|Year : 2021 | Volume
| Issue : 4 | Page : 145-154
Etiopathogenesis of reproductive tract infections and the emerging role of bitter taste receptors: A scoping review
Menizibeya O Welcome1, Abraham Jeremiah2, Dennis O Allagoa3, Senol Dane1, Vladimir A Pereverzev4
1 Department of Physiology, Faculty of Basic Medical Sciences, Nile University of Nigeria, Abuja, Nigeria
2 Department of Surgery, Federal Medical Centre, Yenagoa, Nigeria; Department of Surgery, Belarusian State Medical University, Minsk, Belarus
3 Department of Obstetrics and Gynecology, Federal Medical Centre, Yenagoa, Nigeria
4 Department of Normal Physiology, Belarusian State Medical University, Minsk, Belarus
|Date of Submission||24-Mar-2021|
|Date of Decision||30-May-2021|
|Date of Acceptance||18-Jun-2021|
|Date of Web Publication||20-Jul-2021|
Menizibeya O Welcome
Department of Physiology, Faculty of Basic Medical Sciences, Nile University of Nigeria, Abuja
Source of Support: None, Conflict of Interest: None
Reproductive tract infections pose an immense public health concern worldwide as over 600 million new cases are recorded annually along with several complications, including infertility, ectopic pregnancy, preterm delivery, and neonatal death. Despite improved understanding of the mechanisms of pathogenic invasion, the etiopathogenesis of reproductive tract infections is yet to be completely understood. Recent data has suggested a critical role of bitter taste receptors of the reproductive tract in etiopathogenesis of reproductive tract infections. Here, we review the literature on current etiopathogenesis of reproductive tract infections and the role of bitter taste receptors of the reproductive tract in etiopathogenesis of reproductive tract infections. Emerging evidence suggests a critical role of microbiota disorder of the reproductive tract in reproductive tract infections. Several bacterial, protozoan parasitic, helminthic parasitic and viral pathogens have been identified as causative agents of reproductive tract infections. These pathogens subvert host defenses and activate specific architectural units of the uroepithelium such as Toll-like receptors, which recognize conserved motifs on the pathogens. The activated Toll-like receptors mediate downstream signaling, stimulating nuclear factor-κB, which in turn activates the production of proinflammatory cytokines. This pathway is also associated with recruitment of immunocytes to the site of aggression and release of proteinases, which drive tissue damage in the reproductive tract. Defects in detection of pathogenic components by the bitter taste receptors of the reproductive tract may play a critical role in the etiopathogenesis of reproductive tract infections. This review provides important information for identification of novel frontiers for the treatment of reproductive tract infections.
Keywords: Infection; Genital inflammation; Reproduction; Reproductive tract infections; Bitter taste receptor; Etiopathogenesis; Cytokines
|How to cite this article:|
Welcome MO, Jeremiah A, Allagoa DO, Dane S, Pereverzev VA. Etiopathogenesis of reproductive tract infections and the emerging role of bitter taste receptors: A scoping review. Asian Pac J Reprod 2021;10:145-54
|How to cite this URL:|
Welcome MO, Jeremiah A, Allagoa DO, Dane S, Pereverzev VA. Etiopathogenesis of reproductive tract infections and the emerging role of bitter taste receptors: A scoping review. Asian Pac J Reprod [serial online] 2021 [cited 2021 Sep 17];10:145-54. Available from: http://www.apjr.net/text.asp?2021/10/4/145/321122
| 1. Introduction|| |
Reproductive tract infections pose a significant public health concern worldwide, with an estimated 600 million new cases recorded annually among people aged 15-49 years. Reproductive tract infections are some of the most frequent infectious diseases in clinical practice, substantially surpassing respiratory tract, gastrointestinal tract, and surgical site infections put together. Though the incidence rate among young people is higher, reproductive tract infections can affect all ages, including neonates, children, and pregnant women,,. It is widely accepted that reproductive tract infections such as epididymitis, urethritis, orchitis, and prostatitis constitute critical cause of infertility. Indeed, reproductive tract infections due to Chlamydia have been reportedly associated with approximately 40% incidence of prostatitis. Multiple lines of evidence have consistently shown a key role of reproductive tract infections in development of infertility in both males and females, of the reproductive age. For instance, Ricci et al demonstrated that Enterococcus faecalis, Mycoplasma hominis or Ureaplasma urealyticum in genital samples of infertile couples were associated with reduced sperm quality, bacterial vaginosis, and failure of in vitro fertilization.
Reproductive tract infections are associated with severe complications including ectopic pregnancy, end stage renal disease in adults, premature delivery, neonatal death, chronic pelvic pain and neurological and cardiovascular diseases,, cervical neoplasia in women and penile cancer in men. Furthermore, some types of reproductive tract infections are associated with stigma, stereotyping, shame, vulnerability and can lead to gender related violence, thereby increasing the psychosocial impact on the individual,. The efforts made to characterize the molecular mechanisms of virulence and resistance to antibiotics appear to have had no impact on the incidence rate, diagnosis and effectiveness of treatment of reproductive tract infections. Thus, it is essential to investigate the etiopathogenesis of reproductive tract infections and search for new frontiers that could translate to the development of novel therapeutics.
Emerging data suggest a critical role of bitter taste receptors of the reproductive tract in etiopathogenesis of reproductive tract infections. Bitter taste receptors are 7-transmembrane G protein-coupled receptors that sense bitter substances to trigger signaling downstream several acceptors, mediating responses that ultimately culminate in protection of the cell against pathogenic aggression or toxigenic substances. In humans, 25 bitter taste receptors (T2Rs) have been identified,, whereas murine bitter taste receptors, designated “T2r”, have 35 subtypes. Bitter taste receptors are activated by bitter compounds such as amarogentin, denatonium, caffeine, 6-propyl-2 thiouracil, picrotin, salicin, and cycloheximide,,. These receptors were first discovered in the oral cavity in taste bud cells, where they were thought to act only as detectors of poisonous bitter-tasting compounds to prevent their ingestion. Further research led to the discovery of these receptors in other regions of the gastrointestinal tract, in particular, the stomach and intestines, which suggested that these receptors may perform roles other than just sensing poisonous bitter substances. Bitter taste receptors are now believed to be ubiquitously expressed in several cells and tissues of the body,.
More recently, researchers have reported the expression of bitter taste receptors in multiple tissues and organs of the reproductive tract,,, where they are believed to sense bitter compounds or metabolites produced by pathogenic microbes, in particular, microbial quorum-sensing signal molecules,,. Under normal condition, stimulation of T2R by microbial quorum-sensing signal molecules activates downstream targets that lead to the mobilization of protective mechanisms against the microbial aggression. However, disorders in T2R signaling activate proinflammatory and destructive processes, consequently resulting in the development of diseases. Here, we review the literature on current etiopathogenesis of reproductive tract infections and highlight the role of bitter taste receptors of the reproductive tract in etiopathogenesis of reproductive tract infections. This review provides important data for identification of novel frontiers for the treatment of reproductive tract infections.
| 2. Current perspectives on etiology and pathogenesis of reproductive tract infections|| |
The etiological factors of reproductive tract infections can be grouped as primary and infections resulting from disorders of the microbiome. Our discussion will be based on the former as it is the most widely studied, but emerging data about the latter will also be summarized.
2.1. Role of genital microbiome in etiopathogenesis of reproductive tract infections
The reproductive tract contains several millions of normal microflora,,, which produce a variety of molecules such as lactic acid, hydrogen peroxide, bacteriocins that protect against pathogenic invasion or bacterial overgrowth. Disorders of the microflora of the reproductive tract can predispose to reproductive tract infections.
Though the mechanism of dysfunction of the genital tract microbiome and its role in etiopathogenesis of reproductive tract infections are not exactly understood, available data indicate that disorders arising from the normal microbiome are mainly due to antibiotic use or immunosuppression that causes substantial decrease in beneficial bacterial population and increase in harmful species. Tabatabaei et al recently reported decreased quantity of vaginal Lactobacilli and Bifidobacteria spp. in pregnancy complications due to uterine and vaginal inflammation. Furthermore, the authors showed that vaginal pathogens such as Atopobium vaginae, Gardnerella vaginalis and Veillonellaceae bacterium were associated with reproductive tract inflammation and pregnancy complications. Similar findings were reported by Hocevar et al.
Therefore, disorders of the genital tract microflora can readily predispose to the development of inflammatory diseases of the reproductive tract,,.
2.2. Role of genital pathogens in etiopathogenesis of reproductive tract infections
Though specific etiological agent has peculiar pathogenetic mechanism, here we will give an overview of pathogenesis of reproductive tract infections. The primary etiological factors of reproductive tract infections are pathogenic bacteria, protozoan parasites, helminthic parasites, and virus, and are usually transmitted sexually. These pathogenic microbes can affect different structures of the reproductive,,.
Ascension of infection through the urethra, vagina and cervix is a key mechanism of colonization of the reproductive tract by pathogens,. In addition, certain pathogens including the human immunodeficiency virus and Treponema pallidum that affect the reproductive tract may disseminate through the bloodstream,.
Despite activation of defense mechanisms of the host, genital pathogens still adhere to the mucous surface where they begin their destructive actions, in part, due to the presence of adhesive appendages on their surface,,. The reproductive tract epithelial cells recognize the presence of pathogens by specific cellular signatures on the invading microbes or danger signal molecules released upon pathogenic invasion (vide infra).
2.3. Cellular signaling mechanisms initiated by genital pathogens in pathogenesis of reproductive tract infections
Cellular signatures of the invading microbes [such as lipopolysaccharide (LPS), peptidoglycan, lipoteichoic acid, teichoic acid, lipoarabinomannan, arabinogalactan, lipopeptides, flagellin, pathogenic bacterial DNA and viral RNA] or damage-related signals activate several architectural units of the epithelial cells [e.g. Tolllike receptor (TLR) 2 and TLR4, which belong to the broad class of pattern recognition receptors that enable cells to recognize conserved motifs on the surface of bacteria, protozoa, virus, known as pathogen-associated molecular patterns],,,,. The pattern recognition receptors can also respond to molecules released from cellular damage [(damage-associated molecular patterns (DAMPs)]. Examples of DAMPs include laminin, elastin and collagen-derived peptides, fibronectin, heat shock proteins, RNA, nuclear DNA, mitochondrial DNA, interleukin (IL)-1, high mobility group box 1 protein, histones, adenosine triphosphate, antimicrobial peptides, versican, biglycan, matrix metalloproteinase-3 and -13,,,.
2.3.1. TLR activation by the components of genital pathogens triggers proinflammatory cascades, immune cell chemotaxis and tissue damage
The activation of TLR2 or TLR4 by components of genital pathogens triggers cellular signaling downstream several intracellular acceptors, activating protein kinases and other signaling molecules, including the nuclear factor κ-B (NF-κB) with resultant production of proinflammatory cytokines such as IL-1 β, IL-2, IL-6, IL-8, IL-12, IL-15, IL-21, INF-γ, and TNF- α,,.
The pathogenic components and proinflammatory cytokines recruit and activate the cells of the immune system, which initially is meant to resolve the microbial aggression, but also leads to collateral tissue damage. The secreted cytokines and other factors increase the expression of endothelial adhesion molecules, which in turn promotes chemotaxis of immunocytes to the site of aggression. Recruitment of neutrophils, natural killer cells, monocytes, and plasma cells, as well as homing T and B cells further increases the production of cytokines, in addition to the activities of resident macrophages, which also stimulate cytokine/chemokine synthesis, thereby amplifying the inflammatory response,. Furthermore, the inflammatory response is accompanied by mucosal infiltration. The infected reproductive tract epithelial cells, neutrophils and monocytes secrete matrix metalloproteinase (MMP)-2, MMP-9, and elastase. MMPs participate in resynthesis and remodeling of the extracellular matrix, whereas elastase drives proteolytic cleavage that contributes to tissue damage,. These processes are usually associated with pyuria.
2.3.2. Cellular mechanisms underlying complications associated with reproductive tract infections
Over the past few decades, there has been substantial increase in research interest on the complications of reproductive tract infections. Notwithstanding, however, the cellular and molecular mechanisms fundamental to the development of these complications are not completely understood. Here, we will discuss the cellular mechanisms underlying ectopic pregnancy, preterm labor, female and male infertility as complications of reproductive tract infections. The action of pathogens in the intrauterine and fallopian microenvironment favors implantation of the blastocyst in regions of the reproductive system other than the endometrium, resulting in ectopic pregnancy,,,. Though the molecular signaling cascades are not exactly clear, it is believed that genital pathogens cause disorders in expression of hormones, cytokines, chemokines and cell adhesion molecules that participate or direct the implantation of the blastocyst to the extra-uterine epithelium,. Indeed, the movement of the fertilized egg to the endometrium for implantation is primarily dictated by environmental cues controlled by hormones, endogenous small molecules (including cytokines) and cell adhesion receptors. For instance, Ashshi reported that up-regulation of the expression of IL-6 predisposes to ectopic pregnancy in cytomegalovirus infection. Again, the high nitric oxide (NO) output mediated by inducible NO synthase can cause substantial loss of structural and functional integrity of the reproductive tract epithelium, thereby resulting in implantation of the blastocyst in unusual locations other than the endometrium. Thus, pathogen-induced changes in the milieu of the uterine tube send stronger signal to the blastocyst, dictating the site of implantation at the fallopian tube, rather than the endometrium, consequently resulting in ectopic pregnancy.
Research data have consistently shown that infection or inflammation induces preterm delivery, which is the commonest cause of neonatal death. Statistical estimate indicates that over 40% of preterm deliveries are associated with intrauterine infections. The mucosal reactions resulting from pathogenic invasion or microbial aggression in the reproductive tract are also accompanied by production of prostaglandins (PG), such as PGE2a and PGF2a. These eicosanoids are strong stimulators of uterine contraction, that results in preterm labor. Indeed, microbial invasion of the amniotic cavity and funisitis have been shown to induce a significant increase in PGE2 and PGF2α in preterm labor. Therefore, intrauterine infections in pregnancy can predispose to preterm labor through the action of proinflammatory prostaglandins. However, reproductive tract infection can induce preterm labor by alteration of vaginal, uterine and placental microbiome (vide supra),,. For example, Tabatabaei et al investigated vaginal microbiome between preterm (< 34-36 weeks) and term births and found association between vaginal Lactobacilli and Bifidobacteria spp. with uterine inflammation and preterm delivery. In addition, proinflammatory bacterial species such as Atopobium vaginae, Gardnerella vaginalis, and Veillonellaceae were associated with increased risk of preterm birth. Research has shown that specific pattern of chemokine expression in gestational tissues is associated with preterm labor. Using a model of LPS-induced preterm labor in mice, Mizoguchi et al observed the harmful role of CX3CL1-CX3CR1 in the uterine milieu before and during preterm labor. LPS-treated mice with intact CX3CR1 experienced preterm delivery through a mechanism related to increased recruitment of macrophages by CX3CL1 and its cognate receptor CX3CR1. In contrast, CX3CR1-deficient mice did not experience preterm labor despite LPS treatment. Interestingly, evidence indicates that anti-inflammatory prostaglandin or drug therapy using FP receptor antagonist (e.g. AS604872 and OBE022), cyclooxygenase-2 inhibitors, and non-steroidal anti-inflammatory drug may be helpful in preventing preterm labor,,.
Available data indicate that about 15% of all cases of infertility are due to reproductive tract infections. Ascending infection resulting in pelvic inflammatory diseases can cause infertility in both males and females. Reproductive tract infections involving Chlamydia trachomatis, Neisseria gonorrhoeae, Escherichia coli and Herpes simplex are mostly associated with infertility in both sexes. In females, these pathogenic microbes are involved in cervical, tubal, and peritoneal damage (lacerations and/or obstruction), as well as pelvic inflammatory disease, and adhesions that lead to infertility,. In males, genital pathogens (e.g. Chlamydia trachomatis) can produce antisperm antibodies, and increase the rate of generation of reactive oxygen species that affect not only the structure and functions of the testis and epididymis, but also spermatozoa functions and the process of spermatogenesis, thereby interfering with their development, maturation, and motility, consequently, resulting in infertility,,.
2.3.3. Predisposing factors for reproductive tract infections
The occurrence and severity of complications associated with reproductive tract infections depend on several factors, which include structural and functional abnormalities of the reproductive tract,,,, promiscuous sexual behavior, antibiotic use, comorbidities, etc,.
Genetic predisposing factors include ABH blood group non-secretor phenotype, TLR2, TLR4, Heat Shock Protein Family A, Hsp70 Member 1B (HspA1B), C-X-C motif chemokine receptor (CXCR)-1, CXCR-2, transforming growth factor beta-1 (TGFβ 1), and IFN-λ genes among others,,,. Notably, Caine et al established greater reproductive tract infection following intravaginal Zika virus inoculation in female mice lacking IFN-λ signaling. Additionally, polymorphisms in G protein-coupled estrogen receptor (GPER) 1 gene and NO synthase 2 gene respectively have been associated with recurrent spontaneous abortion and benign prostatic hyperplasia. Furthermore, Liassides et al demonstrated in a sample of 145 pregnant women that minor alleles of single nucleotide polymorphisms of TLR4 gene and autophagy-related gene 16-like-1 (ATG16L1) rs2241880 GG genotype constitute critical predisposing factors to early preterm delivery. Similarly, previous findings by Taylor et al revealed that certain polymorphisms in TLR1 and TLR4 genes increase pathogenic signaling that is associated with increased Chlamydia trachomatis infection in women. Consequently, deletion of TLR4 gene has been found to confer protection against reproductive tract infections. Likewise, deletion of myeloid differentiation factor 88 (MyD88), Toll/interleukin-1 receptor-domain-containing adaptor-inducing interferon- β (TRIF), and TRIF-related adaptor molecule (TRAM) genes (encode MyD88, TRIF, and TRAM signaling proteins, respectively, as cytoplasmic targets of the TLR-NF-κB pathway) reportedly abrogated inflammatory reactions of epithelial cells in response to pathogenic challenge, and protected the host from tissue damage and reproductive tract infections.
Virulence factors also substantially modulate the pathogenesis and outcome of reproductive tract infections,. The role of microbial virulence in the pathogenesis of reproductive tract infections has been extensively discussed elsewhere,,,,.
| 3. Emerging concepts in etiopathogenesis of reproductive tract infections: The role of bitter taste receptors of the reproductive tract|| |
3.1. Bitter taste receptors as novel immune sentinels of the reproductive tract milieu
Over the past few years, accumulating research evidence has shown that bitter taste receptors serve as immune sensors owing to their participation in effectively recognizing not only toxins, but also components of pathogenic microbes and mobilize protective mechanisms against the aggression. For this reason, bitter taste receptors have been regarded as a key part of the sensory and immune system. Taste receptors are expressed in different structures and regions of the reproductive tract [Table 1] and are believed to serve as immune sentinels.
|Table 1: Bitter taste receptor expression in the murine and human reproductive tract.|
Click here to view
Zheng et al demonstrated that chloroquine, a bitter taste receptor agonist, prevented LPS- or mifepristone (progesterone receptor antagonist)-induced preterm delivery in murine models. The researchers also reported that chloroquine was more effective in preventing preterm delivery, compared to currently used tocolytics. However, this effect of chloroquine was lost in α -gustducin-knockout mice, suggesting that bitter taste receptors are critical players in preterm delivery induced by intrauterine infections. In vitro model also showed that T2R14 knockdown abated the effect of chloroquine in human myometrial cells.
Disorders in placental bitter taste receptor signaling may play a role in neonatal death. The bitter taste receptors of the placenta may be involved in detection of toxigenic and pathogenic substances. Under normal condition, these receptors mobilize protective mechanisms that prevent toxigenic and pathogenic substances from getting to the embryo or fetus, thereby preventing inflammatory responses in the placenta. Though there is a severe scarcity of data, it can be suggested that placental bitter taste receptors may be integral to the pathophysiology of villitis, chorioamnionitis and stillbirth. Apart from the inflammatory responses associated with bitter taste receptors, evidence also indicates that myometrial bitter taste receptors are involved in contractile activities in the uterine microenvironment, suggesting that these receptors may be involved in preterm delivery and may serve as potential target for novel tocolytics for more effective management of preterm labor,.
The expression of bitter taste receptors in spermatozoa strongly indicates a possible link between inflammatory/infectious diseases and infertility. Indeed, the uropathogenic microbe Pseudomonas aeruginosa was shown to cause disorders in bitter taste receptor signaling in spermatozoa with resultant multiple damages to these gamete cells. Thus, bitter taste receptors of spermatozoa are involved in detection of toxigenic compounds and uropathogenic microbes and initiate responses that culminate in their elimination or prevention of microbial aggression.
Interactions between the bitter taste receptors and microbiota of the reproductive tract under normal conditions may be required to maintain the integrity of the reproductive tract epithelium via bitter taste receptor-dependent sensing of bitter metabolites (e.g. short chain fatty acids) and other signaling molecules (vide infra) of the microbiota,. Indeed, abundance of the beneficial microflora has been shown to positively correlate with bitter taste receptor expression, suggesting that downregulation of these receptors may predispose to reproductive tract infections,. Thus, disorders of the reproductive tract microbiota can drive pathological signaling by the bitter taste receptors.
3.2. Bitter taste receptors of the reproductive tract mobilize defense mechanisms against pathogens by sensing the “quorum”
Bitter taste receptors of the reproductive tract regulate the activities of pathogens by detecting microbial quorum-sensing signal molecules. Quorum sensing can be defined as a process that allows microbes to communicate amongst themselves and share information about cell density and adjust gene expression through the release of molecules known as microbial quorum-sensing signal molecules,. The virulence of pathogens to a large extent depends on production of quorum-sensing signal molecules,,,. Thus, quorum sensing of signal molecules is an important mechanism used by pathogens to invade the host, in part, by delaying the secretion of virulence factors until adequate number of pathogens is available to counter the host defense,. There are different types of quorum-sensing signal molecules [Table 2],. The quorum-sensing molecules produced by Gram-negative bacteria are called autoinducers,,, whereas Gram-positive bacteria produce autoinducing peptides as their quorum-sensing signal molecules.
|Table 2: Quorum sensing signal molecules produced by Gram-negative bacteria, Gram-negative bacteria, and parasites.|
Click here to view
Quorum-sensing signal molecules serve as targets for bitter taste receptors. Stimulation of these receptors by the quorum-sensing molecules can initiate signaling cascades that activate defense mechanisms against pathogenic aggression. For example, under normal circumstance, spermatozoa is believed to actively sense the signal molecules produced by Pseudomonas aeruginosa and pathogenic fungi Candida albicans to avert potential aggression. However, dysfunctional bitter taste receptor signaling predisposes to impairment in spermatozoa functions. Similarly, bitter taste receptors in multiple regions of the reproductive tract detect the quorum-sensing signal molecules to control colonization of the tract by pathogens through initiation of microbicidal effects and other responses that lead to elimination or control of pathogenic invasion. Thus, investigating the signaling mechanisms of quorum-sensing signal molecules and bitter taste receptors of the reproductive tract may lead to identification of novel frontiers in the treatment of reproductive tract infections. Indeed, current research interest includes the investigation of effectiveness of novel antimicrobial therapy on pathogenic quorum-sensing signal molecules to control multi-resistant species,. Thus, the mechanisms of bitter taste receptor detection of quorum sensing molecules and the molecular basis of downstream signaling that ultimately lead to elimination of pathogenic aggression can provide important data for possible medical application in the treatment of reproductive tract infections [Figure 1].
|Figure 1: Role of bitter taste receptor (T2R) in reproductive tract inflammation. βγ and α-gustducin are subunits of T2R. Functional T2R detects physiological concentration of bitter microbial substances [e.g. quorum sensing (QS)] leading to dissociation of the α- subunit gustducin from the βγ subunits with exchange of guanine diphosphate for guanine triphosphate. The dissociated α-gustducin activates adenylate cyclase, which converts adenosine triphosphate to cyclic adenosine monophosphate (cAMP). Increase in cAMP level can activate protein kinase A (PKA). The βγ subunits activate phospholipase Cβ, which breaks down phosphatidylinositol 4,5-bisphosphate to form diacylglycerol and 1,4,5-inositol trisphosphate (IP3). IP3 is responsible for the release of Ca2+ from intracellular stores. Increased cytosolic Ca2+ activates Ca2+-dependent kinases and transcription factors. IP3 can mediate increase in the activity of SIRT1 (consecutively via PDK-1, Akt and mTORC1), the sensor that can activate NF-KB to regulate the expression of inflammatory mediators and protective factors. diacylglycerol can stimulate protein kinase C (PKC). PKA and PKC can regulate gene expression via interaction with Ca2+-dependent and other transcription factors involved in inflammatory responses. However, Ca2+ can activate calmodulin to form Ca2+-calmodulin complex, which in turn activates nitric oxide synthase (NOS). This enzyme catalyzes the oxidation of L-arginine (L-Arg) to L-citrulline and nitric oxide (NO). The latter has microbicidal effects in living cells. SIRT1: Sirtuin 1 or NAD (nicotinamide-adenine dinucleotide)-dependent deacetylase sirtuin-1. PDK-1: phosphoinositide-dependent protein kinase-1; PKB/Akt: protein kinase B; mTORC1: complex 1 of mammalian target of rapamycin; NF-κB: nuclear factor kappaB.|
Click here to view
| 4. Conclusions|| |
Reproductive tract infections are caused by genital microbiome disorders and/or invasion of the reproductive tract by bacterial, protozoan parasitic, helminthic parasitic or viral pathogens that subvert the host defense mechanisms, activating specific architectural units, including TLR-2 and TLR-4, to stimulate downstream intracellular targets such as NF-κB, which mediates expression of proinflammatory cytokines/chemokines. These processes are associated with recruitment of immunocytes to the site of aggression and secretion of proteinases that drive tissue damage in the reproductive tract. Bitter taste receptors of the reproductive tract also play a critical role in etiopathogenesis of reproductive tract infections by detecting microbial quorum-sensing signal molecules to mediate inflammatory signaling cascades and mobilize defense measures against pathogenic invasion. This paper provides a background on potential therapeutic significance of pharmacological targeting of bitter taste receptors of the reproductive tract for the treatment of reproductive tract infections.
Conflict of interest statement
The authors declare that there is no conflict of interest.
Menizibeya O. Welcome developed the idea and concept, conducted literature search, analyzed the relevant literatures, prepared the draft, edited and revised the text; Abraham Jeremiah participated in conducting the literature search, analyzed the relevant literatures, and edited the text; Dennis O. Allagoa participated in analysis of the literatures, edited and revised the text; Senol Dane participated in analysis of the literatures, edited and revised the text; Vladimir A. Pereverzev participated in analysis of the literatures, edited and revised the text.
| References|| |
Newman L, Rowley J, Vander Hoorn S, Wijesooriya NS, Unemo M, Low N, et al. Global estimates of the prevalence and incidence of four curable sexually transmitted infections in 2012 based on systematic review and global reporting. PLoS One
Cullen IM, Manecksha RP, McCullagh E, Ahmad S, O’Kelly F, Flynn RJ, et al. The changing pattern of antimicrobial resistance within 42 033 Escherichia coli
isolates from nosocomial, community and urology patient-specific urinary tract infections, Dublin, 1999-2009. BJU Int
Becerra BJ, Becerra MB, Safdar N. A nationwide assessment of the burden of urinary tract infection among renal transplant recipients. J Transplant
854640. doi: 10.1155/2015/854640.
Looker KJ, Magaret AS, May MT, Turner KME, Vickerman P, Newman LM, et al. First estimates of the global and regional incidence of neonatal herpes infection. Lancet
Stephanos K, Bragg AF. Pediatric genitourinary infections and other considerations. Emerg Med Clin North Am
(4): 739-754. doi: 10.1016/j.emc.2019.07.010.
Leviton A, Allred EN, Kuban KC, O’Shea TM, Paneth N, Onderdonk AB, et al. The development of extremely preterm infants born to women who had genitourinary infections during pregnancy. Am J Epidemiol
(1): 28-35. doi: 10.1093/aje/kwv129.
Cunningham KA, Beagley KW. Male genital tract chlamydial infection: Implications for pathology and infertility. Biol Reprod
(2): 180-189. doi: 10.1095/biolreprod.108.067835.
Ricci S, De Giorgi S, Lazzeri E, Luddi A, Rossi S, Piomboni P, et al. Impact of asymptomatic genital tract infections on in vitro
fertilization (IVF) outcome. PLoS One
(11): e0207684. doi: 10.1371/journal. pone.0207684
Moragianni D, Dryllis G, Andromidas P, Kapeta-Korkouli R, Kouskouni E, Pessach I, et al. Genital tract infection and associated factors affect the reproductive outcome in fertile females and females undergoing in vitro
fertilization. Biomed Rep
(4): 231-237. doi: 10.3892/ br.2019.1194.
Masika WG, O’Meara WP, Holland TL, Armstrong J. Contribution of urinary tract infection to the burden of febrile illnesses in young children in rural Kenya. PLoS One
Shin HR, Franceschi S, Vaccarella S, Roh JW, Ju YH, Oh JK, et al. Prevalence and determinants of genital infection with papillomavirus, in female and male university students in Busan, South Korea. J Infect Dis
He Z, Liu Y, Sun Y, Xi L, Chen K, Zhao Y, et al. Human papillomavirus genital infections among men, China, 2007–2009. Emerg Infect Dis
Ejrnæs K. Bacterial characteristics of importance for recurrent urinary tract infections caused by Escherichia coli. Dan Med Bull
Finger TE, Kinnamon SC. Taste isn’t just for taste buds anymore. F1000 Biol Rep
Jaggupilli A, Singh N, Upadhyaya J, Sikarwar AS, Arakawa M, Dakshinamurti S, et al. Analysis of the expression of human bitter taste receptors in extraoral tissues. Mol Cell Biochem
Lossow K, Hübner S, Roudnitzky N, Slack JP, Pollastro F, Behrens M, et al. Comprehensive analysis of mouse bitter taste receptors reveals different molecular receptive ranges for orthologous receptors in mice and humans. J Biol Chem
Xu J, Cao J, Iguchi N, Riethmacher D, Huang L. Functional characterization of bitter-taste receptors expressed in mammalian testis. Mol Hum Reprod
Welcome MO, Mastorakis NE, Pereverzev VA. Sweet taste receptor signaling network: Possible implication for cognitive functioning. Neurol Res Int
606479. doi: 10.1155/2015/606479.
Welcome MO, Mastorakis NE, Pereverzev VA. Sweet-taste receptor signaling network and low-calorie sweeteners. In: Mérillon JM, Ramawat KG (eds.) Sweeteners, reference series in phytochemistry
. Cham, Switzerland: Springer International Publishing; 2016. doi: 10.1007/978-3-319-26478-3_25-1.
Adler E, Hoon MA, Mueller KL, Chandrashekar J, Ryba NJ, Zuker CS. A novel family of mammalian taste receptors. Cell
Chandrashekar J, Mueller KL, Hoon MA, Adler E, Feng L, Guo W, et al. T2Rs function as bitter taste receptors. Cell
Caicedo A, Kim KN, Roper SD. Individual mouse taste cells respond to multiple chemical stimuli. J Physiol
(2): 501-509. doi: 10.1113/jphysiol.2002.027862.
Avau B, Depoortere I. The bitter truth about bitter taste receptors: Beyond sensing bitter in the oral cavity. Acta Physiol
(4): 407-420. doi: 10.1111/apha.12621.
Behrens M, Meyerhof W. Oral and extraoral bitter taste receptors. Results Probl Cell Differ
Li F. Taste perception: From the tongue to the testis. Mol Hum Reprod
Liu S, Lu S, Xu R, Atzberger A, Günther S, Wettschureck N, Offermanns S. Members of bitter taste receptor cluster Tas2r143/Tas2r135/Tas2r126 are expressed in the epithelium of murine airways and other non-gustatory tissues. Front Physiol
Wölfle U, Elsholz FA, Kersten A, Haarhaus B, Schumacher U, Schempp CM. Expression and functional activity of the human bitter taste receptor TAS2R38 in human placental tissues and JEG-3 cells. Molecules
Zheng K, Lu P, Delpapa E, Bellve K, Deng R, Condon JC, et al. Bitter taste receptors as targets for tocolytics in preterm labor therapy. FASEB J
Achkar JM, Fries BC. Candida infections of the genitourinary tract. Clin Microbiol Rev
Brubaker L, Wolfe AJ. The female urinary microbiota/microbiome: Clinical and research implications. Rambam Maimonides Med J
Gottschick C, Deng ZL, Vital M, Masur C, Abels C, Pieper DH, et al. The urinary microbiota of men and women and its changes in women during bacterial vaginosis and antibiotic treatment. Microbiome
Ronald AR, Alfa MJ. Microbiology of the genitourinary system
. In: Baron S (ed.) Medical microbiology
. 4th ed. Galveston, Texas: University of Texas Medical Branch at Galveston; 1996.
Tabatabaei N, Eren AM, Barreiro LB, Yotova V, Dumaine A, Allard C, et al. Vaginal microbiome in early pregnancy and subsequent risk of spontaneous preterm birth: A case-control study. BJOG
(3): 349-358. doi: 10.1111/1471-0528.15299.
Hočevar K, Maver A, Šimic MV, Hodžić A, Haslberger A, Seršen TP, et al. Vaginal microbiome signature is associated with spontaneous preterm delivery. Front Med (Lausanne)
201. doi: 10.3389/ fmed.2019.00201.
Thomas-White K, Forster SC, Kumar N, Van Kuiken M, Putonti C, Stares MD, et al. Culturing of female bladder bacteria reveals an interconnected urogenital microbiota. Nat Commun
Baron S. Medical microbiology
. 4th ed. Galveston, Texas: University of Texas Medical Branch at Galveston;1996.
Richens J. Genital manifestations of tropical diseases. Sex Transm Infect
World Health Organization. International statistical classification of diseases and related health problems
.10th revision. Geneva: World Health Organization; 2010.
Cram LF, Zapata MI, Toy EC, Baker B III. Genitourinary infections and their association with preterm labor. Am Fam Physician
Shey MS, Garrett NJ, McKinnon LR, Passmore JAS. The role of dendritic cells in driving genital tract inflammation and HIV transmission risk: Are there opportunities to intervene? Innate Immun
Salazar JC, Cruz AR, Pope CD, Valderrama L, Trujillo R, Saravia NG, et al. Treponema pallidum
elicits innate and adaptive cellular immune responses in skin and blood during secondary syphilis: A flow-cytometric analysis. J Infect Dis
Godaly G, Ambite I, Svanborg C. Innate immunity and genetic determinants of urinary tract infection susceptibility. Curr Opin Infect Dis
Rice JC, Peng T, Spence JS, Wang HQ, Goldblum RM, Corthésy B, et al. Pyelonephritic Escherichia coli
expressing P fimbriae decrease immune response of the mouse kidney. J Am Soc Nephrol
Hull RA, Donovan WH, Del Terzo M, Stewart C, Rogers M, Darouiche RO. Role of type 1 fimbria- and P fimbria-specific adherence in colonization of the neurogenic human bladder by Escherichia coli. Infect Immun
Welcome MO. Immunomodulatory functions of the gastrointestinal tract. In: Welcome MO (ed.) Gastrointestinal physiology: Development, principles and mechanisms of regulation
. Cham, Switzerland: Springer International Publishing AG, part of Springer Nature; 2018, p. 685-771. doi: 10.1007/978-3-319-91056-7.
Laisk T, Peters M, Saare M, Haller-Kikkatalo K, Karro H, Salumets A. Association of CCR5, TLR2, TLR4 and MBL genetic variations with genital tract infections and tubal factor infertility. J Reprod Immunol
Taghavi M, Khosravi A, Mortaz E, Nikaein D, Athari SS. Role of pathogen-associated molecular patterns (PAMPS) in immune responses to fungal infections. Eur J Pharmacol
Liu H, Chen K, Feng W, Wu X, Li H. TLR4-MyD88/Mal-NF-kB axis is involved in infection of HSV-2 in human cervical epithelial cells. PLoS One
(11): e80327. doi: 10.1371/journal.pone.0080327.
O’Connell CM, Ionova IA, Quayle AJ, Visintin A, Ingalls RR. Localization of TLR2 and MyD88 to Chlamydia trachomatis
inclusions: Evidence for signaling by intracellular TLR2 during infection with an obligate intracellular pathogen. J Biol Chem
1652-1659. doi: 10.1074/jbc.M510182200.
Darville T, Hiltke TJ. Pathogenesis of genital tract disease due to Chlamydia trachomatis. J Infect Dis
Zec K, Volke J, Vijitha N, Thiebes S, Gunzer M, Kurts C, et al. Neutrophil migration into the infected uroepithelium is regulated by the crosstalk between resident and helper macrophages. Pathogens
(1): 15. doi:10.3390/pathogens5010015.
Horne AW, Critchley HO. Mechanisms of disease: The endocrinology of ectopic pregnancy. Expert Rev Mol Med
e7. doi: 10.1017/erm.2011.2.
Jia-Rong Z, Shuang-Di L, Xiao-Ping W. Eutopic or ectopic pregnancy: A competition between signals derived from the endometrium and the fallopian tube for blastocyst implantation. Placenta
Ashshi AM. Aberrant expression of interleukin-6 and its receptor in fallopian tubes bearing an ectopic pregnancy with and without tubal cytomegalovirus infection. Virus Dis
Shao R, Zhang SX, Weijdegård B, Zou S, Egecioglu E, Norström A, et al. Nitric oxide synthases and tubal ectopic pregnancies induced by Chlamydia
infection: Basic and clinical insights. Mol Hum Reprod
Amabebe E, Reynolds S, He X, Wood R, Stern V, Anumba DOC. Infection/inflammation-associated preterm delivery within 14 days of presentation with symptoms of preterm labour: A multivariate predictive model. PLoS One
(9): e0222455. doi: 10.1371/journal.pone.0222455.
Mizoguchi M, Ishida Y, Nosaka M, Kimura A, Kuninaka Y, Yahata T, et al. Prevention of lipopolysaccharide-induced preterm labor by the lack of CX3CL1-CX3CR1 interaction in mice. PLoS One
(11): e0207085. doi: 10.1371/journal.pone.0207085.
Agrawal V, Hirsch E. Intrauterine infection and preterm labor. Semin Fetal Neonatal Med
(1): 12-19. doi: 10.1016/j.siny.2011.09.001.
Challis JR, Sloboda DM, Alfaidy N, Lye SJ, Gibb W, Patel FA, et al. Prostaglandins and mechanisms of preterm birth. Reproduction
Hong JS, Romero R, Lee DC, Than NG, Yeo L, Chaemsaithong P, et al. Umbilical cord prostaglandins in term and preterm parturition. J Matern Fetal Neonatal Med
(4): 523-531. doi: 10.3109/14767058.2015.1011120.
Tomlinson MS, Lu K, Stewart JR, Marsit CJ, O’Shea TM, Fry RC. Microorganisms in the placenta: Links to early-life inflammation and neurodevelopment in children. Clin Microbiol Rev
(3): e00103-18. doi: 10.1128/CMR.00103-18.
Sykes L, MacIntyre DA, Teoh TG, Bennett PR. Anti-inflammatory prostaglandins for the prevention of preterm labour. Reproduction
(2): R29-R40. doi: 10.1530/REP-13-0587.
Sharif NA, Klimko PG. Prostaglandin FP receptor antagonists: Discovery, pharmacological characterization and therapeutic utility. Br J Pharmacol
(8): 1059-1078. doi: 10.1111/bph.14335.
Pohl O, Marchand L, Gotteland JP, Coates S, Täubel J, Lorch U. Pharmacokinetics, safety and tolerability of OBE022, a selective prostaglandin F 2α receptor antagonist tocolytic: A first-in-human trial in healthy postmenopausal women. Br J Clin Pharmacol
(8): 1839-1855. doi: 10.1111/bcp.13622.
Sleha R, Boštíková V, Salavec M, Mosio P, Kusáková E, Kukla R, et al. Bacterial infection as a cause of infertility in humans. Epidemiol Mikrobiol Imunol
Pellati D, Mylonakis I, Bertoloni G, Fiore C, Andrisani A, Ambrosini G, et al. Genital tract infections and infertility. Eur J Obstet Gynecol Reprod Biol
Ahmadi F, Zafarani F, Shahrzad G. Hysterosalpingographic appearances of female genital tract tuberculosis: Part I. Fallopian tube. Int J Fertil Steril
Mesbah N, Salem HK. Genital tract infection as a cause of male infertility. In: Darwish A (ed.) Genital infections and infertility
. Croatia: InTech; 2016, p. 63-68.
Tsevat DG, Wiesenfeld HC, Parks C, Peipert JF. Sexually transmitted diseases and infertility. Am J Obstet Gynecol
Comhaire FH, Mahmoud AM, Depuydt CE, Zalata AA, Christophe AB. Mechanisms and effects of male genital tract infection on sperm quality and fertilizing potential: The andrologist’s viewpoint. Hum Reprod Update
Peach BC, Garvan GJ, Garvan CS, Cimiotti JP. Risk factors for urosepsis in older adults: A systematic review. Gerontol Geriatr Med
Hooton TM. Pathogenesis of urinary tract infections: An update. J Antimicrob Chemother
Zaffanello M, Malerba G, Cataldi L, Antoniazzi F, Franchini M, Monti E, et al. Genetic risk for recurrent urinary tract infections in humans: A systematic review. J Biomed Biotechnol
321082. doi: 10.1155/2010/321082.
Lundstedt AC, Leijonhufvud I, Ragnarsdottir B, Karpman D, Andersson B, Svanborg C. Inherited susceptibility to acute pyelonephritis: A family study of urinary tract infection. J Infect Dis
Caine EA, Scheaffer SM, Arora N, Zaitsev K, Artyomov MN, Coyne CB, et al. Interferon lambda protects the female reproductive tract against Zika virus infection. Nat Commun
280. doi: 10.1038/s41467-018-07993-2.
Tang L, Zheng S, Wang Y, Li F, Bao M, Zeng J, et al. Rs4265085 in GPER1
gene increases the risk for unexplained recurrent spontaneous abortion in Dai and Bai ethnic groups in China. Reprod Biomed Online
(4): 399-405. doi: 10.1016/j.rbmo.2017.01.005.
Yoo KH, Kim SK, Chung JH, Chang SG. Nitric oxide synthase 2 gene polymorphisms are associated with prostatic volume in Korean men with benign prostatic hyperplasia. Asian J Androl
(5): 690-696. doi: 10.1038/aja.2010.37.
Liassides C, Papadopoulos A, Siristatidis C, Damoraki G, Liassidou A, Chrelias C, et al. Single nucleotide polymorphisms of Toll-like receptor-4
and of autophagy-related gene 16 like-1 gene
for predisposition of premature delivery: A prospective study. Medicine (Baltimore)
(40): e17313. doi: 10.1097/MD.0000000000017313.
Taylor BD, Darville T, Ferrell RE, Kammerer CM, Ness RB, Haggerty CL. Variants in Toll-like receptor 1 and 4 genes are associated with Chlamydia trachomatis
among women with pelvic inflammatory disease. J Infect Dis
(4): 603-609. doi: 10.1093/infdis/jir822.
Udayalaxmi J, Jacob S, D’Souza D. Comparison between virulence factors of Candida albicans
and non-albicans species of Candida
isolated from genitourinary tract. J Clin Diagn Res
(11): DC15-DC17. doi: 10.7860/JCDR/2014/10121.5137.
Wang MC, Tseng CC, Chen CY, Wu JJ, Huang JJ. The role of bacterial virulence and host factors in patients with Escherichia coli
bacteremia who have acute cholangitis or upper urinary tract infection. Clin Infect Dis
(10): 1161-1166. doi: 10.1086/343828.
Shah C, Baral R, Bartaula B, Shrestha LB. Virulence factors of uropathogenic Escherichia coli
(UPEC) and correlation with antimicrobial resistance. BMC Microbiol
(1): 204. doi: 10.1186/s12866-019-1587-3.
Africa CWJ, Nel J, Stemmet M. Anaerobes and bacterial vaginosis in pregnancy: Virulence factors contributing to vaginal colonisation. Int J Environ Res Public Health
(7): 6979-7000. doi: 10.3390/ ijerph110706979.
Newman JW, Floyd RV, Fothergill JL. The contribution of Pseudomonas aeruginosa
virulence factors and host factors in the establishment of urinary tract infections. FEMS Microbiol Lett
(15). doi: 10.1093/ femsle/fnx124.
Carey RM, Adappa ND, Palmer JN, Lee RJ, Cohen NA. Taste receptors: Regulators of sinonasal innate immunity. Laryngoscope Investig Otolaryngol
(4): 88-95. doi: 10.1002/lio2.26.
Malovini A, Accardi G, Aiello A, Bellazzi R, Candore G, Caruso C, et al. Taste receptors, innate immunity and longevity: The case of TAS2R16
gene. Immun Ageing
Workman AD, Palmer JN, Adappa ND, Cohen NA. The role of bitter and sweet taste receptors in upper airway immunity. Curr Allergy Asthma Rep
(12): 72. doi: 10.1007/s11882-015-0571-8.
Voigt A, Hübner S, Döring L, Perlach N, Hermans-Borgmeyer I, Boehm U, et al. Cre-mediated recombination in Tas2r131 cells: A unique way to explore bitter taste receptor function inside and outside of the taste system. Chem Senses
Wölfle U, Haarhaus B, Schempp CM. Amarogentin displays immunomodulatory effects in human mast cells and keratinocytes. Mediators Inflamm
Deckmann K, Filipski K, Krasteva-Christ G, Fronius M, Althaus M, Rafiq A, et al. Bitter triggers acetylcholine release from polymodal urethral chemosensory cells and bladder reflexes. PNAS
Rennemeier C, Frambach T, Hennicke F, Dietl J, Staib P. Microbial quorum-sensing molecules induce acrosome loss and cell death in human spermatozoa. Infect Immun
Sandell MA, Collado MC. Genetic variation in the TAS2R38 taste receptor contributes to the oral microbiota in North and South European locations: A pilot study. Genes Nutr
Turner A, Veysey M, Keely S, Scarlett C, Lucock M, Beckett L. Interactions between bitter taste, diet and dysbiosis: Consequences for appetite and obesity. Nutrients
(10): 1336. doi: 10.3390/nu10101336.
Dotson CD, Zhang L, Xu H, Shin YK, Vigues S, Ott SH, et al. Bitter taste receptors influence glucose homeostasis. PLoS One
Rutherford ST, Bassler BL. Bacterial quorum sensing: Its role in virulence and possibilities for its control. Cold Spring Harb Perspect Med
Barr HL, Halliday N, Cámara M, Barrett DA, Williams P, Forrester DL, et al. Pseudomonas aeruginosa
quorum sensing molecules correlate with clinical status in cystic fibrosis. Eur Respir J
Dandekar AA, Chugani S, Greenberg EP. Bacterial quorum sensing and metabolic incentives to cooperate. Science
Khan MS, Zahin M, Hasan S, Husain FM, Ahmad I. Inhibition of quorum sensing regulated bacterial functions by plant essential oils with special reference to clove oil. Lett Appl Microbiol
Deep A, Chaudhary U, Gupta V. Quorum sensing and bacterial pathogenicity: From molecules to disease. J Lab Physicians
Hawver LA, Jung SA, Ng WL. Specificity and complexity in bacterial quorum-sensing systems. FEMS Microbiol Rev
Zhou J, Lyu Y, Richlen M, Anderson DM, Caia Z. Quorum sensing is a language of chemical signals and plays an ecological role in algal-bacterial interactions. CRC Crit Rev Plant Sci
Li J, Attila C, Wang L, Wood TK, Valdes JJ, Bentley WE. Quorum sensing in Escherichia coli
is signaled by AI-2/LsrR: Effects on small RNA and biofilm architecture. J Bacteriol
Anderson MT, Byerly L, Apicella MA, Seifert HS. Seminal plasma promotes Neisseria gonorrhoeae
aggregation and biofilm formation. J Bacteriol
Edwards JL, Jennings MP, Apicella MA, Seib KL. Is gonococcal disease preventable? The importance of understanding immunity andpathogenesis in vaccine development. Crit Rev Microbiol
Babb K, von Lackum K, Wattier RL, Riley SP, Stevenson B. Synthesis of autoinducer 2 by the Lyme disease spirochete, Borrelia burgdorferi. J Bacteriol
Lackum K, Babb K, Riley SP, Wattier RL, Bykowski T, Stevenson B. Functionality of Borrelia burgdorferi
LuxS: The Lyme disease spirochete produces and responds to the pheromone autoinducer-2 and lacks a complete activated-methyl cycle. Int J Med Microbiol
Arnold WK, Savage CR, Antonicello AD, Stevenson B. Apparent role for Borrelia burgdorferi
LuxS during mammalian infection. Infect Immun
Simon S, Schell U, Heuer N, Hager D, Albers MF, Matthias J, et al. Inter-kingdom signaling by the Legionella
quorum sensing molecule LAI-1 modulates cell migration through an IQGAP1-Cdc42-ARHGEF9-dependent pathway. PLoS Pathog
Bergsson G, Arnfinnsson J, Karlsson SM, Steingrímsson O, Thormar H. In vitro
inactivation of Chlamydia trachomatis
by fatty acids and monoglycerides. Antimicrob Agents Chemother
Rajput A, Kaur K, Kumar M. SigMol: Repertoire of quorum sensing signaling molecules in prokaryotes. Nucleic Acids Res
(D1): D634-639. doi: 10.1093/nar/gkv1076.
Miller MB, Bassler BL. Quorum sensing in bacteria. Annu Rev Microbiol
[Table 1], [Table 2]