Bacterial interactions in the female genital tract
Singer, M.
2019
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Singer, M. (2019). Bacterial interactions in the female genital tract: A triangle affair between pathogens,
microbiota, and host.
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CHAPTER 1
Effect of cytokine level variations in individuals
on the progression and outcome of bacterial
urogenital infections – a meta-analysis
Martin Singer1, Sander Ouburgc 1
%ƾPMEXMSRW
ABSTRACT
INTRODUCTION
During infection with bacteria the human body can detect pathogen associated molecular TEXXIVRWRIIHIHXSMRMXMEXIMXWMRREXIMQQYRIW]WXIQ7TIGMƼGEPP]EGXMZEXMSRSJXLI2*Σ& TEXL[E]PIEHWXSTVSHYGXMSRSJTVSMRƽEQQEXSV]G]XSOMRIWPMOI-RXIVPIYOMR -0 -0-0 -0 ERH8YQSV2IGVSWMW*EGXSV 82* » 8LIG]XSOMRIJYRGXMSRWEPWSMRGPYHIEGXMZEXMSR of T-helper 1 and 2 cells required for cellular and humoral immune responses, respectively. 8LGIPPWTVSHYGI-*2½ERH-0[LMPI8LGIPPWWIGVIXI-08+*¼ERH-0 8LIWI cytokines and their functions are summarised in Table 1.
Chlamydia trachomatis, Neisseria gonorrhoeae, and Treponema pallidum are the most
common bacterial sexually transmitted disease worldwide. Resulting complications include MRƽEQQEXMSRJSVEPP[MXLQSVIWIZIVIGSQTPMGEXMSRWMRGPYHMRKXYFETEXLSPSK]ERHVIPEXIH fertility problems for N. gonorrhoeae and C. trachomatis, and cutaneous lesions and neu-rosyphilis for T. pallidum. Pathogen recognition receptors such as Toll-like receptors (TLRs) are responsible for identifying pathogens in the human host and initializing the immune VIWTSRWIEKEMRWXXLIQ 3RISJXLIVIWYPXWMWERMRƽY\SJMQQYRIVIPEXIHGIPPWPMOI CD4+ T-helper cells, at the sites of infection (10, 11). However what cells are recruited to the site of infection and which cytokines are released can differ depending on the pathogen and the host.
Cytokine expression follows similar pathways in all humans, but has been shown to vary FIX[IIRMRHMZMHYEPW 8LIMRƽEQQEXSV]REXYVISJXLIGSQTPMGEXMSRWVIPEXIHXSC.
tra-chomatis, N. gonorrhoeae, and T. pallidumQIERWEHMJJIVIRGIMRI\TVIWWMSRWSJMRƽEQQEXSV]
cytokines can alter the course of the disease and the resulting complications in the host. Especially tubapathology and related fertility problems have been shown to be affected by HMJJIVIRGIWMRI\TVIWWIHMRƽEQQEXMSR
The aim of this literature review was to critically analyse, create insight, and create a stan-dardized measurement of effect for cytokine expression differences related to outcome of various bacterial urogenital infections. This will shed light on the overlap and differences in the effects of differing cytokine expressions between multiple pathogens.
Table 1: Cytokine functions and sources of production (4).
Cytokine Primary Function Source
-*2½ Activation of macrophages Th1 cells
8+*¼ Immunoregulation Th1 cells
IL-2 Promotion of T-cell proliferation and differentiation into Th1 8LGIPPW2*Σ&EGXMZEXMSR IL-10 (S[RVIKYPEXMSRSJMRƽEQQEXMSRF]FPSGOMRK
2*Σ&EGXMZEXMSRERH8LGIPPI\TVIWWMSR
Th1 and Th2 cells IL-4 Promotion of differentiation into Th2 cells 8LGIPPW2*Σ&EGXMZEXMSR IL-5 Stimulates B-cell growth and eosinophil activation Th2 cells
IL-6 6IKYPEXMSRSJXIQTIVEXYVIHYVMRKMRƽEQQEXMSR 8LGIPPW2*Σ&EGXMZEXMSR IL-9 6IKYPEXMSRSJLIQEXSTSMIXMGGIPPWHYVMRKMRƽEQQEXMSR Th2 cells
IL-13 6IKYPEXMSRSJEPPIVKMGERHTEVEWMXMGMRƽEQQEXMSR Th2 cells IL-1 Increase of vascular endothelic activity and permeability,
and activates lymphocytes
2*Σ&EGXMZEXMSR IL-12 Activation NK cells 2*Σ&EGXMZEXMSR 82*» Increase of vascular endothelic activity and permeability 2*Σ&EGXMZEXMSR IL-8 / CXCL8 Recruitment of neutro- and basophils to infection site 2*Σ&EGXMZEXMSR
METHODS
Search methods
4YFQIHKSZERH+SSKPI7GLSPEVHEXEFEWIW[IVIYWIHXSSFXEMRXLIWGMIRXMƼGEVXMGPIWJSVXLMW WXYH]8SPMQMXXLIRYQFIVSJEVXMGPIWJSYRHF]WIEVGLMRK+SSKPI7GLSPEVSRP]XLIƼVWX articles from every search in this database were analysed. Search terms used are shown in Table 2. Searches were done in the period of 1 October 2014 till 1 December 2014. No age limit was applied when searching for articles.
Table 2: Search strategy in the PubMed and Google Scholar databases. “Pathogen” indicates any bacterial urogenital pathogen. “Cytokine” indicates any cytokine, chemokine, or interleukin.
Search terms
“cytokine” expression “pathogen” “pathogen” interleukin
Table 3: Exclusion and inclusion criteria. Exclusion criteria
Cytokines not directly related to pathogen 2SG]XSOMRITVSƼPMRK
Secondary: Data not compatible with other studies Inclusion criteria
)0-7%SVQ62%G]XSOMRIUYERXMƼGEXMSR
Bacterial urogenital infections (e.g. C. trachomatis, N. gonorrhoeae, and T. pallidum) Based on in vivo human studies
Selection of studies
%FWXVEGXW[IVIEREP]WIHERHWXYHMIWXLEXHMHRSXMRGPYHIG]XSOMRITVSƼPMRK[IVII\GPYHIH &SXLEVXMGPIWWLS[MRKUYERXMƼIHG]XSOMRITVSƼPIWERHEVXMGPIWWLS[MRKVIPEXMZIG]XSOMRI expression differences were included. Additionally, any articles not linking the cytokine pro-ƼPIWXSXLITEXLSKIRHMVIGXP][IVII\GPYHIH*YPPI\GPYWMSRERHMRGPYWMSRGVMXIVMEEVIWLS[R in Table 3. Statistical data of included studies was extracted and reviewed for compatibility with the Comprehensive Meta-analysis (CMA; Biostat inc., Englewood, NJ) tool. Data of studies that was not compatible with other studies for analysis was excluded from the meta-analysis.
Statistical analysis
Dixon’s Q test for outliers was used to assess for heterogeneity between included study VIWYPXW4ZEPYIWFIPS[[IVIGSRWMHIVIHWMKRMƼGERXP]LIXIVSKIRMGVIWYPXW8EVKIXWJSV the heterogeneity assessment were the standardized values given as output by the CMA tool. When variability between study results was proven we used a random effects model JSVEREP]WMWSJXLITSSPIHWXYH]VIWYPXW[MXLEWMKRMƼGERGIWIXEX4 3XLIV[MWIE Ƽ\IHIJJIGXQSHIP[EWYWIH%SRIWXYH]VIQSZIHEREP]WMW[EWTIVJSVQIHXSEWWIWWJSV effect of large studies on the pooled study results. Cumulative analysis of the results was performed to assess for trends in study results over time. Publication bias was assessed YWMRKJYRRIPTPSXW;LIRTYFPMGEXMSRFMEW[EWWYWTIGXIHEXVMQERHƼPPQIXLSH[EWYWIH XSEHNYWXXLIVIWYPXWSJXLIMRMXMEPƼ\IHIJJIGXSVVERHSQIJJIGXQSHIPEREP]WIW%PPEREP]WIW were conducted using the CMA tool.
RESULTS
The search strategy resulted in 2551 initial search results for analyses. After analyses of the articles, 185 articles were considered for the meta-analysis. 23 articles were included into the meta-analyses based on data in the articles. Figure 1 shows the process of selection of the articles, while Table 4 shows the characteristics of the studies.
Figure 1:%ƽS[HMEKVEQWLS[MRKXLITVSGIWWSJEVXMGPIWIPIGXMSR
Table 4: Characteristics of studies included in the meta-analysis. Number of articles References Year of publication 4 (17-20) 2001 1 (21) 2002 1 (22) 2004 1 (23) 2007 4 (24-27) 2008 2 (28, 29) 2009 5 (30-34) 2012 1 (35) 2013 1 (36) 2014 3 (37-39) Total 23 Origin India 9 (23, 24, 27-33) North America 6 (17, 19-21, 25, 37) Africa 2 (18, 39) Europe 3 (26, 34, 36) South America 2 (35, 38) Australia 1 (22) Total 23
Number of people included 1 (25)
10-49 6 (20, 23, 34-37)
50-99 8 (18, 19, 22, 27, 28, 30, 32, 33)
100-249 4 (17, 21, 26, 29)
250> 4 (24, 31, 38, 39)
Total 23
Sampling type1 Cervical swab 12 (17, 19, 23, 24, 27-33, 37)
Number of articles
References
Targeted study population1 C. trachomatis positive patients 18 (17-19, 21-24, 26-33, 38, 39)
N. gonorrhoeae positive patients 4 (19, 20, 25, 39)
T. pallidum positive patients 3 (34-36)
Male subjects 7 (18, 20, 21, 26, 34-36) Female subjects 22 (17-20, 22-39) Patients with fertility problems 7 (22, 23, 28-30, 32, 33)
Pregnant women 1 (25)
Total 33
5YERXMƼGEXMSRXIGLRMUYI ELISA 17 (17-21, 23-26, 28-33, 36, 38) Cytometric bead array 2 (27, 35)
Luminex multiplex assay 3 (34, 37, 39) Enzyme immune-assay (EIA) 1 (22)
Total 23
1= Articles can be included in multiple categories
Table 5: Meta-analysis odds ratios found for cytokines per pathogen. Cytokine Pathogen Meta-analysis
P value
Meta-analysis OR Number of articles IL-1 C. trachomatis 2.1 5 IL-6 C. trachomatis 0.003 1.5 5 IL-8 C. trachomatis 1.9 7 IL-10 C. trachomatis 0.5 7 -*2½ C. trachomatis 0.03 2.3 7 82*» C. trachomatis 0.001 2.4 3 IL-1 N. gonorrhoeae 0.009 2.5 3 IL-8 N. gonorrhoeae 0.140 2.4 3 -*2½ T. pallidum 0.492 1.5 3 !EJXIVXVMQERHƼPPGSVVIGXMSR
WXYHMIWESRIWXYH]VIQSZIHEREP]WMW[EWGSRHYGXIH *MKYVI& 2SWMKRMƼGERXP]HMJJIVIRX pooled outcome was obtained this way, indicating that no single study affected the pooled SYXGSQIWMKRMƼGERXP]%GYQYPEXMZIEREP]WMWSJXLIWXYH]VIWYPXWWLS[IHPMXXPIXIQTSVEP TVSKVIWWMSRSJXLITSSPIHSYXGSQISZIVXMQI *MKYVI' 8LMWMRHMGEXIWXLEXRSWMKRMƼGERX HIZMEXMSRWJVSQSVMKMREPƼRHMRKWLEZILETTIRIHSZIVXMQI4SXIRXMEPJSVTYFPMGEXMSRFMEW[EW examined using a funnel plot analysis (Figure 2D). It showed that one included study could be considered an outlier with higher standard error and log odds ratio than should be expected. 8LIEREP]WMWSJEVXMGPIWPSSOMRKMRXS82*»I\TVIWWMSRHYVMRKC. trachomatis infection showed XLEXQER]SJXLIQJSYRHEVIPEXMSRFIX[IIR82*»I\TVIWWMSRERHMRJIVXMPMX]PMOIP]HYIXS XYFETEXLSPSK]GEYWIHF]XLIMRJIGXMSR 8LIEREP]WMW[EWHSRIYWMRKXLIƼ\IHIJ-JIGXQSHIPEWXLIVI[EWRSWMKRMƼGERXLIXIVSKIRIMX]SJXLIWXYH]VIWYPXW%WXEXMWXMGEPP] WMKRMƼGERXIJJIGXSJ82*»I\TVIWWMSR[EWJSYRHSRXLIGSQTPMGEXMSRWVIWYPXMRKJVSQEC.
trachomatis infection and is shown in Figure 3 (P=0.001, OR: 2.4, 95%CI: 1.5 – 4.1). Like the
relation found between C. trachomatisMRJIGXMSRERH-*2½I\TVIWWMSRXLMWEREP]WMWEPWS WLS[IHXLEXRSWMRKPIWXYH]LEHEWMKRMƼGERXIJJIGXSRXLISYXGSQISJXLIQIXEEREP]WMW ERHXLEXXIQTSVEPTVSKVIWWMSR[EWRSXEWMKRMƼGERXJEGXSV%HHMXMSREPP]RSTYFPMGEXMSRFMEW was found for the included studies (Appendix 1: Figure A5).
%REP]WMWSJEVXMGPIWI\EQMRMRKXLIPMROFIX[IIR-0I\TVIWWMSRERHMRƽEQQEXMSRHYVMRKN.
gonorrhoeaeMRJIGXMSRWWLS[IHXLILMKLIWXIJJIGXSJG]XSOMRII\TVIWWMSRSRMRƽEQQEXMSR
of all the analyses (19, 25, 39). Using Dixon’s Q test for outliers, we found that there was RSWXEXMWXMGEPP]WMKRMƼGERXLIXIVSKIRIMX]FIX[IIRXLIWXYHMIW[LMGLQIERX[IGSYPHYWI XLIƼ\IHIJJIGXQSHIPWJSVXLIEREP]WMW8LVSYKLXLMW[IJSYRHEWXEXMWXMGEPP]WMKRMƼGERX MRGVIEWIHGLERGIJSVQSVIWIZIVII\TVIWWMSRSJMRƽEQQEXMSRHYVMRKN. gonorrhoeae infec-tions when IL-1 expression was increased (P=0.009, OR: 2.5, 95% CI: 1.3 – 4.9) as can be seen in Figure 4. As can be seen in Figure A6 of Appendix 1, one-study-removed, cumulative, and TYFPMGEXMSRFMEWXIWXMRKWLS[IHRSWMKRMƼGERXJEGXSVW[IMKLMRKSRXLIVIWYPXW
1IXEEREP]WMW SJ EVXMGPIW GSRXEMRMRK VIWIEVGL MRXS -*2½ I\TVIWWMSR HYVMRK T. pallidum MRJIGXMSRMRLYQERWMRHMGEXIHXLEXMRGVIEWIHI\TVIWWMSRSJ-*2½MWPMROIHXSHIZIPSTQIRX of neurosyphilis (34-36). Although in Figure 5 it appears there is an amount of heterogeneity
EREP]WMW HMH RSX VIWYPX MR E WXEXMWXMGEPP] WMKRMƼGERX VIPEXMSR FIMRK JSYRH FIX[IIR -*2½ expression and the chance of developing neurosyphilis during a T. pallidum infection (P=0,492, OR: 1.5, 95% CI: 0.5 – 4.2) as can be seen in Figure 5. However, when adjusting JSVTYFPMGEXMSRFMEWYWMRKEXVMQERHƼPPQIXLSHEREHNYWXIHVIWYPXSJT 36![EW found. One-study-removed analysis showed a larger pooled outcome, indicating that the study of Knudsen et al EJJIGXIHXLITSSPIHSYXGSQIWMKRMƼGERXP] %TTIRHM\ *MKYVI A8B). A cumulative analysis of the study results showed increasing temporal progression of the pooled outcome over time (Appendix 1: Figure A8C). Potential for publication bias was examined using a funnel plot analysis. It showed that all included studies were borderline outliers with higher standard error and log odds ratio than should be expected (Appendix 1: Figure A8D).
1IXEEREP]WMWSJEVXMGPIWMRXSSXLIVG]XSOMRIWEPWSWLS[IHEWMKRMƼGERXIJJIGXSJI\TVIWWMSR on the outcome of infections with C. trachomatis and N. gonorrhoeae. For C. trachomatis a WMKRMƼGERXPMRO[EWJSYRHMRXLIEVXMGPIWFIX[IIRXLII\TVIWWMSRSJ-0-0ERH-0ERH JIVXMPMX]HMWSVHIVW*SV-0 EPMROFIX[IIRI\TVIWWMSRERHPIZIPSJMRƽEQQEXMSR[EWJSYRH though no direct complications could be linked to it. For N. gonorrhoeae a link was found in XLIEVXMGPIWFIX[IIRXLII\TVIWWMSRSJ-0 ERHXLISRWIXERHPIZIPSJMRƽEQQEXMSRMRXLI host. However, no direct complications could be linked to the expression of these cytokines either.
Figure 2 (A): Meta-analysis of pooled results for C. trachomatis WIZIVMX]PMROIHXS-*2½WIGVIXMSRMRLYQERMRJIGXMSRW YWMRKEƼ\IHIJJIGXQSHIP B): 3RIWXYH]VIQSZIHEREP]WMWXSI\EQMRIWMRKPIWXYH]IJJIGXWWLS[IHRSWMKRMƼGERX effects. (C): Cumulative analysis showing some temporal progression of results.(D): Funnel plot indicating that there [EWIZMHIRGISJWXEXMWXMGEPP]WMKRMƼGERXTYFPMGEXMSRFMEWEQSRKSRISJXLIWXYHMIW.
(B)
(C)
(D)
Figure 3:*M\IHIJJIGXQSHIPEREP]WMRKXLIIJJIGXSJ82*»I\TVIWWMSRSRXLISYXGSQIERHWIZIVMX]SJC. trachomatis infections.
Figure 4: Fixed effect model analysis of the effect of IL-1 expression on the severity of N. gonorrhoeae infections in humans.
DISCUSSION
8LMWMWXLIƼVWXQIXEEREP]WMWXSWLS[XLEXI\TVIWWMSRPIZIPHMJJIVIRGIWSJIMKLXHMJJIVIRX G]XSOMRIWHYVMRKFEGXIVMEPYVSKIRMXEPMRJIGXMSRWLEZIEWMKRMƼGERXUYERXMƼIHIJJIGXSRXLI complications and outcome of these diseases. During C. trachomatis infection the most RSXEFPIIJJIGX[EWJSYRHJSV-*2½ERH82*»I\TVIWWMSRPIZIPHMJJIVIRGIWMRHMGEXMRKXLEX higher expression is a risk factor for more severe complications like tubapathology. During
N. gonorrhoeae infection differences between individuals of especially IL-1 expression were
related to clinical outcome of the disease. During T. pallidum infections the effect of differences in cytokine expression were mostly linked to the stage of the disease. Differences in expression SJ-*2½[IVIQSWXRSXMGIEFPIXLSYKLRSXWMKRMƼGERXERH[IVIVIPEXIHXSTVSKVIWWMSRSJXLI infection to neurosyphilis.
Meta-analysis focussing on cytokines expressed during C. trachomatis infection showed XLIQSWXWMKRMƼGERXVIWYPXWERHMRGPYHIHXLIKVIEXIWXZEVMIX]SJWXYHMIHG]XSOMRIW2SXEFP] QYPXMTPIWXYHMIWWTIGMƼGEPP]PMROIHG]XSOMRIWXSERMRGVIEWIMRXYFETEXLSPSK]ERHVIPEXIH complications (18, 22, 24, 28). These results highlight the relevance of the expression of these cytokines. Cytokines found to have an effect on C. trachomatis infection outcome were PMROIHXS2*Σ&ERH8LIPTIVGIPPG]XSOMRII\TVIWWMSR%WXVSRKVIPEXMSR[EWJSYRHJSV-*2½ which is primarily secreted by Th-1 cells to elicit a cellular immune response and has been found vital to controlling C. trachomatis infections (40, 41). Also highlighted was the relation FIX[IIR82*»I\TVIWWMSRERHXLIHIZIPSTQIRXSJMRJIVXMPMX]HYIXSXLIMRJIGXMSR82*»MW WIGVIXIHEJXIVEGXMZEXMSRSJXLI2*Σ&TEXL[E]ERHMWVIWTSRWMFPIJSVMRƽEQQEXSV]GIPPYPEV GLEVEGXIVMWXMGWWYGLEWZEWGYPEVTIVQIEFMPMX],MKLIVPIZIPWSJ82*»LEZITVIZMSYWP]FIIR related to an increase in scarring during trachoma (42). These results indicate that intensity of infection and immune response are related to severity of complications in patients. The meta-analysis aimed at cytokines expressed during N. gonorrhoeae infection produced QYPXMTPIWMKRMƼGERXVIWYPXW)\TVIWWMSRSJ-0ERH-0 [EWJSYRHXSLEZIEWMKRMƼGERXIJJIGX on the development of urethritis during N. gonorrhoeae infection. There was an increase in MRƽEQQEXMSRHYVMRKXLIMRJIGXMSR[LIRI\TVIWWMSRSJXLIWIG]XSOMRIW[EWMRGVIEWIHLS[IZIV no direct links with any further symptoms or complications could be made (19, 25, 39). The
found in the analyses focussing on C. trachomatis. IL-8 was found to have a weaker effect XLEXEPWSMRGVIEWIWMRƽEQQEXMSRERHPMOIPMLSSHSJMRƽEQQEXMSRVIPEXIHGSQTPMGEXMSRWHYVMRK MRGVIEWIHI\TVIWWMSR8LMWMRHMGEXIWXLEXTVMQEVMP]2*Σ&TEXL[E]VIPEXIHG]XSOMRIWEJJIGX the outcome of N. gonorrhoeae infections, and that the innate immune response is the most important factor in formation of complications.
Meta-analysis focussing on cytokines expressed during T. pallidum infections and the effect XLMWLEHSRXLIWIZIVMX]SJXLIHMWIEWI[EWSRP]TSWWMFPISR-*2½8LMW[EWHYIXSXLIVIP-atively low amount of articles found for the T. pallidumQIXEEREP]WIW*SVI\EQTPI-*2½ [EWGSZIVIHMRSRP]XLVIIEVXMGPIWERHPIEHXSEWXEXMWXMGEPP]MRWMKRMƼGERXVIPEXMSRFIX[IIR HMWIEWITVSKVIWWMSRERHI\TVIWWMSRSJ-*2½%XVMQERHƼPPTVSGIHYVIJSGYWWIHSRVIQSZMRK publication bias from this article pool adjusted the data in such a way that it did become WXEXMWXMGEPP]WMKRMƼGERXLS[IZIVXLI36JSYRHMRXLIQIXEEREP]WMW[IRXJVSQXS8LMW MRHMGEXIWXLEXXLIXVMQERHƼPPQIXLSHLEHWYGLERIJJIGXSRXLIHEXESJXLMWEREP]WMWXLEXXLI VIWYPXWWLSYPHFIXEOIREWERMRHMGEXMSRVEXLIVXLERWXEXMWXMGEPP]WMKRMƼGERXTVSSJSJEVIPEXMSR FIX[IIR-*2½I\TVIWWMSRERHSYXGSQISJT. pallidumMRJIGXMSRW8LIJEGXXLEX-*2½I\TVIWWMSR was also linked to tubapathology in C. trachomatis infections would support the idea that it EPWSLEWERIJJIGXSRXLIMRƽEQQEXMSRFEWIHGSQTPMGEXMSRWSJT. pallidum infections. The results found in this meta-analysis are largely supported by studies that could not be included. An interesting point brought up by another article showed that cytokine expres-sion levels also differed depending on the presence of bacterial vaginosis or lactobacillus HSQMREXIHZEKMREPQMGVSFMSQIW %WFEGXIVMEPZEKMRSWMWMWSJXIRHMƾGYPXXSHIXIGXWSQI MRGPYHIHWXYH]VIWYPXWQE]FIMRƽYIRGIHF]MXWTVIWIRGI&IWMHIWXLMWRSRMRGPYHIHEVXMGPIW also showed that the expression of a number of cytokines not included in this study have a WMKRMƼGERXIJJIGXSRXLISYXGSQISJ78(W*SVMRWXERGI-0I\TVIWWMSR[EWWLS[RXSFI linked to development of asymptomatic and symptomatic neurosyphilis (41). Additionally, the level of expression of CXCL13 and CXCR5 was linked to upper genital tract pathology during C.
trachomatisMRJIGXMSR 9RJSVXYREXIP]HYIXSPEGOSJWYƾGMIRXHEXEXLIWIG]XSOMRIWGSYPH
not be analysed in the meta-analyses.
T. pallidum infections. The link between immune responses and the severity of C. trachomatis
and N. gonorrhoeae infections was previously suggested by studies into the genetics of com-TSRIRXWSJXLI2*Σ&TEXL[E] 9RJSVXYREXIP]XLIVIEVIGYVVIRXP]RSWXYHMIWPMROMRK genetic targets from the immune response to severity of both T. pallidum and C. trachomatis. Targets that affect the severity of multiple pathogens can potentially lead to therapy solutions that also affect multiple pathogens.
Looking beyond the scope of the included pathogens some additional predictions can be QEHI8LIMRƽEQQEXSV]REXYVIERHI\TVIWWMSRSJGSQTPMGEXMSRWHYVMRKSVEJXIVC. trachomatis or N. gonorrhoeae infections shows remarkable similarities with Mycoplasma genitalium. This TSSVP]WXYHMIHTEXLSKIRGSQQSRP]WXE]WEW]QTXSQEXMGSVTVIWIRXWEWMRƽEQQEXMSRMRXLI YVSKIRMXEPXVEGX,S[IZIVMXLEWEPWSFIIRVIPEXIHXS4IPZMG-RƽEQQEXSV](MWIEWIEW[IPPEW tubapathology leading to infertility (46, 47). Additionally, cytokines expressed during infection with M. genitalium are similar to those expressed during infection with C. trachomatis or N.
gonorrhoeae, though no analysis of the effect of different expression levels has been done
for this yet (48). We suggest that the apparent similar disease progression and complications linked to M. genitaliumQIERXLEXI\TVIWWMSRSJG]XSOMRIWWLS[RXSLEZIEWMKRMƼGERXIJJIGX on the severity of C. trachomatis or N. gonorrhoeae infections could also affect the outcome of M. genitalium in a similar way.
Whereas an M. genitalium infection shows similarities to infection with C. trachomatis or N.
gonorrhoeae, an infection with Haemophilus ducreyi shows some similarities with the
skin-based complications arising during infection with T. pallidum. These similarities are mainly found in the ulcers or lesions on the skin where immune-cells such as macrophages and '(8GIPPWGSRZIVKI*SVFSXLSJXLIWITEXLSKIRW-*2½ETTIEVWXSFISRISJXLIQSWXMJ not the most, important cytokine in combatting the infection (49). It is therefore likely that any HMJJIVIRGIMRI\TVIWWMSRSJ-*2½LEWWMQMPEVIJJIGXWSRXLITVSKVIWWMSRERHSYXGSQISJH.
ducreyi infections as they have been shown to do for infections with T. pallidum.
Higher expression of cytokines and the link with complications during infection with STDs has also been explored from a genetics perspective. Effects similar to the ones found in this EVXMGPI[IVIJSYRHMREREP]WMWSJ82*»ERH-0KIRIWMRTISTPIMRJIGXIH[MXLC. trachomatis
as studies into cytokine expression, and have included fewer different cytokine genes. This means that many of the results found for cytokines included in this study cannot be compared to a comparable genetics study. This rings especially true for studies into N gonorrhoeae and
T. pallidum.
A limitation of this study was the use of a funnel plot to check for publication bias. Although this method suggested multiple studies were affected by publication bias, an outlying result from the funnel plot should not be seen as conclusively biased. Besides publication bias, an outlying study may also have genuinely found varying results. Seeing as the affected studies only WLS[IHWXVSRKIVIJJIGXWXLEX[IVIEPWSMRPMRI[MXLƼRHMRKWJSYRHMRSXLIVWXYHMIWTYFPMGEXMSR bias is debatable. Another limitation was the lack of access to data from articles. This lead to a large number of excluded articles with data that could not be processed in the meta-analysis ]IXHMHWLS[WMKRMƼGERXVIWYPXWSRXLIXSTMG
-RGSRGPYWMSRXLMWQIXEEREP]WMWLEWWLS[RXLEXXLIVIMWEWXEXMWXMGEPP]WMKRMƼGERXPMROFIX[IIR -0-0-0 -0-*2½ERH82*»I\TVIWWMSRERHWIZIVMX]SJC. trachomatis infections, and a link between IL-1 and IL-8expression and severity of N. gonorrhoeae infections. Analysis could not be run on pathogens besides these and T. pallidum due to the low number of studies into them.
DECLARATIONS
Supplementary data
Supplementary data are available at FEMSPD online. 'SRƽMGXSJMRXIVIWX
None declared.
REFERENCES
1. 0E[VIRGI 8 8LI RYGPIEV JEGXSV 2*OETTE& TEXL[E] MR MRƽEQQEXMSR 'SPH 7TVMRK ,EVF 4IVWTIGX &MSP 2009;1(6):a001651.
2. Caamano J, Hunter CA. NF-kappaB family of transcription factors: central regulators of innate and adaptive immune functions. Clin Microbiol Rev. 2002;15(3):414-29.
3. Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood. 2008;112(5):1557-69.
4. 0MPIW;':ER:SSVLMW;'6IZMI[ RSQIRGPEXYVIERHFMSPSKMGWMKRMƼGERGISJG]XSOMRIWMRZSPZIHMRMRƽEQQE-tion and the host immune response. J Infect Dis. 1995;172(6):1573-80.
5. Karimi O, Ouburg S, de Vries HJ, Pena AS, Pleijster J, Land JA, et al. TLR2 haplotypes in the susceptibility to and severity of Chlamydia trachomatis infections in Dutch women. Drugs Today (Barc ). 2009;45 Suppl B:67-74. 6. Ouburg S, Lyons JM, Land JA, den Hartog JE, Fennema JS, de Vries HJ, et al. TLR9 KO mice, haplotypes and
CPG indices in Chlamydia trachomatis infection. Drugs Today (Barc ). 2009;45 Suppl B:83-93.
7. Massari P, Ram S, Macleod H, Wetzler LM. The role of porins in neisserial pathogenesis and immunity. Trends Microbiol. 2003;11(2):87-93.
8. Salazar JC, Hazlett KR, Radolf JD. The immune response to infection with Treponema pallidum, the stealth pathogen. Microbes Infect. 2002;4(11):1133-40.
9. Brightbill HD, Libraty DH, Krutzik SR, Yang RB, Belisle JT, Bleharski JR, et al. Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science. 1999;285(5428):732-6.
10. Rarick M, McPheeters C, Bright S, Navis A, Skefos J, Sebastiani P, et al. Evidence for cross-regulated cytokine response in human peripheral blood mononuclear cells exposed to whole gonococcal bacteria in vitro. Microb Pathog. 2006;40(6):261-70.
11. Podwinska J, Lusiak M, Zaba R, Bowszyc J. The pattern and level of cytokines secreted by Th1 and Th2 lymphocytes of syphilitic patients correlate to the progression of the disease. FEMS Immunol Med Microbiol. 2000;28(1):1-14.
12. Danis VA, Millington M, Hyland VJ, Grennan D. Cytokine production by normal human monocytes: inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism. Clin Exp Immunol. 1995;99(2):303-10.
13. Kruse N, Greif M, Moriabadi NF, Marx L, Toyka KV, Rieckmann P. Variations in cytokine mRNA expression during normal human pregnancy. Clin Exp Immunol. 2000;119(2):317-22.
14. )WTSWMXS/2ETTS*1EVJIPPE6+MYKPMERS++MYKPMERS*'MSXSPE1IXEP-RƽEQQEXSV]G]XSOMRIGSRGIRXVEXMSRW are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation. 2002;106(16):2067-72. 15. Whitney AR, Diehn M, Popper SJ, Alizadeh AA, Boldrick JC, Relman DA, et al. Individuality and variation in gene
expression patterns in human blood. Proc Natl Acad Sci U S A. 2003;100(4):1896-901.
16. den Hartog JE, Lyons JM, Ouburg S, Fennema JS, de Vries HJ, Bruggeman CA, et al. TLR4 in Chlamydia trachomatis infections: knockout mice, STD patients and women with tubal factor subfertility. Drugs Today (Barc ). 2009;45 Suppl B:75-82.
17. Arno JN, Ricker VA, Batteiger BE, Katz BP, Caine VA, Jones RB. Interferon-gamma in endocervical secretions of women infected with Chlamydia trachomatis. J Infect Dis. 1990;162(6):1385-9.
19. Hedges SR, Sibley DA, Mayo MS, Hook EW, III, Russell MW. Cytokine and antibody responses in women infected with Neisseria gonorrhoeae: effects of concomitant infections. J Infect Dis. 1998;178(3):742-51.
20. 6EQWI]/,7GLRIMHIV,'VSWW%7&SWPIKS.;,SSZIV(07XEPI]80IXEP-RƽEQQEXSV]G]XSOMRIWTVSHYGIH in response to experimental human gonorrhea. J Infect Dis. 1995;172(1):186-91.
21. Pate MS, Hedges SR, Sibley DA, Russell MW, Hook EW, III, Mestecky J. Urethral cytokine and immune responses in Chlamydia trachomatis-infected males. Infect Immun. 2001;69(11):7178-81.
22. Debattista J, Timms P, Allan J, Allan J. Reduced levels of gamma-interferon secretion in response to chlamyd-MEPO(ELIEXWLSGOTVSXIMREQSRKWX[SQIR[MXLTIPZMGMRƽEQQEXSV]HMWIEWIERHELMWXSV]SJVITIEXIH Chlamydia trachomatis infections. Immunol Lett. 2002;81(3):205-10.
23. Reddy BS, Rastogi S, Das B, Salhan S, Verma S, Mittal A. Cytokine expression pattern in the genital tract of Chlamydia trachomatis positive infertile women - implication for T-cell responses. Clinical and Experimental Immunology. 2004;137(3):552-8.
24. Agrawal T, Vats V, Salhan S, Mittal A. Local markers for prediction of women at higher risk of developing sequelae to Chlamydia trachomatis infection. Am J Reprod Immunol. 2007;57(2):153-9.
25. Cauci S, Culhane JF. Modulation of vaginal immune response among pregnant women with bacterial vaginosis by Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, and yeast. Am J Obstet Gynecol. 2007;196(2):133-7.
26. Mazzoli S, Cai T, Rupealta V, Gavazzi A, Castricchi PR, Mondaini N, et al. Interleukin 8 and anti-chlamydia tra-chomatis mucosal IgA as urogenital immunologic markers in patients with C. tratra-chomatis prostatic infection. Eur Urol. 2007;51(5):1385-93.
27. Vats V, Agrawal T, Salhan S, Mittal A. Primary and secondary immune responses of mucosal and peripheral lymphocytes during Chlamydia trachomatis infection. FEMS Immunol Med Microbiol. 2007;49(2):280-7. 28. Agrawal T, Vats V, Wallace PK, Salhan S, Mittal A. Role of cervical dendritic cell subsets, co-stimulatory
mol-IGYPIWG]XSOMRIWIGVIXMSRTVSƼPIERHFIXEIWXVEHMSPMRHIZIPSTQIRXSJWIUYEPEIXS'LPEQ]HMEXVEGLSQEXMW infection. Reprod Biol Endocrinol. 2008;6:46.
29. Srivastava P, Jha R, Bas S, Salhan S, Mittal A. In infertile women, cells from Chlamydia trachomatis infected sites release higher levels of interferon-gamma, interleukin-10 and tumor necrosis factor-alpha upon heat-shock-protein stimulation than fertile women. Reprod Biol Endocrinol. 2008;6:20.
30. Agrawal T, Gupta R, Dutta R, Srivastava P, Bhengraj AR, Sathan S, et al. Protective or pathogenic immune VIWTSRWIXSKIRMXEPGLPEQ]HMEPMRJIGXMSRMR[SQIR%TSWWMFPIVSPISJG]XSOMRIWIGVIXMSRTVSƼPISJGIVZMGEP mucosal cells. Clinical Immunology. 2009;130(3):347-54.
31. Agrawal T, Vats V, Wallace PK, Singh A, Salhan S, Mittal A. Recruitment of myeloid and plasmacytoid dendritic cells in cervical mucosa during Chlamydia trachomatis infection. Clin Microbiol Infect. 2009;15(1):50-9. 32. Gupta R, Srivastava P, Vardhan H, Salhan S, Mittal A. Host immune responses to chlamydial inclusion
mem-brane proteins B and C in Chlamydia trachomatis infected women with or without fertility disorders. Reprod Biol Endocrinol. 2009;7:38.
33. Gupta R, Vardhan H, Srivastava P, Salhan S, Mittal A. Modulation of cytokines and transcription factors (T-Bet and GATA3) in CD4 enriched cervical cells of Chlamydia trachomatis infected fertile and infertile women upon stimulation with chlamydial inclusion membrane proteins B and C. Reprod Biol Endocrinol. 2009;7:84. 34. /RYHWIR%&IRƼIPH8/SJSIH/']XSOMRII\TVIWWMSRHYVMRKW]TLMPMWMRJIGXMSRMR,-:MRJIGXIHMRHMZMHYEPW
35. Cruz AR, Ramirez LG, Zuluaga AV, Pillay A, Abreu C, Valencia CA, et al. Immune evasion and recognition of the syphilis spirochete in blood and skin of secondary syphilis patients: two immunologically distinct compart-ments. PLoS Negl Trop Dis. 2012;6(7):e1717.
36. Pastuszczak M, Jakiela B, Wielowieyska-Szybinska D, Jaworek AK, Zeman J, Wojas-Pelc A. Elevated cerebro-WTMREPƽYMHMRXIVPIYOMR%ERHMRXIVJIVSRKEQQEPIZIPWMRIEVP]EW]QTXSQEXMGRIYVSW]TLMPMW7I\8VERWQ(MW 2013;40(10):808-12.
37. %M]EV%5YE]PI%.&YGORIV067LIVGLERH74'LERK80>IE%,IXEP-RƽYIRGISJXLIXV]TXSTLERMRHSPI-*2-gamma axis on human genital Chlamydia trachomatis infection: role of vaginal co-infections. Front Cell Infect Microbiol. 2014;4:72.
38. Marconi C, Santos-Greatti MM, Parada CM, Pontes A, Pontes AG, Giraldo PC, et al. Cervicovaginal levels of TVSMRƽEQQEXSV]G]XSOMRIWEVIMRGVIEWIHHYVMRKGLPEQ]HMEPMRJIGXMSRMRFEGXIVMEPZEKMRSWMWFYXRSXMRPEGXSFE-GMPPMHSQMREXIHƽSVE.0S[+IRMX8VEGX(MW
39. 1EWWSR01PMWERE/0MXXPI*;IVRIV01OLM^I226SREGLIV/IXEP(IƼRMRKKIRMXEPXVEGXG]XSOMRIWMKREXYVIW of sexually transmitted infections and bacterial vaginosis in women at high risk of HIV infection: a cross-sec-tional study. Sex Transm Infect. 2014;90(8):580-7.
40. 7Y,'EPH[IPP,('(8GIPPWTPE]EWMKRMƼGERXVSPIMREHSTXMZIMQQYRMX]XS'LPEQ]HMEXVEGLSQEXMWMRJIGXMSR of the mouse genital tract. Infect Immun. 1995;63(9):3302-8.
41. Wang S, Fan Y, Brunham RC, Yang X. IFN-gamma knockout mice show Th2-associated delayed-type L]TIVWIRWMXMZMX]ERHXLIMRƽEQQEXSV]GIPPWJEMPXSPSGEPM^IERHGSRXVSPGLPEQ]HMEPMRJIGXMSR)YV.-QQYRSP 1999;29(11):3782-92.
42. Conway DJ, Holland MJ, Bailey RL, Campbell AE, Mahdi OS, Jennings R, et al. Scarring trachoma is associated with polymorphism in the tumor necrosis factor alpha (TNF-alpha) gene promoter and with elevated TNF-alpha PIZIPWMRXIEVƽYMH-RJIGX-QQYR
43. Jiang J, Karimi O, Ouburg S, Champion CI, Khurana A, Liu G, et al. Interruption of CXCL13-CXCR5 axis increases upper genital tract pathology and activation of NKT cells following chlamydial genital infection. 2012. 44. Natividad A, Hanchard N, Holland MJ, Mahdi OS, Diakite M, Rockett K, et al. Genetic variation at the TNF
locus and the risk of severe sequelae of ocular Chlamydia trachomatis infection in Gambians. Genes Immun. 2007;8(4):288-95.
45. Taylor BD, Darville T, Ferrell RE, Ness RB, Haggerty CL. Racial variation in toll-like receptor variants among [SQIR[MXLTIPZMGMRƽEQQEXSV]HMWIEWI.-RJIGX(MW
46. Clausen HF, Fedder J, Drasbek M, Nielsen PK, Toft B, Ingerslev HJ, et al. Serological investigation of Myco-plasma genitalium in infertile women. Human Reproduction. 2001;16(9):1866-74.
47. Cohen CR, Manhart LE, Bukusi EA, Astete S, Brunham RC, Holmes KK, et al. Association between Mycoplasma genitalium and acute endometritis. The Lancet. 2002;359(9308):765-6.
48. McGowin CL, Popov VL, Pyles RB. Intracellular Mycoplasma genitalium infection of human vaginal and cervical ITMXLIPMEPGIPPWIPMGMXWHMWXMRGXTEXXIVRWSJMRƽEQQEXSV]G]XSOMRIWIGVIXMSRERHTVSZMHIWETSWWMFPIWYVZMZEP niche against macrophage-mediated killing. BMC microbiology. 2009;9(1):139.
49. 7TMRSPE713VE^M%%VRS.2*SVXRI]//SX]PS4'LIR'=IXEP,EIQSTLMPYWHYGVI]MIPMGMXWEGYXERISYWMRƼP-trate of CD4 cells during experimental human infection. Journal of Infectious Diseases. 1996;173(2):394-402. 50. Murillo LS, Land JA, Pleijster J, Bruggeman CA, Pe+¦a AS, Morr+¬ SA. Interleukin-1B (IL-1B) and interleukin-1
51. Ohman H, Tiitinen A, Halttunen M, Lehtinen M, Paavonen J, Surcel HM. Cytokine polymorphisms and severity of tubal damage in women with Chlamydia-associated infertility. Journal of Infectious Diseases. 2009;199(9):1353-9.
52. Ohman H, Tiitinen A, Halttunen M, Paavonen J, Surcel HM. Cytokine gene polymorphism and Chlamydia XVEGLSQEXMWWTIGMƼGMQQYRIVIWTSRWIW,YQERMQQYRSPSK]
