Parasites may exit immunocompromised northern pig-tailed macaques (Macaca leonina) infected with SIVmac239

2018·16.9 MB·

by  Song, Tian-Zhang

ZOOLOGICAL RESEARCH
Parasites may exit immunocompromised northern
pig-tailed macaques (Macaca leonina) infected with
SIVmac239
Tian-ZhangSong1,2,#,Ming-XuZhang1,#,Yu-JieXia3,YuXiao1,WeiPang1,Yong-TangZheng1,3,*
1KeyLaboratoryofAnimalModelsandHumanDiseaseMechanismsoftheChineseAcademyofSciences/KeyLaboratoryofBioactive
PeptidesofYunnanProvince,KunmingInstituteofZoology,ChineseAcademyofSciences,KunmingYunnan650223,China
2UniversityofChineseAcademyofSciences,Beijing100049,China
3KunmingPrimateResearchCenter,KunmingInstituteofZoology,ChineseAcademyofSciences,KunmingYunnan650223,China
ABSTRACT Keywords: AIDS; Immunocompromised; Northern
pig-tailedmacaque;Parasite;SIVmac239
Parasites can increase infection rates and
INTRODUCTION
pathogenicity in immunocompromised human
Acquired Immune Deficiency Syndrome (AIDS), induced by
immunodeficiency virus (HIV) patients. However, in
human immunodeficiency virus (HIV), was first recognized in
vitro studies and epidemiological investigations
1981 and has emerged from initially being a concern among
also suggest that parasites might escape high-riskgroupstorepresentingaworldwidepandemic(Jeang
immunocompromised hosts during HIV infection. et al., 2007). According to estimates by WHO and UNAIDS,
Due to the lack of direct evidence from animal 36.7 million people were living with HIV globally at the end
experiments, the effects of parasitic infections on of 2015. That same year, approximately 2.1 million people
became newly infected and 1.1 million died of HIV-related
immunocompromised hosts remain unclear. Here,
causes. As HIV specifically acts on the immune system,
we detected 14 different parasites in six northern
destroyingorimpairingitsfunction,themostcommoncauses
pig-tailed macaques (NPMs) before or at the 50th of death for HIV patients are various pathogenic infections
weekofsimianimmunodeficiencyvirus(SIV)infection (including fungal, viral, bacterial, and parasitic infections) and
byELISA.TheNPMsallcarriedparasitesbeforeviral cancer (Bonnet et al., 2005; Antiretroviral Therapy Cohort
Collaboration,2010;Palladinoetal.,2011).
injection. At the 50th week after viral injection, the
Both parasites and HIV infection have major effects on
individualswithnegativeresultsinparasiticdetection
the host immune system, and co-infection is widespread
(i.e., 08247 and 08287) were characterized as the
(Bentwich,2000). HelminthscaninduceaTh2bias,leadingto
Parasites Exit (PE) group, with the other individuals
(i.e.,09203,09211,10205,and10225)characterized
astheParasitesRemain(PR)group. Comparedwith
Received:30November2017;Accepted:02January2018
the PR group, the NPMs in the PE group showed
Foundation items: This work was partly supported by grants from
higher viral loads, lower CD4+ T cells counts, and the National Natural Science Foundation of China (81471620;
lowerCD4/CD8rates. Additionally,thePEgrouphad 81671627; 81571606; 81601808; 81172876; U0832601), the
higher immune activation and immune exhaustion of National Basic Research Program of China (2012CBA01305), the
bothCD4+ andCD8+ Tcells. Pathologicalobservation 13th Five-Year Key Scientific and Technological Program of China
showed greater injury to the liver, cecum, colon, (2017ZX10304402-002-004; 2017ZX10202102-001-005), and the
spleen,andmesentericlymphnodesinthePEgroup. NationalKeyResearch&Development(R&D)Plan(2016YFC1201000)
This study showed more seriously compromised #Authorscontributedequallytothiswork
immunity in the PE group, strongly indicating that *Correspondingauthor,E-mail:[email protected]
parasitesmightexitanimmunocompromisedhost. DOI:10.24272/j.issn.2095-8137.2018.015
42 SciencePress ZoologicalResearch39(1):42-51,2018
suppressionofTh1responsestoHIV,aswellastoexpansion knowlesi, Toxoplasma gondii, Giardia lamblia, Echinococcus
ofTh2lymphocytesthataremoresusceptibletoHIVinfection granulosus, Clonorchis sinensis, Schistosoma japonicum,
(Bentwichetal.,1999).Severalepidemiologicalandsystematic Paragonimus spp.,filarialworms,andTrichinellaspiralis were
studies claim that deworming is a preventive and possibly detected by their respective parasitic antigen ELISA kits
therapeutic measure in patients co-infected with helminths (MEIMIAN, China) following the manufacturer’s instructions.
and HIV (Borkow & Bentwich, 2006; Walson et al., 2009; Spirometra mansoni and Angiostrongylus cantonensis were
Walson & John-Stewart, 2007), thus indicating the potential detected by their respective human antibodies ELISA
sideeffectofparasites.However,amorerecentmeta-analysis kits (MEIMIAN, China; JIANLUN, China) following the
showed that deworming has little or no favorable effect on manufacturer’s instructions. For all ELISA experiments, the
HIV treatment (Means et al., 2016). Unfortunately, direct CalculateCritical(CUTOFF)valuewasequaltotheaverageof
experimentalevidencefromanimalmodelsisstillmissing,and thenegativecontrolwellplus0.15.ThewellwithanODgreater
the relationship between parasites and HIV remains complex thanorequaltotheCUTOFFwasregardedasapositiveresult.
andunclear.
Fullblooddifferentialcounts
Non-humanprimates(NHPs)arecrucialanimalmodelsfor
understanding the pathogenesis of HIV infection (Karlsson BeforeseparationofPBMCs,80µLofbloodwasremovedfrom
et al., 1997; Letvin, 1992). Simian immunodeficiency virus the EDTAK2 vacutainer. Whole blood differential counts were
(SIV) infections in rhesus macaques and northern pig-tailed performed by an auto hematology analyzer (RR-OB101338,
macaques (NPMs) result in an immunocompromised and MINDRAY,Shenzhen, China)accordingtothemanufacturer’s
AIDS-like disease similar to that seen in HIV patients, as instructions.
established in our laboratory (Pang et al., 2017; Zhang et
Plasmaviralloads
al. 2017a, b). In this study, NPMs with different parasitic
loads after infection with SIVmac239 were used to detect Viral loads in plasma were measured by quantitative
immunological and pathological differences to reveal the PCR for SIV gag RNA, as described previously (Tian et
relationshipbetweenviralinfectionandparasites. al., 2015) (SIV F: 5'-TCGGTCTTAGCTCCATTAGTGCC-3';
SIV R: 5'-GCTTCCTCAGTGTGTTTCACTTTC-3'; SIV probe:
MATERIALSANDMETHODS 5'-CTTCTGCGTGAATGCACCAGATGACGC-3').
Ethicsstatement
Flowcytometry
All animal experiments were performed according to the
Multicolorflowcytometricanalysiswasperformedasdescribed
guidelines of the Committee on Animals of the Kunming
previously(Xiaetal.,2009;Zhengetal.,2014). Anti-CD3PE
Institute of Zoology, Chinese Academy of Sciences (approval
(clone SP34-2), anti-CD8 PECy7 (clone RPA-T8), anti-CD20
number: SYDW-2015023). NPMsincludedinthisstudywere
FITC (clone 2H7), anti-CD14 APC (clone M5E2), anti-CD3
housed at the Kunming Primate Research Center under the
APC-Cy7(cloneSP34-2),andanti-HLA-DRAPC(cloneG46-6)
guidance of the American Association for Assessment and
were purchased from BD Pharmingen (Franklin Lakes, New
AccreditationofLaboratoryAnimalCare(AAALAC).
Jersey, USA). Anti-CD4 PerCP (clone OKT4) was purchased
Animalsandsamplecollection from Biolegend (San Diego, CA, USA). Anti-CD38 FITC
AfterevaluatingeachindividualforBvirus,SIV,STLV,andSRV (clone AT-1) was purchased from STEMCELL (Vancouver,
by PCR, six negative male NPMs (5–7 years old, numbered Canada). Anti-PD-1PE(cloneeBioJ105)waspurchasedfrom
08247,08287,09203,09211,10205,and10225)wereenrolled eBioscience(SanDiego,CA,USA).Sampleswereprocessed
in this study. Each NPM was inoculated with 2 mL of on a BD FACSVerse flow cytometer (Franklin Lakes, New
normal saline containing a 3 000 50% tissue culture infection Jersey, USA),anddatawereanalysedusingFlowJosoftware
dose (TCID ) of SIVmac239 into the posterior tibial vein. (vX.0.7,TreeStar).
50
Peripheral blood was collected into an EDTAK vacutainer by
2 Tissuecollectionandhistopathology
venipuncture. Subsequently, peripheral blood mononuclear
Both 08247 and 09211 died naturally on the 70th and 68th
cells (PBMCs) were separated by Ficoll density gradient
weeks after viral infection, respectively. Tissues were fixed
centrifugation(2500r/min,20min). PBMCsandplasmawere
stored in liquid nitrogen and frozen at –80 ◦C , respectively. in 10% formaldehyde and later embedded in paraffin. The
paraffin-embeddedsampleswerecutinto4-µm-thicksections
Ketaminehydrochloride(0.2mL/kg)wasusedtoanaesthetize
and stained with hematoxylin-eosin (H&E). All samples were
animalspriortoexperiments.
photographed and examined using a LEICA DMI 4000B
Parasitedetection microscope(Germany).
Pre-infectionandatthe50thweekafterviralinfection,plasma
from the NPMs was collected and evaluated for parasitic Statisticalanalysis
status. In total, 14 types of parasites were included in For all data, GraphPad 6.0 was used to perform statistical
this study. Entamoeba histolytica was detected by thick analyses. Two-way analysis of variance (ANOVA) was used
smear, as described previously (Warhurst & Williams, 1996). to compare all data. P<0.05 were regarded as statistically
Trypanosoma brucei, Cryptosporidium parvum, Plasmodium significant.
ZoologicalResearch39(1):42-51,2018 43
RESULTS NPMs in the PE group showed higher immune activation and
moreseriousexhaustionofCD4+andCD8+Tcells.
Parasiticinfectionstatusandcategories
The parasitic infection statuses of the NPMs are shown in Celldistributioninperipheralblood
Table 1. None of the NPMs was infected with Plasmodium Thefluctuantcelldistributioninperipheralbloodwasshownin
knowlesi, Echinococcus granulosus, Clonorchis sinensis, Figure4.Thenumberofwhitebloodcellsshowednosignificant
Paragonimus spp., Angiostrongylus cantonensis, Trichinella differences between the two groups (Figure 4C). However, in
spiralis, or Spirometra mansoni. Both 08247 and 08287 the SIV acute and chronic phases, NPMs in the PE group
showed positive parasitic reactions before viral infection, and showedfewerredbloodcellscomparedwiththePRgroup,as
negative reactions after infection. However, 09203, 09211, showninFigure4A.Thenumberofplateletsalsosignificantly
10205, and 10225 exhibited substantially different results. At declinedinthePEgroupcomparedwiththePRgroupduring
the50thweekafterinfection,theparasitesdetectedbeforeviral the SIV chronic phase (Figure 4B), which is important given
infectionremained, andnonewparasitesweredetectedafter that platelet count is a main marker for immunocompromised
viral infection. Therefore, we grouped 08247 and 08287 into thrombocytopenicpurpurainducedbyHIVorSIV(O’Bryanet
the Parasites Exit (PE) group and the other four NPMs into al.,2015).
the Parasites Remain (PR) group to evaluate the relationship
Dynamicsofmonocytes,Bcells,andTcellsinperipheral
betweenSIVandparasiticinfection.
blood
HigherviralloadsinthePEgroup Cellcountsbeforeviralinfectionwerecalculatedas100%.The
NPMsinbothgroupshadpeakplasmaviralloadsatthesecond dynamics of the three cell types were evaluated, as shown
tothirdweekpost-infection,afterwhichtheviralloadsshowed in Figure 5. Monocytes, which play an important role in
a downward trend until the sixth week after injection (Figure innateimmunity,showedasignificantincreaseinthePEgroup
1). Afterwards, the PE and PR groups showed substantially compared with the PR group (Figure 5A). Conversely, T cells
different trends. Viral loads in the PE group stopped and B cells, markers of acquired immunity, were significantly
decreasing and generally stabilized at 104–105 copies/mL. reduced in the PE group compared with the PR group, as
However,thePRgroupshowedacontinuingdownwardtrend, showninFigure5B,C.
andapproacheddetectionlimitsatthe40th–50thweeksafter
Pathologicalobservationofinjuredorgans
infection.Inthisstudy,the50experimentalweeksweredivided
Intotal,22organsfromeachNPMwerecollectedandstained
intoSIVacutephaseandSIVchronicphaseatthe12thweek
by H&E, four of which displayed obvious damage, as shown
post infection to perform additional analysis (Pantaleo et al.,
inFigure6. ComparedtoPR-09211,whichmaintainedalmost
1993b). Compared with the PR group, the PE group showed
normalhepaticlobuleappearance, liverdamageinPE-08247
significantly higher plasma viral loads in the chronic stage
wasobvious(Figure6A).Alimentarycanaldamageisstrongly
(P<0.0001).
related to chronic immune activation (Griffin, 1990; Mestecky
LowerCD4+TcelllevelsinthePEgroup et al., 2009), and was detected in our study. In Figure 6C, D,
AbsolutecountsofCD4+ Tcells,theprimarycellsinfectedby obvious damage in the ileum of both 08247 and 09211 could
HIVorSIV,wereevaluatedbyflowcytometry. Comparedwith beseen. Comparedto09211, PE-08247demonstratedmore
the PR group, NPMs in the PE group had significantly fewer seriousinjuriesinthececumwithoutanyobservedenteraden
CD4+ Tcellsinperipheralblood(P<0.0001,Figure2A).This andinthecolonwithadiscreteanddefectivemucosalsurface.
was in accordance with the results in Figure 2B, which show
Pathologicalobservationofimmuneorgans
a significantly lower CD4+/CD8+ T cell rate in the PE group
Thespleenhasnodirectconnectiontothelymphaticsystem;
(P<0.001).ThesetworesultsstronglyindicatedthattheNPMs
instead, it collects antigens from the blood and is involved
inthePEgrouphadmoreseriouslydamagedCD4+Tcells.
in immune responses to blood-borne pathogens (Murphy &
Immuneactivationandexhaustion Weaver, 2016). Compared to 09211, the white pulp of
Chronicimmuneactivationisproposedtobeakeydeterminant 08247 in the PE group had severe fibrosis and decreased
of AIDS pathogenesis (Rajasuriar et al., 2013), and was lymphocytes, as shown in Figure 7A. Lymph nodes are the
marked by CD38 and HLA-DR in this study. There were most important organ in HIV or SIV infection, spread, and
significantdifferencesbetweenthePEandPRgroupsinCD38 damagetolymphocytes(Pantaleoetal.,1993a). Asshownin
expression during the whole study period and in HLA-DR Figure7C–F,lymphoidfolliclescouldbeobservedinallimages,
expressionduringthechronicphaseinCD4+andCD8+Tcells andtherewerenosignificantdifferencesbetweenthePEand
(Figure3A,B,D,E).ThesedatastronglyindicatedthatNPMs PR groups in axillary and inguinal lymph nodes. However,
inthePEgroupshowedmoreobviousimmuneactivationthan comparedto09211inthePRgroup,mesentericlymphnodes
thoseinthePRgroupduringSIVinfection.Additionally,thePE in08247inthePEgroupwereobservedwithlymphoidfollicle
group had a higher level of PD-1 expression in CD4+ T cells fibrosisanddecreasedlymphocytesintheparacortex,strongly
duringthewholestudyperiod(P<0.0001)andinCD8+Tcells indicatingmoreseriousdamageinthePEgroup(Figure7G).
duringthechronicphase(P=0.0273),asshowninFigure3C
and 3F respectively. Collectively, these results revealed that
44 www.zoores.ac.cn
Table1Parasiticinfectionstatus
SIV Protozoa
No. Infection Trypanosoma Cryptosporidium Plasmodium Entamoeba Toxoplasma Giardia
(N/Y) brucei parvum knowlesi histolytica gondii lamblia
N + + - - + +
08247
Y - - - - - -
N + + - - + +
08287
Y - - - - - -
N + + - - - -
09203
Y + + - - + -
N + - - - - -
09211
Y + - - - - -
N + + - - - -
10205
Y + + - - - -
N + + - + + -
10225
Y + + - + + +
7 PE
L) PR
m 6 P<0.0001
s/
e
pi
o 5
c
g10
o 4
L
d (
a 3
o
al l
vir 2
a
m
s 1
a
Pl
0
0 2 4 6 8 10 12 18 24 30 36 42 48
Weeks post infection
Figure1PlasmaviralloadsinthePEandPRgroups
A B
2500 PE 2.0 PE
P<0.0001 PR P<0.0001 PR
L2000
µ 1.5
s/ 8
ell1500 D
c C
T 4/1.0
+ 1000 D
4 C
D
C 0.5
500
0 0.0
0 10 20 30 40 50 0 10 20 30 40 50
Weeks post infection Weeks post infection
Figure2DynamicsofCD4+Tcellsinperipheralblood
A:AbsolutecountsofCD4+Tcells;B:RatiobetweenCD4+TcellsandCD8+Tcells.
ZoologicalResearch39(1):42-51,2018 45
Figure3Expressionofimmuneactivationandexhaustionmarkers
A,D:ExpressionofCD38inCD4+andCD8+Tcells;B,E:ExpressionofHLA-DRinCD4+andCD8+Tcells;C,F:ExpressionofPD-1inCD4+andCD8+T
cells.
A 12 P<0.0001 P=0.0032 PE B 1500 P=0.0204 P<0.0001 PE C 30 PE
PR PR PR
21L/01 CBR 96 9L/01 TLP1050000 9L/01 CBW2100
3 0 0
0 2 4 6 8 10 12 18 24 30 36 42 48 0 2 4 6 8 10 12 18 24 30 36 42 48 0 2 4 6 8 10 12 18 24 30 36 42 48
Weeks post infection Weeks post infection Weeks post infection
Figure4Celldistributioninperipheralblood
A:Redbloodcell(RBC)counts;B:Platelet(PLT)counts;C:Whitebloodcell(WBC)counts.
A B C
500 PE 200 PE 200 PE
P=0.0002 PR PR P=0.0001 PR
400
150 150
)%( etyconoM321000000 )%( sllec B10500 )%( sllec T10500
00 10 20 30 40 50 00 10 20 30 40 50 00 10 20 30 40 50
Weeks post infection Weeks post infection Weeks post infection
Figure5Dynamicsofmonocytes,Bcells,andTcellsinperipheralblood
46 www.zoores.ac.cn
PE-08247 PR-09211
A B
Liver
C D
lleum
E F
Cecum
G H
Colon
Figure6Histologicalchangesinliver,ileum,cecum,andcolon
A,B:Liver(×200);C,D:Ileum(×100);E,F:Cecum(×100);G,H:Colon(×100).Redarrow:Fibrosis;Bluearrow:Hemorrhage;Yellowarrow:Hepaticlobule;
Blackarrow:Enteraden;Whitearrow:Connectivetissueexposure;Redrectangle:Mucosalsurface.
ZoologicalResearch39(1):42-51,2018 47
PE-08247 PR-09211
A B
Spleen
C D
Axillary
Lymoph nodes
E F
Inguinal
Lymph nodes
G H
Mesenteric
Lymph nodes
Figure7Histologicalchangesinimmuneorgans(×100)
A,B:Spleen;C,D:Axillarylymphnodes;E,F:Inguinallymphnodes;G,H:Mesentericlymphnodes.Redarrow:Abnormalwhitepulp;Yellowarrow:Whitepulp;
Blackarrow:Lymphoidfollicle;Whitearrow:Abnormallymphoidfollicle.
48 www.zoores.ac.cn
DISCUSSION effect on HIV treatment (Means et al., 2016). These studies
suggest that changes in the host induced by HIV or SIV
Inthisstudy, noparasitesweredetectedin08247and08287 produceadverseeffectsonparasites,andparasitesmightnot
inthePEgroupatthe50thweekafterviralinfection,although contribute to the progression of HIV disease, matching the
both were positive for parasites before viral injection. In hypothesisofBrownetal.(2006).
addition, in the PE group, more significant damage to the
Therewerethreenotablelimitationstothisstudy.First,there
mucosal barrier, mesenteric lymph nodes, and immune cells
were only six NPMs enrolled, which might not fully represent
wereobserved.
the differences between PE and PR groups. Second, feces
CD4+ T cell counts and viral loads are the most important detectionisregardedasthegoldstandardforthedetectionof
indicesusedtopredictdiseaseprogressandimmunesystem someparasites,particularlyintestinalparasites. Unfortunately,
damage (Rowley, 2014). The persistent decrease in CD4+ we did not collect fecal samples from the six NPMs before
T cell counts with viral load increase represents serious viral infection. Therefore, all experiments were performed
immunological compromise and poor prognosis, which was using antigen or antibody ELISA kits. Finally, tissues were
observed in the PE group. In addition, immune activation collected from only two NPMs. The other survivors were
is a sensitive index for predicting disease progression and is kept for long-term parasitic experiments. Euthanasia was not
central to the understanding of HIV-1 disease pathogenesis performed in this study. However, most of the results in this
and progression in association with inflammation (Ipp et al., study showed an identical trend suggesting the conclusions
2014). Therefore,CD38andHLA-DR,twomarkersofimmune wereeffectiveandmeaningful.
activation,weredetectedbyflowcytometryinthisstudy,which
CONCLUSIONS
indicated more significant immune activation in the PE group
comparedwiththePRgroup. Tothebestofourknowledge, thisstudyisthefirsttoprovide
The loss of enteric mucosal barrier integrity is associated direct evidence on the changes in parasitic infection status
withrapiddepletionofentericlymphocytes,immuneactivation, before and after SIV injection in an animal model. Both HIV
and microbial translocation (Brenchley et al., 2006; Douek, and SIV destroy the host immune system, leading to serious
2007). As shown in Figure 6, PE-08247 exhibited serious immunological compromise, which enhances the possibility
damagetothemucosalbarrier. Unsurprisingly, antigenorigin for pathogenic microorganisms, including bacteria, fungi, and
fromthetranslocationofmicrobesandotherbacterialproducts viruses,toinvadeandcausedamage. Incontrast,ourresults
stimulates mesenteric lymph nodes, resulting in lymphoid indicatedthatparasitesmayexitanimmunocompromisedhost.
tissue hyperplasia and ultimately in the diffuse effacement of These prospective results should be evaluated further with a
lymph nodearchitecture (Lederman & Margolis,2008), which largersamplesize.
was observed in the PE group (Figure 7). The decrease in
platelets, which is correlated with immunological compromise COMPETINGINTERESTS
and virus-related mechanisms, was also detected in the PE
Theauthorsdeclarethattheyhavenocompetinginterests.
group. The significant increase in monocytes and decrease
inTcellsinperipheralbloodindicatedchangestotheimmune AUTHORS’CONTRIBUTIONS
system in the PE group. These results showed that NPMs in
thePEgroupweremoreseriouslyimmunocompromised. T.Z.S.andY.T.Zdraftedtheexperiments. T.Z.S.,M.X.Z.,Y.J.X.,Y.X.,W.P.
performedtheexperiments.T.Z.S.andM.X.Z.analyzedthedata.T.Z.S.and
Considering the parasitic detection results in the PE
Y.T.Z.wrotethepaper.Allauthorsreadandapprovedthefinalmanuscript.
group before and after viral infection, parasites may exit
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