical Research: FY11-FY15 • Apply One Health approach: Target cross-disciplinary research that benefits the health of not only marine mammals, but that of other animal populations, including humans • Determine unique needs for aging bottlenose dolphins and sea lions: physiology of aging, preventing negative effects of aging, prolonging quality of life • Detect, treat, and prevent infectious and metabolic diseases: viral disease, gastric and respiratory microbiota, nephrolithiasis, hemochromatosis, metabolic syndrome, host response to disease, including immunology, genomics, proteomics, and metabolomics • Provide protection against disease: non-specific innate immune activation, use of off-label vaccines, adult adipose-derived regenerative cells, and probiotics

39. Building Bridges with USPHS High quality, needs-driven outcomes at relatively low cost Funding Agencies = $ Marine Mammal Institutions = animals, archived samples, data & personnel Research and Public Health Institutions = expertise, laboratories, personnel

40. Contact Us! Stephanie Venn-Watson Director, Clinical Research National Marine Mammal Foundation stephanie.venn-watson@nmmpfoundation.org www.nmmfoundation.org Ph: 619-993-1440