1 NONHUMAN PRIMATE NONHUMAN PRIMATE PATHOLOGY PATHOLOGY Srinivas S Rao Srinivas S Rao Srinivas S. Rao Srinivas S. Rao DVM, DVM, Ph.D Ph.D, MBA, , MBA, Diplomate ACVP Diplomate ACVP [email protected][email protected][email protected][email protected]Acknowledgements Acknowledgements Gross Photos/Histology Gross Photos/Histology Images Images: Gary Baskin, Anne : Gary Baskin, Anne Lewis Lewis 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 references summaries, and references Alyse Zajac and Patrick Alyse Zajac and Patrick Gorres Gorres New Iberia and staff New Iberia and staff Univ of MD and staff Univ of MD and staff Bioqual and Staff Bioqual and Staff JHU and staff JHU and staff Tulane Primate Center Tulane Primate Center Goals of this talk Goals of this talk Present an overview of the ‘natural’ disease Present an overview of the ‘natural’ disease entities of NHPs entities of NHPs-specially Macaques spp. specially Macaques spp. Discuss ‘most important’ disease entities in Discuss ‘most important’ disease entities in more detail more detail more detail more detail Discuss ‘not so important’ disease entities as Discuss ‘not so important’ disease entities as appropriate appropriate Make a case that the disease processes in NHP Make a case that the disease processes in NHP are similar to other higher order mammals are similar to other higher order mammals
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Srinivas S RaoSrinivas S. Rao · Srinivas S RaoSrinivas S. Rao DVM, DVM, Ph.D Ph.D, MBA, , MBA, Diplomate ACVP [email protected][email protected] Acknowledgements Gross Photos/Histology
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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
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
•• 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.
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)
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:
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)
Larsen, et al. Pathologic Findings Associated with Delayed Death in Nonhuman Primates Experimentally Infected with Zaire Ebola Virus. J Infect Dis. 2007