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Vaccine 31 (2013) 52025209
Contents lists available at ScienceDirect
Vaccine
j ournal homepage: www.elsevier .com/ locate /vaccine
An adult zebrafish model for preclinical tuberculosis vaccinedevelopment
Kaisa E. Oksanena,, NicholasJ.A. Halfpennya, Eleanor Sherwooda,Sanna-Kaisa E. Harjulaa, Milka M. Hammarna, MaaritJ. Ahavaa, Elina T. Pajulaa,MarikaJ. Lahtinena, Mataleena Parikkaa,1, Mika Rmeta,b,1
a Institute of Biomedical Technology, BioMediTech,University of Tampere, FIN-33014 Tampere, Finlandb Department of Pediatrics, Tampere UniversityHospital, FIN-33521Tampere, Finland
a r t i c l e i n f o
Article history:
Received 20May2013
Received in revised form 16 August 2013
Accepted 28 August 2013
Available online 20 September 2013
Keywords:
Zebrafish
Tuberculosis
Vaccine
Mycobacteriummarinum
a b s t r a c t
Tuberculosis remains a major global health challenge despite extensive vaccination schemes with the
current live vaccine, Bacillus CalmetteGurin. Tuberculosis vaccine research has been hampered by a
scarcity of animal models which replicate human disease and are suitable for large-scale studies. We
have shown recently thatMycobacteriummarinum, a closerelative ofMycobacterium tuberculosis, causes
an infection resembling human tuberculosis in adult zebrafish (Danio rerio). In the present study we
use this model to show that BCG vaccination as well as DNA vaccination with selected mycobacterial
antigens (Ag85B, CFP-10 and ESAT-6) protects adult zebrafish frommycobacterial infection. Using a low-
dose (2030 bacteria) intraperitoneal M. marinum infection, both the number ofgranulomas and the
amountofinfectedorganswere reduced in theDNAvaccinatedfish. Likewise,when infectingwitha lethal
infection dose (20,00027,000bacteria), vaccination significantly reduced bothmortality and bacterial
counts in a manner dependent on the adaptive immune response. Protective effects ofvaccination were
associated with enhanced expression of interferon gamma. Our results indicate that the zebrafish is a
promising new model for preclinical tuberculosis vaccine research.
2013 Elsevier Ltd. All rights reserved.
1. Introduction
Despite an existing Bacillus CalmetteGurin (BCG) vaccine
and available antibiotic treatments, the global burden of tuber-
culosis (TB) remains enormous. TB is responsible for 1.4 million
deaths annually, and 8.7 million new cases occurred in 2011 [1].
One third of the worlds population is estimated to carry a latent
Mycobacterium tuberculosis infection, and 310% of these eventu-
ally develop active TB [2,3]. Individuals with impaired immunity
have an increased risk of disease progression.
AlthoughBCGprotects childrenagainst thedisseminated forms
of TB, its efficacy in adults is inconsistent [2,4]. Moreover, BCG
does not prevent the establishment ofM. tuberculosis infection or
the reactivation of the latent disease [3,5] and as a live vaccine
is unsafe among the immunocompromised [6]. Introducing vac-
cines that could replace and/or boost the BCG is a key strategy in
Abbreviations: dpi, days post infection; wpi, weeks post infection; CFU, colony
forming unit. Corresponding author. Tel.: +358 50 3832823.
E-mail address: [email protected] (K.E. Oksanen).1 Both authors contributedequally.
controlling theTB pandemic. Proposednewapproaches includeM.
tuberculosis mutants [7,8], recombinant BCG strains [9], and DNA
[10,11] or subunit vaccines basedon mycobacterialantigens[5,12].
The three main animal models used for TB vaccine develop-
ment aremice, guineapigs andnon-human primates, usually used
sequentially in this order [13]. Other commonmodels include the
rabbit [14] and the bovinemodel [15,16]. All current animal mod-
els have limitations; mice, for instance, cannot completely reflect
human TB as they do not form caseating granulomas or sponta-
neously develop latency [17,18]. Non-human primates reproduce
the human disease well yet their use raises ethical concerns. Gen-
erally, mammalian models are relatively expensive and laborious
to be used for large-scale studies.
The small, low-cost zebrafish (Danio rerio) is gaining popularity
as a model for infectious diseases and immune function [1921].
It is neurophysiologically the simplest well-established vertebrate
model organism with both innate and adaptive arms of immu-
nity [20,22,23] and can be considered an ethical choice compared
to mammalian models. Mycobacterium marinum, a natural fish
pathogen genomically closely related toM. tuberculosis, induces a
zebrafish disease sharing the main histological and pathological
features of humanTB [17,18,24]. A low-doseM.marinum infection
spontaneouslydevelops intoa latentfishinfection,controlofwhich
0264-410X/$ seefrontmatter 2013 Elsevier Ltd. All rights reserved.
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depends on the adaptive immune response [18,25]. Notably, pre-
infection with attenuated M. marinum has been shown to protect
zebrafish against mycobacteriosis [26], confirming that zebrafish
canbe vaccinated againstM. marinum.
In this study, we show that adult zebrafish can be vaccinated
against mycobacterial infection both with BCG and a DNA vac-
cine encoding known immunoprotective mycobacterial antigens,
Ag85B, ESAT-6 and CFP-10. Zebrafish thus presents itself as an
attractive model for TB vaccine research.
2. Materials and methods
2.1. Fish
Adult (58month-old)wild typeAB zebrafishor adultrag1(/)
hu1999 mutant fish were used for experiments. The fish were
maintained in a flow-through system with a light/dark cycle of
14h/10h under identical husbandry and water quality conditions.
Animal studies were approved by the National Animal Experiment
Boardin FinlandandconductedinaccordancewiththeEU-directive
2010/63/EU on the protection of animals used for scientific pur-
poses.
2.2. DNA construction
The pCMV-EGFP plasmid (Addgene plasmid 11153 [27]) was
used as the basis for all plasmid constructs. Ag85B (MMAR 2777),
CFP-10 (MMAR 5449) and ESAT-6 (MMAR 0188)were amplified by
colony PCR fromM. marinum grown on 7H10 Middlebrook OACD
plates (BD Biosciences, Franklin Lakes, NJ) using Phusion High-
Fidelity PCR Kit (NEB, Ipswich, MA). PCR products were purified
and restriction cloned to be expressed with a C-terminal EGFP
tag.pCMV-plasmidwithout theEGFP-encoding gene(blankvector)
was constructed by excising the EGFPgene from pCMV-EGFP. Plas-
mids were transformed into Escherichia coli One Shot TOP10 cells
(Invitrogen) and constructs confirmed by sequencing. For in vivo
experiments,plasmidDNAwaspreparedusingtheQIAGENPlasmid
PlusMaxi Kit (Qiagen, Venlo, TheNetherlands).
2.3. Vaccination experiments
Before vaccination, fish were briefly anaesthetized in 0.02%
3-aminobenzoic acid ethyl ester (pH 7.0) (SigmaAldrich). For
BCG vaccinations, fishwere intraperitoneally (i.p.) or intramuscu-
larly (i.m.) injected with 8103 CFU BCG Danish 1331 (Statens
Serum Institut, Copenhagen, Denmark). The i.p. injection was
performed using an Omnican 100 30G insulin needle (Braun,
Melsungen, Germany). For DNA vaccinations, 615g of plas-
mid/fish was injected in the dorsal muscle using aluminosilicate
capillary needles and PV830 Pneumatic PicoPump microinjec-
tor (World Precision Instruments, Sarasota, FL). The target tissue
was electroporated (6 pulses of 50V, 5ms each) using tweezer-type electrodes (BTX/Harvard Apparatus, Holliston, MA) and a
GenePulser-electroporator (Bio-Rad, Hercules, CA). Injection with
sterile PBSor thepCMV-EGFPplasmidwas used asnegativecontrol
for all vaccination experiments.
2.4. Fluorescence microscopy, Western blotting and GFP ELISA
In vivo expressionof theplasmidDNA-derived proteinproducts
(EGFP and its antigen recombinants) was verified by fluores-
cence microscopy, Western blotting and ELISA. Microscopy was
done with a Lumar V.12 fluorescence stereomicroscope (Carl Zeiss
MicroImaging, Jena, Germany). For Western blotting and ELISA,
samplefishwerecollectedat adesiredtimepointandhomogenized
with a PowerLyzerTM
24BenchTopBead-Based Homogenizer (MO
BIO Laboratories). Pierce BCA Protein Assay Kit (Thermo Fisher
Scientific, Waltham,MA)was used to define the total protein con-
centration of each lysate. ForWestern blotting, fish homogenates
were resolved on a 10% SDS-PAGE gel, blotted on a nitrocellulose
membraneand ananti-GFPantibodyNB600-303 (Novusbiological,
Littleton, CO) and a HRP conjugate of goat anti-rabbit IgG (Invi-
trogen) were used for target protein detection. GFP ELISA Kit (Cell
Biolabs, San Diego, CA) was used for determining relative levels
(normalized with the total protein concentration of the samples)of EGFP or its recombinants in fish tissuehomogenates.
2.5. Bacterial infections
M.marinum (ATCC927)was culturedandpreparedfor infections
as in [18]. For experimental infections, fishwere anaesthetized as
described above and i.p. injected 34 weeks after immunizations.
Toverifythebacterialdose,samplesofbacterialdilutionweretaken
during infecting and plated on 7H10 plates.
2.6. RNA and DNA extraction and qPCR
RNA extraction from infected zebrafish was done as previ-
ouslydescribed[18]. For cytokinegene-expressionmeasurements,Bio-Rad iScript One-Step RT-PCR Kit with SYBR Green was used.
The expression of GAPDH (ZDB-GENE-030115-1) was used for
normalization, and analysis of relative changes in gene expres-
sion was done using the ddCt algorithm [28]. 12wpi with a high
(20,00027,000CFU) dose ofM. marinum, fish were euthanized,
the contents of their abdominal cavities were collected and DNA
extraction andM. marinum specific qPCR to quantify bacteria per
fish were carried out as reported [18].
2.7. Histology
Fish were euthanized with 0.04% 3-aminobenzoic acid ethyl
ester (SigmaAldrich) and tissue cross-sections were prepared
and stained as in [18]. In brief, the fish were fixed in formalin,decalcifiedwithEDTAcitrate andembedded inparaffin.5m lon-
gitudinal sections were cut and every 40th section was placed
on a slide. The fish were sectioned thoroughly so that the entire
kidney tissue lining the spine was included. The slides were
stained with ZiehlNeelsen staining and analyzed with an Olym-
pusBX51microscope. Bacterial load perfishwas assayed from the
ZiehlNeelsen-stained tissue cross-sections by (1) counting gran-
ulomas and (2) identifying and counting the organs containing
bacteria per slide. Additionally, some sections were stained using
anti-EGFP antibody NB600-303 (Novus Biologicals) and DAKO
EnVisionTM+ System, HRP (Dako, Glostrup, Denmark) following
standard procedures.
2.8. Survival experiments
Fish were monitored daily and humane end point criteria
approved by the national ethical board were followed. Fish were
euthanizedwith an anesthetic overdose if they showed any of the
followingsigns:abnormalswimming, gasping,observable swelling
or wasting, tissuedamage, lack of response to touch.
2.9. Statistical analysis
Statistical analyses were carried out using the log rank
MantelCox test(for thesurvivalexperiments)oranon-parametric
MannWhitney test (one-tailed). Values ofp
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3. Results
3.1. BCG protects adult zebrafish against an experimental M.
marinum infection
As BCG vaccination has been shown to restrict the progression
of mycobacteriosis inmultiple animal models [13], we first exam-
ined whether BCG is also protective in the zebrafish. Groups of
adult, wild type zebrafish were vaccinated with 8103 CFU of
BCG, eitheri.m.or i.p. Control fishwereinjectedi.p.withsterilePBS.
Four weeks after vaccination, the fishwere infected i.p. with a high
dose (19,500800CFU) ofM. marinum. The experimental groups
were then followed for35weeks for survival. BCGvaccinationwas
unabletopreventinfectionwithmycobacteria,andmortalitydueto
mycobacterialdiseaseoccurredin allgroups.However,vaccination
with BCGimprovedfish survival: in theBCG-vaccinatedgroupsthe
end-pointmortalitieswere45.0% (i.p. route) and57.1% (i.m. route),
whereas in thecontrol group themortalitywassignificantlyhigher
(84.2%) (Fig. 1). Non-vaccinated (buffer injected or non-injected,
n=70 in both groups), non-infected fish kept in the same fish unit
had mortality rates of under 10% in 70 weeks (data not shown).
Therewasno significant difference between theend-pointmortal-
ities of the twovaccination routes, althoughfishvaccinatedvia the
i.m. route began to die earlier, suggesting that the i.p. BCG vacci-nationmaymore efficiently control theearly phase ofM.marinum
infection.
3.2. Mycobacterial antigens can be expressed in adult zebrafish
by DNAvaccination
Next,wetestedwhetherDNA-basedvaccines couldalsobeused
in adult zebrafish. As in vivo electroporation has been shown to
enhance transgene expression and DNA vaccine immunogenicity
in animal models and humans [2931], we microinjected EGFP-
encoding plasmid (pCMV-EGFP) into the dorsal muscle of adult
zebrafish and exposed the injection site to different numbers of
Fig. 1. Vaccination with the Bacillus CalmetteGurin (BCG) vaccine improves
adult zebrafish survival from infection with a high mycobacterial dose. Groups of
zebrafish (n=20 in each group) were immunized with BCG intramuscularly (i.m.)
or intraperitoneally (i.p.). The control group was injected i.p. with PBS. Four weeks
after immunization, the fish were infected with 19,500800CFU ofM. marinum.
Fish were then followed for35 weeks forsurvival. *P
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virulence factors shared between M. tuberculosis and M. marinum
and have appeared promising in vaccine trials in different exper-
imental animal models [5,11,3234], as well as in human trials
[35,36]. The corresponding genes were separately cloned into the
pCMVplasmid tobeexpressedwitha C-terminal EGFP tag(Fig. S2).
Following i.m. plasmid injection, CFP-10, ESAT-6 andAg85B-EGFP
recombinants were detectable in fish tissue by both fluorescence
microscopy and GFP ELISA (Fig. 2b and c). Expression of recombi-
nant CFP10-EGFP, ESAT6-EGFP and Ag85B-EGFPwas confirmed by
Western blotting (Fig. S2b).
Supplementary material related to this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.vaccine.
2013.08.093.
3.3. Zebrafish DNA vaccination with Ag85B, ESAT-6 and CFP-10
leads to enhanced interferon gamma expression upon
mycobacterial infection
Subsequently, we investigated whether DNA vaccination with
Ag85B, CFP-10 and ESAT-6 has an immunogenic effect in the
zebrafish. Fish were immunizedeitherwith a combination of the3
antigen-encodingplasmids(pCMV-Ag85B/CFP-10/ESAT-6),pCMV-
EGFP plasmid, or PBS. The pCMV-EGFP control was included toverify that the observed effects are due to an antigen-specific
response rather than unspecific immune stimulation caused by
bacterial DNA [37]. Four weeks later, fish were challenged with
1500CFUM. marinum (a dose leading to high long-termmortality
but very limited mortality in the first weeks of infection). Inter-
ferongamma (IFN1-1;ZDB-GENE-060210-1) expression levels in
the infectedfishwere thenmeasuredbyqRT-PCR 1, 7 or14dpi. No
differences were seen between the groups during the first week,
although IFN1-1 expression was highly (approximately 70-fold)
upregulated in all groups 7dpi (Fig. 3). 14dpi the fish vaccinated
with pCMV-Ag85B/CFP-10/ESAT-6 showed IFN1-1 induction of
over 100-fold, whilst induction levels in the pCMV-EGFP and PBS
control groupswere lower than 20-fold on average.
3.4. A DNA vaccine encoding Ag85B, ESAT-6 and CFP-10 protects
adult zebrafish against low-doseM. marinum infection
IFN- production levels or other biomarkers do not necessarily
correlate with protection against mycobacterial disease [38]. We
havepreviously setupmethodology to investigatemycobacteriosis
Fig. 3. Interferon gamma expression in vaccinated zebrafish upon infection with
M. marinum. Adult zebrafish were immunized with pCMV-Ag85B/CFP-10/ESAT-
6, pCMV-EGFP or PBS. Four weeks after immunization, the fish were infected
with 1500130CFU ofM. marinum. Fish were then collected 1, 7 or 14dpi for
gene expression analysis; n=20/group at 7dpi, otherwise n=10/group. Data were
combined from two independent experiments. *P
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Fig. 4. (Continued).
have been linked to a reduced chance of developing an active dis-ease [3].
Supplementary material related to this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.vaccine.
2013.08.093.
3.5. DNA vaccination improves zebrafish survival and reduces
mycobacterial burden during an active, rapidly progressing
infection
To assay the effect of fish DNA vaccination on an active, rapidly
progressing mycobacterial infection, DNA-vaccinated fish were
infected with a high dose (20,5004300CFU) ofM. marinum 3
weeks after immunization. Survival was then monitored for 12
weeks. Vaccination with the combination ofAg85B, ESAT-6 and
CFP-10 increased fish survival rates upon infection by 29.8% com-pared to pCMV-EGFP-vaccinated controls (Fig. 5a). 12wpi, M.
marinum-specific qPCR was used to determine the mycobacterial
loads both in vaccinated and control groups. The mean bacterial
loadin themock-vaccinatedfishwas2.8-fold(64.5%)higherthan in
the vaccinated group (Fig. 5b). No bacteria could be detected from
non-infected fish (n=10; data not shown). Taken together, these
results support the observation that zebrafish can be protected
against anM.marinum infection by DNA-vaccination.
3.6. Adaptive immunity is required for the protection gained by
zebrafish vaccination
Aszebrafishare knowntohavestronginnateimmuneresponses
[39], we next examined whether the vaccine-induced protection
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Fig. 5. Effect of adult zebrafish DNA vaccination on the course of infection with a
high mycobacterial dose. Fish were vaccinated with a cocktail of plasmids encod-
ing Ag85B, ESAT-6 and CFP-10 (Ag) (10g DNA/fish). The control group (GFP) was
injected with 10g of pCMV-EGFP. Three weeks later, the fish were infected with
20,5004300CFUofM. marinum. (a)Survival analysis of DNA-vaccinated (Ag) and
control (GFP) fish after infection. Data was averaged from two independent experi-
ments; n(Ag)=40, n(GFP)= 38.*P
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