Finding crossroads in marine mammal medicine and public health: An overview of research at the Navy...

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

Circle of Public Health…

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


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.

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?

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)

Large Cetaceans (whales)

• 19 pathogens• Not enough information to assess risk

Small Cetaceans: 40 pathogens

PathogenRaw Risk

ScoreRaw Confidence

ScoreWeighted Risk

ScoreMorbillivirus 11.7 3.5 10.3Parapoxvirus 11 3.8 10.6Brucella spp. 9.8 3.6 8.8Anisakis 9.2 3.5 7.9Calicivirus 9 3.7 8.2Herpesvirus 9 3.4 7.8Clostridium spp. 8.7 3.8 8.4Escherichia coli 8.3 3.5 7.4Papillomavirus 8.3 3.6 7.4Aspergillus spp. 7.6 3.6 6.6Vibrio spp. 7.5 3.8 7.1Candida spp. 7.4 3.8 6.9Cryptocooccus spp. 7.4 3.6 6.8Toxoplasma gondii 7.3 3.6 6.4Pseudomonas spp. 7.3 3.4 6Zygomyces 7.2 3.2 5.3

Otariids: 40 pathogens

PathogenRaw Risk

ScoreRaw Confidence

ScoreWeighted Risk

ScoreLeptospira interrogans 14 4 14Calicivirus 12 4 12Herpesvirus 12 3.6 11.3Parapoxvirus 12 3.6 11.3Pseudomonas spp. 11.5 3.5 10.3Toxoplasma gondii 10 3.8 9.1Klebsiella spp. 9.5 3.5 8.6Salmonella spp. 9.5 3.6 8.5Pasteurella spp. 9.5 3.5 8.3Clostridium spp. 9 3.5 8.5Mycobacterium spp. 8.5 2.9 6.5Escherichia coli 8 3.8 7.4Anopleura spp. 8 3.5 6.9Nasal mites 8 3.3 6.9Mycoplasma spp. 8 3 6.5Coccidiodes immitis 7.7 3.3 6.3

Phocids: 53 pathogens

PathogenRaw Risk

ScoreRaw Confidence

ScoreWeighted Risk

ScoreMorbillivirus 12 3.9 12Leptospira interrogans 11 3.9 10.9Toxoplasma gondii 9.3 3.6 8.1Rabies 9 3.5 8.1West Nile virus 8.8 3.5 8Salmonella spp. 8.8 3.5 7.8Streptococcus spp. 8.8 3.6 7.8Escherichia coli 8.5 3.6 7.8Influenzavirus A or B 8.5 3.4 7.4Clostridium spp. 8.5 3.3 6.8Pasteurella spp. 8.3 3.7 7.6Herpesvirus 8 3.6 7.4Mycoplasma spp 8 3.6 7.4Parapoxvirus 8 3.6 7.2Vibrio spp 8 3.2 6.5Sarcocystis spp. 7.8 3.4 6.3Brucella spp. 7.5 3.1 5.6

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

Talk Overview


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 32:572-580Colagross-Schoten et al. (2002) Diagnosis and seroprevalence of leptospirosis in California sea lions from coastal California J Wldlf Dis 38:7-17

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

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 3:729-738Sohn et al. (2003) Human neurobrucellosis with intracerebral granuloma caused by a marine mammal Brucella spp. Emerg Infect Dis 9.

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

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

Case Onset Histogram of Epizootic among Sea Lions and Dolphins: 04 JAN – 15 MAR 2010

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3

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11-Jan

18-Jan

25-Jan

1-Feb

8-Feb

15-Feb

22-Feb

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15-Mar

Num

ber o

f new

cas

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Illness onset date

Initial Recurrence

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

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

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

Recombination of CSLAstV3/Human AstV

100

66.6

33.3

0Boot

stra

p Su

ppor

t (%

)

1 369 739 1109 1479

Human Astrovirus 4 - California Sea Lion Astrovirus 3California Sea Lion Astrovirus 2 - California Sea Lion Astrovirus 3

Human Astrovirus 4 - California Sea Lion Astrovirus 2

Position in Alignment

Rivera et al .(2010) Characterization of phylogenetically diverse astroviruses of marine mammals J Gen Virol 91:166-173

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/

Talk Overview


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?

Talk Overview


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

Why Bottlenose Dolphins?

• Order = Cetacea, Family = Delphinidae• Diverged from terrestrial species 55 million years ago• Closest relatives = pigs, camels, ruminants (artiodactyl)

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 = 5.3CHIMPANZEE = 2.4

MOUSE = 0.5


‘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

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


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

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

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.

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.

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Low stone prevalence High stone prevalence

Mean urine citrate level (mg citrate/g creatinine)

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

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

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

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

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

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

Contact Us!

Stephanie Venn-Watson

Director, Clinical Research


[email protected]

www.nmmfoundation.org

Ph: 619-993-1440

mailto:[email protected]

Finding crossroads in marine mammal medicine and public health: An overview of research at the Navy...

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