silahkan kunjungi jurnal (http: //. Dx doi org mekanisme yang terlibat dalam respon host selama IPD belum
Desain dan pengaturan kasus kontrol prospektif studi
/ 10,1136 / bmjpo-2.017-000.092.). sepenuhnya dipahami.
observasional di sebuah rumah sakit tersier di Malawi
BWK dan FM kontribusi metode We used the human genome HGU133A Affymetrix array to
What this study hopes to add?
sama. explore differences in gene expression between cases with
pneumococcal meningitis (n=12) and controls, and between HIV-infected
► We demonstrate for the first time differences in
Menerima Mei 2017 23 and uninfected cases, and validated gene expression profiles for 34
transcriptional profiles between HIV-infected and
Revisi 20 Juli 2017 Diterima genes using real-time quantitative PCR (RT-qPCR) in an independent set
HIV-uninfected children with pneumococcal meningitis (as
24 Juli 2017
of cases with IPD (n=229) and controls (n=13). Pathway analysis was
a homogeneous disease entity of invasive pneumococcal
used to explore genes differentially expressed.
disease and healthy controls).
Kulohoma BW, et al. BMJ Pediatri Terbuka 2017; 1: e000092. doi: 10,1136 / bmjpo-2.017-000.092 1
Akses terbuka
Ekspresi gen profiling selama sepsis memberikan wawasan baru ke (229 from cases with IPD and 13 from controls), which included all
dalam respon host terhadap penyakit bakteri invasif. Beberapa studi those used for microarray analysis. There were no known coinfections
sepsis telah menunjukkan peningkatan regulasi reseptor patogen apart from HIV, and we did not test for other viruses in the CSF, like
pengakuan dan jalur transduksi sinyal, dan downregulation seng cytomegalovirus (CMV) or Epstein Barr Virus (EBV), which have been
homeostasis. 4-6 The rumit tuan respon inflamasi berhubungan dengan reported to be associated with increased mortality in Malawian adults
cedera neuronal dan pembuluh darah, bahkan setelah cairan with bacterial meningitis. 11 12
serebrospinal (CSF) sterilisasi dengan antibiotik. terapi baru tambahan
untuk meningitis bakteri harus tanggal belum menunjukkan manfaat
konklusif, mendorong kebutuhan untuk peningkatan pemahaman samples
mekanisme kunci yang akan mengungkapkan target potensial terapi Whole blood was drawn at admission from consecutive children with
baru. 7 koinfeksi kronis dapat mempengaruhi ekspresi gen, bahkan di IPD. The methodology for downstream transcriptome analysis from
antara pasien tanpa gejala. HIV merupakan faktor risiko utama untuk small blood samples has been previously described. 13
IPD, ditandai dengan memudarnya imunitas dan fisiologi teregulasi
antara individu-individu yang terinfeksi, sangat meningkat kerentanan
penyakit dan hasil kematian, 8 9 sehingga mempengaruhi ekspresi gen rnA extraction, quantification and hybridisation
inang. Kami menguji perbedaan ekspresi gen menggunakan sampel Total RNA was extracted from whole blood using an optimised method
darah dari anak-anak dengan meningitis pneumokokus dan kontrol for the PAXgene blood RNA kit (Qiagen, West Sussex, UK), as
sehat cocok, dan juga membandingkan profil transkripsi antara anak previously described. 13 The total RNA concentration (ng/µL) and ratios
dengan meningitis pneumokokus dengan dan tanpa infeksi HIV. (260/280 and 260/230) were measured using a NanoDrop ND-100
UV-vis spectrophotometer (NanoDrop Technologies, Delaware, USA)
and the RNA integrity was assessed using the Agilent 2100
BioAnalyzer (Agilent Technologies, Edinburgh, UK) before and after
concentration. RNA (2 µg) was reverse transcribed into cDNA using
the Superscript double-stranded cDNA synthesis kit (Invitrogen,
Paisley, UK) according to the manufacturer’s instructions. The
double-stranded cDNA was purified using a GeneChip sample
Bahan dan Metode Pasien clean-up module (Invitrogen). The purified cDNA was then biotin
dan kontrol labelled with the ENZO BioArray high-yield RNA transcript labelling kit
Anak-anak (n = 377) direkrut sebagai bagian dari penelitian yang lebih (Affymetrix, High Wycombe, UK) and cleaned with a cRNA clean-up
besar menyelidiki faktor penentu tuan rumah kerentanan terhadap IPD module (Invitrogen). Aliquots of labelled cRNA (20 µg) were
dilakukan di Rumah Sakit Pusat Queen Elizabeth, Blantyre, Malawi, fragmented at 94°C for 35 min and then hybridised to a Human
antara April 2004 dan Oktober 2006. 10 Ethical approval was granted from Genome U133A GeneChip array for 16 hours rotating at 60 rpm at
the College of Medicine Research Committee, Malawi and the Liverpool 45°C in a GeneChip Hybridization Oven 640 (Affymetrix). Each chip
School of Tropical Medicine Local Research Ethics Committee. Written was washed and stained on a GeneChip Fluidics Station 450
informed consent was given prior to recruitment. We excluded children (Affymetrix) and scanned using a GeneChip Scanner 3000 (Affymetrix)
(n=135) infected with other commonly prevalent microbes ( Salmonella employing standard recommended protocols (Affymetrix).
typhimurium, Escherichia coli, Haemophilus influenzae b, Neisseria
meningitidis,
2 Kulohoma BW, et al. BMJ Pediatri Terbuka 2017; 1: e000092. doi: 10,1136 / bmjpo-2.017-000.092
Open Access
accessed using accession number GSE47172 at the NCBI GEO database. endogen gen C q nilai dari rata-rata gen sasaran C q Nilai: C q menargetkan
gen - C q Rata-rata gen endogen = Δ C q.
transcribed with SuperScript II RNase H- Reverse Transcriptase and Δ C q menargetkan gen ( kasus) - Δ C q menargetkan gen ( control) = ΔΔ C q.
oligo (dT)12–18 (0.5 µg/ µL) following the manufacturer’s guidelines. 2- ΔΔ Cq adalah ekspresi relatif gen target dalam kasus dibandingkan
The cDNA was stored at −40°C until required. dengan kontrol.
Berikutnya, kami menguji perbedaan yang signifikan secara statistik dalam
ekspresi gen relatif antara kasus dan kontrol menggunakan Welch dua-sample
rt-qPcr measurement of target genes t-test dilaksanakan dalam paket R. Kami menghasilkan boxplots untuk
The Human Universal ProbeLibrary (UPL, Roche, Switzerland) memvisualisasikan ekspresi berarti dan media relatif dalam kasus dan kontrol
employing proprietary locked nucleic acid analogues was used to secara terpisah, dan Welch dua-sample t-test nilai p untuk menunjukkan
design qPCR assays to measure expression levels in genes of perbedaan yang signifikan secara statistik dalam ekspresi gen relatif antara dua
interest. Using the Roche Online Assay Design Centre, specific kelompok tersebut.
primers and an associated probe were selected for the reference and
target transcripts. Gene expression was determined using RT-qPCR
on a Roche LightCycler 480 (online supplementary table 2).
hasil
profil transkripsi antara kasus dan kontrol
Berikut ini 34 gen diidentifikasi dari literatur dan diprioritaskan untuk In the microarray discovery cohort, there were 12 children with
RT-qPCR analisis ekspresi diferensial antara kasus dan kontrol: pneumococcal meningitis (six male, six female, median age 1.1 years)
ACSL1, ANXA3, ATP, Bag1, BPGM, C3AR1, CA4, CD177, CD55, and 3 controls (two male, one female, median age 7 years). The
CD59, CEACAM, protein flice-i, FOLR3, GNAI3, GNLY, GYG1, IL1R2, breakdown was as follows: HIV-infected survivors (n=3), HIV-infected
IL1RN, ITGAM, KLRF1, LCK, LCN2, LTF, MAPK14, MMP9, mati rasa, non-survivors (n=3), HIV-uninfected survivors (n=3) and
OLAH, PSEN1, RETN, S100A12, SAMSN, SERPINA1, Sub1 dan
HIV-uninfected non-survivors (n=3) (online supplementary table 1).
VNN1. Kami menggunakan RT-qPCR metode Data normalisasi
The RT-PCR validation cohort had a median age of 3.09 years.
dijelaskan sebelumnya. 22
Figure 1 Distribution plot of the differentially expressed genes. The significantly differentially expressed genes are shown in red colour. The significance
threshold (p<1.5e-3) is indicated by a dashed red line, and a fold change threshold of more than 2 is shown by the dashed vertical lines. The green line shows
p<0.05. (A) Shows results for unadjusted p values, (B) results for BH-adjusted p values and (C) stringent Bonferroni-adjusted p values, which represent an
overcorrection. BH, Benjamini and Hochberg.
following: S100 calcium-binding protein A12 (S100A12); vanin-1 the two groups with the exception of guanine nucleotide-binding
(VNN1); arginase, liver (ARG1); matrix metallopeptidase 9 (gelatinase protein subunit alpha-13 (GNA13), protein numb (NUMB) and
B, 92 kDa gelatinase, 92 kDa type IV collagenase) (MMP9); annexin presenilin-1 (PSEN1) ( figure 2 ). There was no significantly increased
A3 (ANXA3); interleukin 1 receptor, type II (IL1R2); CD177 molecule gene expression in HIV-infected compared with HIV-uninfected cases
(CD177); S100 calcium-binding protein A9 (S100A9), (online supplementary figure 3). Interestingly, there was significant
cytoskeleton-associated protein 4 (CKAP4); and glycogenin 1 (GYG1). upregulation of folate receptor 3 (FOLR3), NUMB and S100A12 in
survivors compared with non-survivors (online supplementary figure 4).
There was wide variability in relative gene expression in cases, but not
controls.
Differential expression, underlying hIV infection and disease outcomes
Figure 2 Validation of RNA transcription profile differential expression using real-time quantitative PCR. Relative gene expression in cases compared with
controls for 34 genes assessed. The black line shows the boxplot median. The red dot shows the mean, and the Welch two-sample t-test p value is shown
on the top right corner.
Gambar 3 The gene network for significantly differentially expressed genes in the cases. Networks reconstructed to support the most direct connectivity
between genes differentially expressed between cases and controls. IPA (Qiagen) software's Core analysis application has been used to perform an automatic
graphical reconstruction of the network via utilisation of IPA's Knowledge Base database of protein interactions. The meaning of links and shapes is explained
in the inserted legend. Functional connections are presented in blue, information connections to the associated categories in pink and grey. (A) Network
reconstructed only for the DE genes identified by microarray analysis. (B) Network reconstructed for the merged data sets of DE genes identified via microarray
(red) and PCR analysis (green). White blocks correspond to nodes added by IPA's network editor automatically to ensure network connectivity. DE, differential
expression; IPA, Ingenuity Pathway Analysis.
serta leukosit migrasi dan adhesi ( angka 3B ). Jalur kanonik dipetakan Diskusi dan kesimpulan
oleh gen didefinisikan dalam percobaan microarray menunjukkan We have shown significant differences in RNA transcriptional profiles
perubahan terbesar dalam jalur arginin dan granulosit. jalur Canonical in children with pneumococcal meningitis compared with controls.
di microarray gabungan dan eksperimen RT-qPCR menunjukkan Children with pneumococcal meningitis demonstrated increased
perubahan terbesar dalam leukosit, dan aktivasi terutama neutrofil dan expression in genes involved in the inflammatory response, and
migrasi, Notch dan reseptor jalur sinyal glukokortikoid (secara online glucose and L-arginine metabolic pathways. Dysregulation of these
tabel tambahan 3 dan 4). pathways can lead to an impaired adaptive host response to
pneumococcal infection, thereby contributing to the
Kulohoma BW, et al. BMJ Pediatri Terbuka 2017; 1: e000092. doi: 10,1136 / bmjpo-2.017-000.092 5
Open Access
increased morbidity and mortality. Our findings in the initial cohort of expression of ARG1, ANXA3, CKAP4, IL1R2, MMP9 and VNN1.
pneumococcal meningitis were validated in the larger cohort of all ANXA3 promotes endothelial cell junction integrity in animal models,
children with IPD, which includes presentations with pneumonia as and endothelial cell motility in vitro. ANXA3 is upregulated following
well as meningitis. These findings add validity to the initial results from neuronal injury, which may explain the finding in pneumococcal
the microarray experiments, and suggest that the host response meningitis. 33
observed is systemic, and not simply localised to the process of
blood–brain barrier disruption per se. We observe wide variability in S100A12 plays a prominent role in the regulation of proinflammatory
relative gene expression in cases, which perhaps reflects differences processes and immune response by recruiting leucocytes, promoting
in disease onset and robustness of host response within this group. cytokine and chemokine production, and regulating leucocyte
Elevation of S100A12, VNN, ARG1, MMP9, ANXA3, IL1R2, CD177, adhesion and migration. 34 The S100A8/A9 heterodimer is expressed by
S100A9, CKAP4 and GYG1 in pneumococcal meningitis supports myeloid cells, especially neutrophils, and has a protective effect in the
previous findings that have highlighted the important roles of some of host response to pneumococcal infection by increasing circulating
these genes during host pathogen response. These genes have neutrophils through increased granulocyte colony-stimulating factor
important interconnected functions for cellular interactions and production. 35 It is an antimicrobial peptide, but plays an important role in
response to infection ( figure 3A and online supplementary file 7), and leucocyte migration. 36 During infection, S100 proteins stimulate the
play crucial roles during host immune response; cell regulatory proinflammatory immune response through interaction with the
processes such as apoptosis and differentiation; and metabolic immunoglobulin family transmembrane pattern recognition receptors:
processes such as amino acid and glucose metabolism. receptor for advanced glycation end-products and Toll-like receptor 4.
This leads to nuclear factor kappa B-mediated proinflammatory
response with production of proinflammatory cytokines. This
inflammatory response in turn leads to increased expression of S100
proteins, and the start of a positive feedback loop. Although as
Vanin-1 (VNN1) protein is expressed by human phagocytes, and antimicrobial proteins they protect against infection, they can also have
involved in leucocyte adhesion and migration. 23 a negative detrimental effect on the host by amplifying the destructive
The VNN1 knockout mice model has provided clear evidence that proinflammatory responses. The increased expression in survivors
VNN1 modulates redox and immune pathways. 24 Exposure of human may be explained by this positive feedback loop. 37
mononuclear cells to oxidative stress results in upregulation of human
VNN1 and downregulation of peroxisome proliferator-activated
receptor (PPAR). 25 IL1R2 and IL1RN were upregulated in cases, which
is consistent with our previous report of the IL-1Ra single-nucleotide
polymorphism rs4251961 playing a key role in the pathophysiology of Glucocorticoids also play a significant role in immune response
IPD and in other human infections. 10 Recent reports also demonstrate regulation by supressing immune and inflammatory responses, and
IL1R2 expression upregulation in sepsis, being more pronounced in modulating cytokines that promote host immune responses. 38 We
Gram-negative than Gram-positive infections. 26 speculate that these responses are important in regulating immune
responses to avoid host tissue damage. NUMB negatively regulates
Notch, which in turn attenuates proinflammatory cytokines and
increases anti-inflammatory cytokines, which may explain the increase
During infection, host production of the cytokine nitric oxide (NO) in NUMB expression in survivors. 39 40
after non-opsonic phagocytosis exerts microbicidal effects. 27 28 ARG1
expression is inducible in the lungs of mice in response to
pneumococcal infection. 29 Phagocytosis of pneumococci by Our results are consistent with previous studies on transcription profiling in
macrophages also results in increased production of nitric oxide other bacterial diseases, suggesting that some of the mechanisms are not
synthase 2-dependent production of NO and reactive nitrogen species. 30 specific to IPD. Although it could be argued that the lack of age matching in
Increased plasma arginase activity depletes L-arginine concentrations, cases versus controls could cause differential expression due to maturation
the substrate for NO synthesis, leading to vascular dysfunction during of the immune system in older children, the consistency of our results with
severe sepsis and supressed NO-mediated microbicidal effects. 31 other studies makes this unlikely. 41 42 Keterbatasan penelitian kami adalah
bahwa analisis microarray dilakukan dengan menggunakan array Affymetrix
Human Genome U133A, dan nomor sampel dibatasi pada saat itu oleh biaya.
Increased ARG1 activity may also be a bacterial survival strategy to Microarray kumpulan data itu tidak cukup besar untuk memungkinkan semua
escape the NO-dependent host antimicrobial immune response. 30 model multifaktorial kemungkinan hasil komorbiditas dan penyakit diperiksa
secara mendalam, tetapi berusaha untuk memvalidasi temuan kami
Neutrophil-specific glycoprotein CD177 is expressed on a subset of menggunakan RT-qPCR dalam kelompok yang lebih besar dari anak-anak.
human neutrophils, and is involved in neutrophil transendothelial evaluasi lebih lanjut dalam kelompok yang lebih besar menggunakan seluruh
migration. A previous microarray study of purified neutrophils from sekuensing genom akan memberikan lebih banyak wawasan tentang
patients with septic shock revealed CD177 mRNA has the highest mekanisme respon host.
differential expression between cases and controls. 32 Consistent with
our data, the study also demonstrated increased
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samples. FM performed experiments. BWK, FM, OV, KN, PJRD and EDC performed the analysis. BWK,
15. Irizarry R. et al Dari file CEL ke daftar dijelaskan gen yang menarik.
FM, PJRD and EDC wrote the first draft of the manuscript. BWK, FM, LM, KN, OV, MEM, EMM, PJRD and
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Funding EDC was supported by a Wellcome Trust Career Development Grant (068026). BWK was
expression in microarray experiments. Stat Appl Genet Mol Biol 2004;3:1–25.
supported by a Wellcome Trust Major Overseas programme award (084679/Z/08/Z).
17. Smyth GK. et al Limma: linear models for microarray data. In:
Disclaimer The funding bodies had no role in collection, analysis or interpretation of data or in writing Gentleman RCV, Dudoit S, Irizarry R, . eds. Bioinformatics and Computational Biology
the manuscript. Solutions using R and Bioconductor. New York: Springer, 2005:397–420.
competing interests None declared. 18. hgu133a. db. Affymetrix Human Genome U133 Set annotation data (chip hgu133a)
[program]. R package version 2.7.1 version. 2009.
Patient consent Obtained.
19. annotate. Annotation for microarrays. R package version 1.34.1. [program]. R package
ethics approval College of Medicine Research Committee (COMREC), Malawi. version1.34.1. version. 2008.
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Data sharing statement Transcription data are openly available. 21. KEGG. db. A set of annotation maps for KEGG [program]. R package version 2.7.1 version.
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Open Access This is an Open Access article distributed in accordance with the terms of the Creative 22. Vandesompele J, De Preter K, Pattyn F, et al. Accurate
Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build normalization of real-time quantitative RT-PCR data by geometric averaging of multiple
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