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NONHUMAN PRIMATE NONHUMAN PRIMATE PATHOLOGYPATHOLOGY

Srinivas S RaoSrinivas S RaoSrinivas S. Rao Srinivas S. Rao DVM, DVM, Ph.DPh.D, MBA, , MBA,

Diplomate ACVPDiplomate ACVP

srao1@mail.nih.govsrao1@mail.nih.gov

srinirao3@gmail.comsrinirao3@gmail.com

Acknowledgements Acknowledgements

Gross Photos/Histology Gross Photos/Histology ImagesImages: Gary Baskin, Anne : Gary Baskin, Anne LewisLewis

Rick J. Montali and Ira Rick J. Montali and Ira Baum for images,Baum for images,

Thank you to:

Baum for images, Baum for images, summaries, and referencessummaries, and references

Alyse Zajac and Patrick Alyse Zajac and Patrick GorresGorres

New Iberia and staffNew Iberia and staff Univ of MD and staffUniv of MD and staff Bioqual and StaffBioqual and Staff JHU and staffJHU and staff Tulane Primate CenterTulane Primate Center

Goals of this talkGoals of this talk

Present an overview of the ‘natural’ disease Present an overview of the ‘natural’ disease entities of NHPsentities of NHPs--specially Macaques spp.specially Macaques spp.

Discuss ‘most important’ disease entities in Discuss ‘most important’ disease entities in more detailmore detailmore detailmore detail

Discuss ‘not so important’ disease entities as Discuss ‘not so important’ disease entities as appropriateappropriate

Make a case that the disease processes in NHP Make a case that the disease processes in NHP are similar to other higher order mammalsare similar to other higher order mammals

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Now for the punch line(s)…Now for the punch line(s)… The response to an ‘insult’ in NHP is The response to an ‘insult’ in NHP is

almost exactly similar to those in other almost exactly similar to those in other higher order mammals…a granuloma is a higher order mammals…a granuloma is a granuloma is a granulomagranuloma is a granuloma

Beware of ‘unique’ anatomic features andBeware of ‘unique’ anatomic features and Beware of unique anatomic features and Beware of unique anatomic features and corresponding pathology. Eg., cheek pouch corresponding pathology. Eg., cheek pouch infection (airsacculitis) ; diverticulosis; infection (airsacculitis) ; diverticulosis;

If you are unable to get a Stromberg style If you are unable to get a Stromberg style “shoot from the hip” answer, go to your “shoot from the hip” answer, go to your basics…again, a granuloma is a ….basics…again, a granuloma is a ….

Now for the punch line(s) (cont.)…Now for the punch line(s) (cont.)…

Even if you don’t learn anything in the next 2 Even if you don’t learn anything in the next 2 hours, KNOW THE FOLLOWING:hours, KNOW THE FOLLOWING: Assure yourself of minimum protective conditions Assure yourself of minimum protective conditions

while doing a monkey necropsywhile doing a monkey necropsy Know “THE” B virusKnow “THE” B virus

Very high mortality rate in humans (80%)Very high mortality rate in humans (80%) Very high mortality rate in humans (80%)Very high mortality rate in humans (80%) Asymptomatic carriers can shed virusAsymptomatic carriers can shed virus

Know TBKnow TB Know SIV + opportunistic infections (especially Know SIV + opportunistic infections (especially

histopathhistopath); have Bruce’s’ “CAN diagnosis(); have Bruce’s’ “CAN diagnosis(eses)”)” Know the invading bugsKnow the invading bugs-- salsal, , shishi, , yeryer, , EntomebaEntomeba Know EndometriosisKnow Endometriosis Know BloatKnow Bloat KnowKnow--KnowKnow--Know Know -------- you get the idea!!!you get the idea!!!

CatarrhineCatarrhine (down(down--nosed) or nosed) or Old World MonkeysOld World Monkeysmacaque

Common chimpanzee

patas

baboonmandrill

Cercopithecus aethiops

langur

proboscis

colobus

aethiops Swamp monkey

gibbon orangutan

guenon

Vervet monkeybonobo

Leaf monkey

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PlatyrrhinePlatyrrhine (flat(flat--nosed) or nosed) or New World Monkeys New World Monkeys

Family Aotidaenight monkeys

Family Alouatta howler monkeys

Family: Ateles geoffroyi

Central American spider monkey

F il C lli b

Family Callithrix jacchus

white-tufted-ear marmoset

Family Callicebus molochdusky titi

Genus Cacajao (uakaris)

Family Leontopithecus rosalia

golden lion tamarin

Family Cebus capucinuscapuchin monkey

Family Saimiri sciureusSouth American squirrel monkey

Callithrix pygmaeapygmy marmoset

Genus Pithecia(saki monkeys)

BACTERIAL DISEASESBACTERIAL DISEASES Mycobacterium Mycobacterium

tuberculosis tuberculosis

Streptococcus Streptococcus pneumoniaepneumoniae

KlebsiellaKlebsiella pneumoniaepneumoniae

YersiniosisYersiniosis

SalmonellaSalmonella

CampylobacteriosisCampylobacteriosis

ListeriosisListeriosis

E h i hi liE h i hi liKlebsiellaKlebsiella pneumoniaepneumoniae Mycobacterium Mycobacterium

lepraemuriumlepraemurium Staphylococcus Staphylococcus aureusaureus ShigellosisShigellosis

Escherichia coliEscherichia coli BordetellaBordetella bronchisepticabronchiseptica ClostriduiumClostriduium tetanitetani

* Gram* Gram--positivepositive* Gram* Gram--negative negative

TuberculosisTuberculosisM. tuberculosis M. tuberculosis and and M. M. bovisbovis

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TB Slide – Human lung histology

Central necrosis

Langhans-type giant cells

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Hepatic Tuberculosis Hepatic Tuberculosis

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IMMUNODEFICIENCY-ASSOCIATED MYCOBACTERIOSIS

Mycobacterium avium paratuberculosis (Johne’s Disease)

Streptococcus pneumoniaeStreptococcus pneumoniae(Diplococcus pneumoniae, Pneumococcus pneumoniae(Diplococcus pneumoniae, Pneumococcus pneumoniae))

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Klebsiella pneumoniaeKlebsiella pneumoniae

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Leprosy Leprosy -- Hansen's diseaseHansen's diseaseMycobacterium Mycobacterium lepraeleprae

Staphylococcus Staphylococcus aureusaureus

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Bacterial Bacterial EnteritidiesEnteritidies SalmonellaSalmonella ShigellaShigella YersiniaYersinia CampylobacterCampylobacter E. ColiE. Coli EntamoebaEntamoeba histolyticahistolytica (parasite)(parasite)

ShigellosisShigellosisShigella flexneri Shigella flexneri Shigella sonneiShigella sonnei

Gram negative, aerobic, invasive

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YersiniosisYersiniosisYersinia pseudotuberculosis Yersinia enterocoliticaYersinia pseudotuberculosis Yersinia enterocolitica

*from squirrel monkey

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Affected

Normal

Yersiniosis Histopathology

Common histopathology:

•Leukocytosis

Yersinia colonies

Hepatic microabscess

Leukocytosis

•Hyponatremia

•Hypochloremia

•Prerenal azotemia

•hyperfibrinogenemia

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CampylobacteriosisCampylobacteriosisCampylobacter fetus ss. JejuniCampylobacter fetus ss. JejuniCampylobacter fetus ss. coliCampylobacter fetus ss. coli

ListeriosisListeriosisListeria monocytogenesListeria monocytogenes

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Escherichia coliEscherichia coli

•• ETEC: ETEC: EnterotoxigenicEnterotoxigenic E. coliE. coli AdhesinsAdhesins to bind to bind enterocytesenterocytes

ProteinaceousProteinaceous enterotoxinsenterotoxins –– LT and LT and STST

NonNon--invasiveinvasiveKoushik Roy, et al. Enterotoxigenic Escherichia coli EtpA mediates adhesion between flagella and host cells. Nature. 457: 594-598, 2008.

•• EPECEPEC: : EnteropathogenicEnteropathogenic E. coliE. coli Lack Lack fimbriaefimbriae, , ST ST and LT and LT enterotoxinsenterotoxins

Shiga Shiga toxintoxin

ActinActin rearrangementrearrangement

Associated Associated with ulcerative colitis in with ulcerative colitis in cotton top cotton top tamarinstamarins and marmosetsand marmosets

Escherichia coli Escherichia coli (cont.)(cont.)•• EHEC: EHEC: EnterohemorrhagicEnterohemorrhagic E. E.

colicoli HemolyticHemolytic--uremic uremic syndrome and syndrome and

sudden kidney failuresudden kidney failure

FimbriaeFimbriae

Shiga Shiga toxintoxin

•• EAECEAEC: : EnteroaggregativeEnteroaggregative E. E. colicoli Aggregative Aggregative fimbriaefimbriae

HemolysinHemolysin and ST and ST enterotoxinenterotoxin

•• EIECEIEC: : EnteroinvasiveEnteroinvasive E. coliE. coli Resembles Resembles ShigellosisShigellosis

Xicohtencatl-Cortes Juan, et al. Intestinal adherence associated with type IV pili of enterohemorrhagic Escherichia coli O157:H7. Journal of Clinical Investigation. 117(11): 3519-3529. 2007.

http://www.cdc.gov/ncidod/eid/vol4no2/nataro.htm

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Bordetella bronchisepticaBordetella bronchiseptica

TetanusTetanusClostridium tetaniClostridium tetani

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Common Viral Diseases in NHPsCommon Viral Diseases in NHPs

DNA VirusesDNA Viruses

Herpes virusesHerpes viruses Herpes BHerpes B Herpes Simplex virusHerpes Simplex virus

PapillomaPapilloma virusvirus AdenovirusAdenovirus Simian virus 40 (SVSimian virus 40 (SV--40)40)

HerpesvirusHerpesvirus saimirisaimiri EpsteinEpstein--Barr VirusBarr Virus Simian Simian VaricellaVaricella VirusVirus

Pox viruses Pox viruses MonkeypoxMonkeypox YabapoxYabapox

Simian virus 40 (SVSimian virus 40 (SV 40)40) SRVSRV--22

B VirusB Virus

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Herpes Simplex VirusHerpes Simplex Virus

Herpes Herpes saimirisaimiri

*squirrel monkey

*from marmoset

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Herpes Virus Saimiri

*from marmoset

Herpes Virus Saimiri

EpsteinEpstein--Barr VirusBarr Virus

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Simian Varicella VirusSimian Varicella Virus

Orthopoxviridae (Monkeypox)Orthopoxviridae (Monkeypox)

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Benign Epidermal Monkey Pox Benign Epidermal Monkey Pox (BEMP)(BEMP)

OrTeCa Pox VirusOrTeCa Pox Virus

RNA VIRUSESRNA VIRUSES Simian hemorrhagic fever virusesSimian hemorrhagic fever viruses

Measles virusMeasles virus

Simian TSimian T--lymphotropiclymphotropic virus Ivirus I

Simian TSimian T--cell leukemia virus (STLVcell leukemia virus (STLV--1)1)

Y ll F iY ll F i Yellow Fever virusYellow Fever virus

SIVSIV

RabiesRabies

Lymphocytic Lymphocytic choriomeningitischoriomeningitis virus (LCMV)virus (LCMV)

Hepatitis A virusHepatitis A virus

EncephalomyocarditisEncephalomyocarditis virus (EMCV)virus (EMCV)

Simian Foamy VirusSimian Foamy Virus

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Measles (Rubeola) VirusMeasles (Rubeola) Virus

Measles Virus

Measles Virus

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Measles Virus Histology

NHP Measles VaccineNHP Measles Vaccine Discontinuation of ATTENUVAXDiscontinuation of ATTENUVAX®® Measles vaccine by Merck & Measles vaccine by Merck &

Co. routinely used for NHPsCo. routinely used for NHPs

Other options to consider:Other options to consider:

MM--MM--RR®® II VaccineII Vaccine Live virus human vaccine for Measles, Mumps and RubellaLive virus human vaccine for Measles, Mumps and Rubella

Highly immunogenic and generally well tolerated in humansHighly immunogenic and generally well tolerated in humans

VanguardVanguard®® Canine DistemperCanine Distemper--Measles VaccineMeasles Vaccine Canine DistemperCanine Distemper--Adenovirus Type 2Adenovirus Type 2--MeaslesMeasles--Parainfluenza VaccineParainfluenza Vaccine

High degree of High degree of epitopicepitopic homology between MV, CDV, and RPVhomology between MV, CDV, and RPV

Contains Adenovirus which can interfere with vaccine researchContains Adenovirus which can interfere with vaccine research

RinderpestRinderpest VaccineVaccine single single vacciniavaccinia virus recombinants expressing the H and F genes of RPV. virus recombinants expressing the H and F genes of RPV.

((GiavedoniGiavedoni L, et al, 1991 and Jones L, et al, 1997)L, et al, 1991 and Jones L, et al, 1997)

Provides partial protection; multiple vaccinations requiredProvides partial protection; multiple vaccinations required

Simian Immunodeficiency VirusSimian Immunodeficiency Virus ClassificationClassification::

Family: Family: RetroviridaeRetroviridae Genus: Genus: LentivirinaeLentivirinae Species: Species: SIVmacSIVmac, , SIVcynSIVcyn, , SIVsmSIVsm, , SIVmneSIVmne, , SIVstmSIVstm, , SIVagmSIVagm, , SIVmndSIVmnd, , SIVcmzSIVcmz, ,

SIVsykSIVsyk Very similar to HIV in humansVery similar to HIV in humans

Species effectedSpecies effected: Old World NHPs: Old World NHPs Clinical SignsClinical Signs::gg

Animals become Animals become immunosuppressedimmunosuppressed and are susceptible to and are susceptible to opportunistic opportunistic infectionsinfections Infection by cytomegalovirus, adenovirus, Infection by cytomegalovirus, adenovirus, papoviruspapovirus, , PnemocystisPnemocystis cariniicarinii, Mycobacterium , Mycobacterium

aviumavium complexcomplex, Cryptosporidium sp., , Cryptosporidium sp., CrytococcusCrytococcus neoformansneoformans, , ToxoplasmaToxoplasma gondiigondii, and , and CandiddiaCandiddiaalbicansalbicans

Chronic diarrhea and wastingChronic diarrhea and wasting Disseminated Disseminated cutaneouscutaneous eruptioneruption on the trunk, groin, medial thighs and face on the trunk, groin, medial thighs and face

with resolution in 1with resolution in 1--7 weeks7 weeks Generalized Generalized lymphadenopathylymphadenopathy and/or and/or splenomegalysplenomegaly

Pathology:Pathology: Lesions independent of Lesions independent of immunosuppressionimmunosuppression in a variety of organ systems: skin, GI in a variety of organ systems: skin, GI

tract, cardiopulmonary, nervous and lymphoid systemstract, cardiopulmonary, nervous and lymphoid systems

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SIV (cont’d)SIV (cont’d)

Diagnosis of Simian Type D RetrovirusDiagnosis of Simian Type D Retrovirus--Induced AIDSInduced AIDS Generalized Generalized lymphadenopathylymphadenopathy and/or and/or splenomegalysplenomegaly accompanied by at least accompanied by at least

four of the following clinical and laboratory findings:four of the following clinical and laboratory findings: Weight loss (>10%)Weight loss (>10%) Fever (>103Fever (>103°°F)F) Persistent refractory diarrheaPersistent refractory diarrhea Chronic infections unresponsive to therapyChronic infections unresponsive to therapy Opportunistic infectionsOpportunistic infections Opportunistic infectionsOpportunistic infections NomaNoma ((cancrumcancrum orisoris)) Retroperitoneal or SQ Retroperitoneal or SQ fibromatosisfibromatosis Hematologic abnormalities:Hematologic abnormalities:

Anemia (PCV <30%)Anemia (PCV <30%) NeutropeniaNeutropenia (<1700)(<1700) LymphopeniaLymphopenia (<1600)(<1600) Thrombocytopenia (<50,000)Thrombocytopenia (<50,000) PancytopeniaPancytopenia

Bone marrow hyperplasiaBone marrow hyperplasia Characteristic lymph node lesionsCharacteristic lymph node lesions

Where Does HIV Come From?Where Does HIV Come From?

Sooty mangabey

SIVsyk

Sykes monkey

SIVcol SIVgsn

SIVsmm

Greater spot-nosed

HIV-2

SIVmac

SIVcpz

ChimpanzeeHIV-1

SIVcol

Mantled guereza

L’Hoest’s monkey Mandrill

SIVlho

SIVrcm

g

SIVmnd

Red-capped mangabey

SIVver

Vervet monkey

Slide adapted from Beatrice Hahn

SIV

Pneumocystis carinii

Opportunistic Infections associated with SIV

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Pneumocystis carinii

Opportunistic Infections associated with SIV

Retroperitoneal Fibromatosis

Lymphocryptovirus-induced hairy leukoplakia

Simian/Human Immunodeficiency Virus (SHIV)

Although SIV causes AIDSAlthough SIV causes AIDS--like like disease in monkeys, immune reactive disease in monkeys, immune reactive epitopesepitopes of SIV env are different from of SIV env are different from HIVHIV--1 1 diminishes predictive value diminishes predictive value of SIV modelof SIV model

SIV

of SIV modelof SIV model SHIV is molecular hybrid of SIV and SHIV is molecular hybrid of SIV and

HIVHIV--1, replacing 1, replacing env, tat, env, tat, and and revrevgenes of SIVgenes of SIV--mac239 with HIVmac239 with HIV--1 1 counterpartscounterparts

Combines SIV’s Combines SIV’s replicativereplicative ability in ability in macaques with ability to encode macaques with ability to encode HIVHIV--1 envelope proteins 1 envelope proteins more more valid model for assessing HIV valid model for assessing HIV vaccine efficacy vaccine efficacy

HIV

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Recent Detection of Simian Foamy Virus in Bushmeat

April 2010: Two strains of April 2010: Two strains of HIVHIV--like virus detected in like virus detected in bushmeatbushmeat from two from two mangabeysmangabeys and chimpanzeeand chimpanzeemangabeysmangabeys and chimpanzeeand chimpanzee

Can infect humans but longCan infect humans but long--term effects unknownterm effects unknown

BushmeatBushmeat trade a threat to trade a threat to public health and wildlife public health and wildlife populationspopulations

Simian TSimian T--Cell Leukemia Virus I Cell Leukemia Virus I (STLV(STLV--I)I)

Simian Hemorrhagic Fever VirusSimian Hemorrhagic Fever Virus

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Ebola VirusEbola Virus

Larsen, et al. Pathologic Findings Associated with Delayed Death in Nonhuman Primates Experimentally Infected with Zaire Ebola Virus. J Infect Dis. 2007

Marburg VirusMarburg Virus

From: CDC/PHIL

Lymphocytic Lymphocytic ChoriomeningitisChoriomeningitis Virus Virus (LCMV)(LCMV)

* Marmoset

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Family Family AdenoviridaeAdenoviridae

FUNGAL DISEASESFUNGAL DISEASES

HistoplasmosisHistoplasmosis

HistoplasmaHistoplasma capsulatumcapsulatum varvar duboisiiduboisii

Candida Candida albicansalbicans

Pneumocystis Pneumocystis cariniicarinii

Miscellaneous Miscellaneous fungal infectionsfungal infections

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HistoplasmosisHistoplasmosisHistoplasma capsulatum var capsulatumHistoplasma capsulatum var capsulatum

African African HistoplasmosisHistoplasmosisHistoplasmaHistoplasma capsulatumcapsulatum varvar duboisiiduboisii

http://upload.wikimedia.org/wikipedia/commons/thumb/0/0e/Histoplasma_capsulatum_var._duboisii._PHIL_4221_lores.jpg/280px-Histoplasma_capsulatum_var._duboisii._PHIL_4221_lores.jpg

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CandidiasisCandidiasis, , moniliasismoniliasis, or “Thrush”, or “Thrush”Candida Candida albicansalbicans

Miscellaneous Fungal infection in NHP

Pyogranulomatous panniculitisCoccidioides immitis

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Parasitic DiseasesParasitic Diseases Internal Parasites:Internal Parasites:

Plasmodium (Malaria)Plasmodium (Malaria)

EntamoebaEntamoeba histolyticahistolytica

AcantocephalaAcantocephala (Thorny(Thorny--headed worms)headed worms)

HepatocystisHepatocystis kochikochi

BalantidiumBalantidium colicoli

SarcocystisSarcocystis spp.spp.

Cryptosporidium sp.Cryptosporidium sp.))

Respiratory mitesRespiratory mites

PentastomesPentastomes

CestodesCestodes

External Parasites:External Parasites:

LiceLice

CutaneousCutaneous mitesmites

Cryptosporidium sp.Cryptosporidium sp.

TrichomonasTrichomonas sp.sp.

NochtiaNochtia nochtinochti

MalariaMalaria

Plasmodium Plasmodium cynomolgicynomolgi

P. P. inuiinui

PP knowlesiknowlesi P. P. knowlesiknowlesi

P. P. gonderigonderi

P. P. brasilianimbrasilianim

P. P. coatneyicoatneyi

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EntamoebaEntamoeba histolyticahistolytica((amebiasisamebiasis))

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AcantocephalaAcantocephala(Thorny(Thorny--headed Worms)headed Worms)

ProsthenorchisProsthenorchis eleganselegans ProsthenorchisProsthenorchis spirulaspirula

*White-footed Tamarin

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RespiratoryRespiratory MitesMitesPneumonyssus simicola, Pneumonyssoides sp., Rhinophaga sp.Pneumonyssus simicola, Pneumonyssoides sp., Rhinophaga sp.

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Pentastomes (Pentastomiasis)ArmilliferArmillifer porocephalusporocephalus

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Cestodes (Cestodiasis)

Adults Cyclophyllidean

LarvaeC l h llid Cyclophyllidean cysticercoid, cycticercus,

coenurus, hydatid);

Pseudophyllidean spargana

Cysticercus cellulosaeCysticercus cellulosae

Cysticercus cellulosaeCysticercus cellulosae

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CestodiasisCestodiasis

*from Greater galago

Hepatocystis kochiHepatocystis kochi

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Balantidium coliBalantidium coli

Sarcocystis sp.Sarcocystis sp.

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Cryptosporidium sp.Cryptosporidium sp.

TrichomonasTrichomonas spp.spp.

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Nochtia nochtiNochtia nochti

External Parasites: LiceExternal Parasites: Lice

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External Parasites: External Parasites: CutaneousCutaneous MitesMites

Sarcoptes sp.Sarcoptes sp.

Demodex sp.Demodex sp.

Psorergates sp.Psorergates sp.

Systemic PathologySystemic Pathology

Periodontal DiseasePeriodontal Disease

Gingival Gingival HyperplasiaHyperplasia

A G iA G i

ArterioArterio--venus fistulavenus fistula

Generalized Generalized amyloidosisamyloidosis

I l l id iI l l id i Acute Gastric Acute Gastric Dilation/ BloatDilation/ Bloat

Gastric InfarctionGastric Infarction

DiverticulosisDiverticulosis

Insular amyloidosisInsular amyloidosis

EndometriosisEndometriosis

Periodontal DiseasePeriodontal Disease

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Gingival HyperplasiaGingival Hyperplasia

Acute Gastric Dilatation (Bloat)Acute Gastric Dilatation (Bloat)

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Gastric infarctionGastric infarction

DiverticulosisDiverticulosis

Tenia coli

Diverticulosis Histology

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Generalized AmyloidosisGeneralized Amyloidosis

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EndometriosisEndometriosis

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Nutritional & Metabolic DiseasesNutritional & Metabolic Diseases

Vitamin C deficiency (scurvy)Vitamin C deficiency (scurvy) Fat necrosisFat necrosis Fatal fatty liver syndrome Fatal fatty liver syndrome Simian Bone Disease (Vitamin DSimian Bone Disease (Vitamin D33 deficiency deficiency (( 33 yy

in NWM)in NWM) Anemia of owl monkeysAnemia of owl monkeys Chronic colitis of macaquesChronic colitis of macaques HypoglycemiaHypoglycemia

Vitamin C DeficiencyVitamin C DeficiencyScurvyScurvy

*squirrel monkey

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Fatty Liver Syndrome Or Fatal Fasting Fatty Liver Syndrome Or Fatal Fasting Syndrome Of Obese MacaquesSyndrome Of Obese Macaques

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Vitamin D3 Deficiency In New World Vitamin D3 Deficiency In New World Monkeys, Simian Bone DiseaseMonkeys, Simian Bone Disease

*cotton top tamarin

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Anemia Of Owl MonkeysAnemia Of Owl Monkeys

http://www.monkeyland.co.za/Images/Douroucouli2.jpg

*owl monkey

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Chronic Colitis Of MacaquesChronic Colitis Of Macaques

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Hypoglycemia

blood glucose < 40 mg/dl

Squirrel monkeys predisposed high metabolic rate

limited glycogen reserves

low body fat

limited ability to utilize ketones & fatty acids

Thank You!!!Thank You!!!

http://www.andyw.com/ruth/pics/funny%20monkey.jpg