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 (Tursiops truncatus) –California sea lions (Zalophus californianus) 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 Pathogen Raw Risk Score Raw Confidence Score Weighted Risk Score Morbillivirus11.73.510.3 Parapoxvirus113.810.6 Brucella spp.9.83.68.8 Anisakis9.23.57.9 Calicivirus93.78.2 Herpesvirus93.47.8 Clostridium spp.8.73.88.4 Escherichia coli8.33.57.4 Papillomavirus8.33.67.4 Aspergillus spp.7.63.66.6 Vibrio spp.7.53.87.1 Candida spp.7.43.86.9 Cryptocooccus spp.7.43.66.8 Toxoplasma gondii7.33.66.4 Pseudomonas spp.7.33.46 Zygomyces7.23.25.3

9. Otariids: 40 pathogens Pathogen Raw Risk Score Raw Confidence Score Weighted Risk Score Leptospira interrogans144 Calicivirus124 Herpesvirus123.611.3 Parapoxvirus123.611.3 Pseudomonas spp.11.53.510.3 Toxoplasma gondii103.89.1 Klebsiella spp.9.53.58.6 Salmonella spp.9.53.68.5 Pasteurella spp.9.53.58.3 Clostridium spp.93.58.5 Mycobacterium spp.8.52.96.5 Escherichia coli83.87.4 Anopleura spp.83.56.9 Nasal mites83.36.9 Mycoplasma spp.836.5 Coccidiodes immitis7.73.36.3

10. Phocids: 53 pathogens Pathogen Raw Risk Score Raw Confidence Score Weighted Risk Score Morbillivirus123.912 Leptospira interrogans113.910.9 Toxoplasma gondii9.33.68.1 Rabies93.58.1 West Nile virus8.83.58 Salmonella spp.8.83.57.8 Streptococcus spp.8.83.67.8 Escherichia coli8.53.67.8 Influenzavirus A or B8.53.47.4 Clostridium spp.8.53.36.8 Pasteurella spp.8.33.77.6 Herpesvirus83.67.4 Mycoplasma spp83.67.4 Parapoxvirus83.67.2 Vibrio spp83.26.5 Sarcocystis spp.7.83.46.3 Brucella spp.7.53.15.6

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: Cryptococcus spp. Rhabdovirus West Nile Virus Listeria monocytogenes Mycobacterium tuberculosis Salmonella spp. Shigella spp. Group B Streptococcus Vibrio cholera

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 1.Pathogens move readily from land to ocean, ocean to land 2.Marine mammals can be reservoirs for emerging disease 3.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. 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 Odd goings on: Relationships between humans and bottlenose dolphins *Craik et al. (1998) GLUT-1 mediation of rapid glucose transport in dolphin red blood cells. Am J Physiol 274:R112-R119. Encephalization Quotients (EQ) HUMAN = 7.4 BOTTLENOSE DOLPHIN = 5.3 CHIMPANZEE = 2.4 MOUSE = 0.5

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. 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 Odd goings on: Relationships between humans and bottlenose dolphins

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 normal high FISH MEAL SUGAR 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 urate nephrolithiasis in bottlenose dolphins (Tursiops truncatus), Dis Aqua Org In press Venn-Watson et al., Hypocitraturia in Atlantic bottlenose dolphins (Tursiops tiruncatus): Assessing a potential risk factor for urate nephrolithiasis. 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 Funding Agencies = $ Research and Public Health Institutions = expertise, laboratories, personnel Marine Mammal Institutions = animals, archived samples, data & personnel High quality, needs- driven outcomes at relatively low cost

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