NONHUMAN PRIMATE PATHOLOGY Acknowledgements Goals of This Talk

Home , Capuchin monkey, Mantled guereza, Simian foamy virus

NONHUMAN PRIMATE PATHOLOGY

Srinivas S . Rao DVM, Ph.D,Ph.D, MBA, Diplomate ACVP [email protected] [email protected]

Acknowledgements Thank you to:

 Gross Photos/Histology Images: Gary Baskin, Anne Lewis  Rick J. Montali and Ira Baum for images, summaries, and references  Alyse Zajac and Patrick Gorres  New Iberia and staff  Univ of MD and staff  Bioqual and Staff  JHU and staff  Tulane Primate Center

Goals of this talk

 Present an overview of the ‘natural’ disease entities of NHPs-NHPs-speciallyspecially Macaques spp.  Discuss ‘most important’ disease entities in more detail  Discuss ‘not so important’ disease entities as appropriate  Make a case that the disease processes in NHP are similar to other higher order mammals

1 Now for the punch line(s)…

 The response to an ‘insult’ in NHP is almost exactly similar to those in other higher order mammals…a granuloma is a granuloma is a granuloma  Beware of ‘unique’ anatomic features and corresponding pathology. Eg., cheek pouch infection (airsacculitis) ; diverticulosis;  If you are unable to get a Stromberg style “shoot from the hip” answer, go to your basics…again, a granuloma is a ….

Now for the punch line(s) (cont.)…

 Even if you don’t learn anything in the next 2 hours, KNOW THE FOLLOWING:  Assure yourself of minimum protective conditions while doing a monkey necropsy  Know “THE” B virus  Very high mortality rate in humans (80%)  Asymptomatic carriers can shed virus  Know TB  Know SIV + opportunistic infections (especially histopathhistopath);); have Bruce’s’ “CAN diagnosis(diagnosis(eses)”)”  Know the invading bugsbugs--salsal,, shi,shi, yeryer,, Entomeba  Know Endometriosis  Know Bloat  KnowKnow--KnowKnow--KnowKnow ---- you get the idea!!!

Catarrhine (down(down--nosed)nosed) or

macaque Old World Monkeys

mandrill baboon Common chimpanzee proboscis patas langur Cercopithecus aethiops Swamp monkey

colobus guenon

gibbon orangutan

bonobo Leaf monkey Vervet monkey

2 Platyrrhine (flat(flat--nosed)nosed) or New World Monkeys Family Aotidae night monkeys Family: Ateles geoffroyi Central American Family Alouatta spider monkey howler monkeys

FilFamily Ca llice bus moloch dusky titi Callithrix pygmaea Family Cebus capucinus Family Callithrix pygmy marmoset capuchin monkey jacchus white-tufted-ear Family Leontopithecus marmoset rosalia golden lion tamarin

Family Saimiri sciureus Genus Pithecia South American squirrel monkey Genus Cacajao (uakaris) (saki monkeys)

BACTERIAL DISEASES  Mycobacterium  Yersiniosis tuberculosis  Salmonella  Streptococcus  Campylobacteriosis pneumoniae  Listeriosis  Klebsiella pneumoniae  EEhihilischerichia coli  Mycobacterium  Bordetella bronchiseptica lepraemurium  Clostriduium tetani  Staphylococcus aureus  Shigellosis * GramGram--positivepositive * GramGram--negativenegative

Tuberculosis M. tuberculosis and M. bovis

3 TB Slide – Human lung histology

Central necrosis

Langhans-type giant cells

4 Hepatic Tuberculosis

5 IMMUNODEFICIENCY-ASSOCIATED MYCOBACTERIOSIS

 Mycobacterium avium paratuberculosis (Johne’s Disease)

Streptococcus pneumoniae (Diplococcus pneumoniae, Pneumococcus pneumoniae)

6 Klebsiella pneumoniae

7 Leprosy - Hansen's disease Mycobacterium leprae

Staphylococcus aureus

8 Bacterial Enteritidies  Salmonella  Shigella  Yersinia  Campylobacter  E. Coli  Entamoeba histolytica (parasite)

Shigellosis Shigella flexneri Shigella sonnei

Gram negative, aerobic, invasive

9 Yersiniosis Yersinia pseudotuberculosis Yersinia enterocolitica

*from squirrel monkey

10 Affected

Normal

Yersiniosis Histopathology

Common Yersinia colonies histopathology: •Leukocytosis •Hyponatremia •Hypochloremia •Prerenal azotemia •hyperfibrinogenemia

Hepatic microabscess

11 Campylobacteriosis Campylobacter fetus ss. Jejuni Campylobacter fetus ss. coli

Listeriosis Listeria monocytogenes

12 Escherichia coli

• ETEC: Enterotoxigenic E. coli . Adhesins to bind enterocytes . Proteinaceous enterotoxins – LT and ST . NonNon--invasiveinvasive

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

• EPECEPEC:: Enteropathogenic E. coli . Lack fimbriae,fimbriae, ST and LT enterotoxins . Shiga toxin . Actin rearrangement . Associated with ulcerative colitis in cotton top tamarinsand marmosets

Escherichia coli (cont.)

• EHEC: Enterohemorrhagic E. coli . HemolyticHemolytic--uremicuremic syndrome and sudden kidney failure . Fimbriae . Shiga toxin

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. • EAECEAEC:: Enteroaggregative E. coli . Aggregative fimbriae . Hemolysin and ST enterotoxin

• EIECEIEC:: EnteroinvasiveE. coli http://www.cdc.gov/ncidod/eid/vol4no2/nataro.htm . Resembles Shigellosis

13 Bordetella bronchiseptica

Tetanus Clostridium tetani

14 Common Viral Diseases in NHPs DNA Viruses

 Herpes viruses  Papilloma virus  Herpes B  Adenovirus  Herpes Simplex virus  Simian virus 40 (SV -40)  Herpesvirus saimiri  SRVSRV--22  EpsteinEpstein--BarrBarr Virus  Simian Varicella Virus  Pox viruses  Monkeypox  Yabapox

B Virus

15 16 Herpes Simplex Virus

Herpes saimiri

*squirrel monkey

*from marmoset

17 Herpes Virus Saimiri

*from marmoset

Herpes Virus Saimiri

EpsteinEpstein--BarrBarr Virus

18 Simian Varicella Virus

Orthopoxviridae (Monkeypox)

19 Benign Epidermal Monkey Pox (BEMP)

OrTeCa Pox Virus

RNA VIRUSES

 Simian hemorrhagic fever viruses  Measles virus  Simian TT--lymphotropiclymphotropic virus I  Simian TT--cellcell leukemia virus (STLV-(STLV-1)1)  YllYellow Fever v irus  SIV  Rabies  Lymphocytic choriomeningitisvirus (LCMV)  Hepatitis A virus  Encephalomyocarditis virus (EMCV)  Simian Foamy Virus

20 Measles (Rubeola) Virus

Measles Virus

21 Measles Virus Histology

NHP Measles Vaccine  Discontinuation of ATTENUVAX® Measles vaccine by Merck & Co. routinely used for NHPs  Other options to consider:  MM--MM--RR® II Vaccine  Live virus human vaccine for Measles, Mumps and Rubella  Highly immunogenic and generally well tolerated in humans  Vanguard® Canine DistemperDistemper--MeaslesMeasles Vaccine  Canine DistemperDistemper--AdenovirusAdenovirus Type 2-2-MeaslesMeasles--ParainfluenzaParainfluenza Vaccine  High degree of epitopichomology between MV, CDV, and RPV  Contains Adenovirus which can interfere with vaccine research  Rinderpest Vaccine  single vaccinia virus recombinants expreexpressingssing the H and F genes of RPV. ((GiavedoniGiavedoni L, et al, 1991 and Jones L, et al, 1997)  Provides partial protection; multiple vaccinations required

Simian Immunodeficiency Virus  Classification:  Family: Retroviridae  Genus: Lentivirinae  Species: SIVmacSIVmac,, SIVcynSIVcyn,, SIVsmSIVsm,, SIVmneSIVmne,, SIVstmSIVstm,, SIVagmSIVagm,, SIVmndSIVmnd,, SIVcmzSIVcmz,, SIVsyk  Very similar to HIV in humans  Species effected: Old World NHPs  Clinical Signs:  Animals become immunosuppressed and are susceptible to opportunistic infections  Infection by cytomegalovircytomegalovirus,us, adenovirus, papoviruspapovirus,, Pnemocystis cariniicarinii,, Mycobacterium avium complex, Cryptosporidium sp., Crytococcus neoformans, neoformans, Toxoplasma gondii, and Candiddia albicans  Chronic diarrhea and wasting  Disseminated cutaneouseruption on the trunk, groin, medial thighs and face with resolution in 1-1-77 weeks  Generalized lymphadenopathy and/or splenomegaly  Pathology:  Lesions independent of immunosuppression in a variety of organ systems: skin, GI tract, cardiopulmonary, nervous and lymphoid systems

22 SIV (cont’d)

 Diagnosis of Simian Type D RetrovirusRetrovirus--InducedInduced AIDS  Generalized lymphadenopathyand/or splenomegaly accompanied by at least four of the following clinical and laboratory findings:  Weight loss (>10%)  Fever (>103°(>103°F)F)  Persistent refractory diarrhea  Chronic infections unresponsive to therapy  Opportunistic infections  Noma ((cancrumcancrumoris) oris)  Retroperitoneal or SQ fibromatosis  Hematologic abnormalities:  Anemia (PCV <30%)  Neutropenia (<1700)  Lymphopenia (<1600)  Thrombocytopenia (<50,000)  Pancytopenia  Bone marrow hyperplasia  Characteristic lymph node lesions

Where Does HIV Come From?

SIVmac

Sykes monkey Sooty mangabey HIV-2

SIVsyk SIVsmm

SIVcol SIVgsn Greater spot-nosed

Mantled guereza SIV SIVcpz

SIVver SIVrcm HIV-1 Chimpanzee

SIVlho SIVmnd

Vervet monkey Red-capped mangabey

L’Hoest’s monkey Mandrill Slide adapted from Beatrice Hahn

Opportunistic Infections associated with SIV

Pneumocystis carinii

23 Pneumocystis carinii

Opportunistic Infections associated with SIV

Lymphocryptovirus- Retroperitoneal induced hairy Fibromatosis leukoplakia

Simian/Human Immunodeficiency Virus (SHIV) SIV  Although SIV causes AIDS-AIDS-likelike disease in monkeys, immune reactive epitopes of SIV env are different from HIVHIV--11  diminishes predictive value of SIV model  SHIV is molecular hybrid of SIV and HIVHIV--1,1, replacing env, tat, and rev genes of SIV-SIV-mac239mac239 with HIV-HIV-11 HIV counterparts  Combines SIV’s replicative ability in macaques with ability to encode HIVHIV--11 envelope proteins  more valid model for assessing HIV vaccine efficacy

24 Recent Detection of Simian Foamy Virus in Bushmeat

 April 2010: Two strains of HIVHIV--likelike virus detected in bushmeat from two mangabeys and chimpanzee  Can infect humans but longlong-- term effects unknown  Bushmeat trade a threat to public health and wildlife populations

Simian TT--CellCell Leukemia Virus I (STLV(STLV--I)I)

Simian Hemorrhagic Fever Virus

25 Ebola Virus

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

Marburg Virus

From: CDC/PHIL

Lymphocytic Choriomeningitis Virus (LCMV)

* Marmoset

26 Family Adenoviridae

FUNGAL DISEASES

 Histoplasmosis  Histoplasma capsulatum var duboisii  Candida albicans  Pneumocystis carinii  Miscellaneous fungal infections

27 Histoplasmosis Histoplasma capsulatum var capsulatum

African Histoplasmosis Histoplasma capsulatum var duboisii

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

28 CandidiasisCandidiasis,, moniliasis,moniliasis, or “Thrush” Candida albicans

Miscellaneous Fungal infection in NHP

Coccidioides immitis Pyogranulomatous panniculitis

29 Parasitic Diseases

 Internal Parasites:  Plasmodium (Malaria)  Hepatocystis kochi  Entamoeba histolytica  Balantidium coli  Acantocephala (Thorny- (Thorny-  Sarcocystis spp. headed worms)  Cryptosporidium sp.  Respiratory mites  Trichomonas sp.  Pentastomes  Nochtia nochti  Cestodes

 External Parasites:  Lice  Cutaneous mites

Malaria

 Plasmodium cynomolgi  P. inui  P. knowlesi  P. gonderi  P. brasilianim  P. coatneyi

30 Entamoeba histolytica ((amebiasisamebiasis))

31 32 Acantocephala (Thorny(Thorny--headedheaded Worms) Prosthenorchis elegans Prosthenorchis spirula

*White-footed Tamarin

33 Respiratory Mites Pneumonyssus simicola, Pneumonyssoides sp., Rhinophaga sp.

34 Pentastomes (Pentastomiasis) Armillifer porocephalus

35 Cestodes (Cestodiasis)

 Adults  Cyclophyllidean  Larvae  Cyc lop hy llidean  cysticercoid, cycticercus, coenurus, hydatid);  Pseudophyllidean  spargana

Cysticercus cellulosae

36 Cestodiasis

*from Greater galago

Hepatocystis kochi

37 Balantidium coli

Sarcocystis sp.

38 Cryptosporidium sp.

Trichomonas spp.

39 Nochtia nochti

External Parasites: Lice

40 External Parasites: Cutaneous Mites

Sarcoptes sp.

Demodex sp.

Psorergates sp.

Systemic Pathology

 Periodontal Disease  ArterioArterio--venusvenus fistula  Gingival  Generalized Hyperplasia amyloidosis  AGiAcute Gastric  IlInsular amy lidiloidosis Dilation/ Bloat  Endometriosis  Gastric Infarction  Diverticulosis

Periodontal Disease

41 Gingival Hyperplasia

Acute Gastric Dilatation (Bloat)

42 Gastric infarction

Diverticulosis

Tenia coli

Diverticulosis Histology

43 Generalized Amyloidosis

44 Endometriosis

45 Nutritional & Metabolic Diseases

 Vitamin C deficiency (scurvy)  Fat necrosis  Fatal fatty liver syndrome

 Simian Bone Disease (Vitamin D3 deficiency in NWM)  Anemia of owl monkeys  Chronic colitis of macaques  Hypoglycemia

Vitamin C Deficiency Scurvy

*squirrel monkey

46 Fatty Liver Syndrome Or Fatal Fasting Syndrome Of Obese Macaques

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

*cotton top tamarin

48 Anemia Of Owl Monkeys

*owl monkeyhttp://www.monkeyland.co.za/Images/Douroucouli2.jpg

49 Chronic Colitis Of Macaques

50 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!!!

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