HPV is a double-stranded DNA virus without an envelope with epithelial tropism, often invading the human oral cavity, skin, and perianal and genital tract. According to their carcinogenic potential, they are further classified as low-risk human papillomavirus (LR-HPV) and high-risk human papillomavirus (HR-HPV) [14].

The coding region of HPV is divided into the long control region (LCR), early gene region (E), and late gene region (L). Early genes (E1–E7) encode proteins associated with the regulation of viral replication, regulating the life cycle of viruses, DNA replication, DNA transcription, and viral protein translation. Among them, E6 and E7 are oncogenes encoding oncoproteins that play an essential role in interfering with signaling pathways to induce cell immortalization [15]. Late genes (L1 and L2) are responsible for encoding capsid proteins involved in cell surface adsorption, viral particle packaging, and virus entry into the cytoplasm. CpG sequences are present in the HPV genome. Furthermore, the HPV16E6 coding DNA sequence is recognized by TLR9 [16]. Research has found that HPV16 L1 virus-like particles (VLPs) directly activate B cell-mediated humoral immunity via TLR4 and MyD88-dependent signaling [17]. Han R et al. [18] explained that the HPV6b/11E7 protein could promote TLR7 and TLR9 expression. When plasmacytoid dendritic cells (PDCs) were treated with E7 protein, the expression of key factors of the TLR signaling pathway and the JNK/p38MAP kinase signaling pathway were increased. Weng H et al. [19] reported that novel pro-inflammatory cytokine high mobility group protein B1 (HMGB1) is significantly increased in pointed condyloma samples, which also binds to TLR4 to activate downstream responses. Therefore, these immunogenic proteins are all potential PAMPs for HPV recognition by TLRs.

LR-HPV infection often causes benign lesions like condyloma to acuminate (CA). Moreover, the common genotypes are HPV6 and HPV11. TLR9 expression in the skin tissue of CA patients was lower than in normal skin tissue, and TLR4 levels were significantly higher than in normal tissue [20]. HPV11-transfected HACAT cells had reduced TLR9 expression and reversed activation of NF-$\kappa$B p65 expression [20], whereas elevated TLR4 expression promoted NF-$\kappa$B activation [19].

HR-HPV infection often triggers invasive cervical cancer (ICC); most commonly HPV16 and HPV18. In clinical studies [21, 22], the expression of TLR4, TLR5, and TLR9 is increased, and the expression of TLR7 is decreased in the skin tissue of HR-HPV patients. Besides, the expression levels of TLR4 and TLR9 showed a trend consistent with pathologic histology grading. TLR4 expression was higher in ICC tissue than in cervical intraepithelial neoplasia (CIN) samples, whereas it was lower in normal cervical tissue [23]. Similarly, during the progression of CIN, TLR9 expression increased sequentially [24, 25]. There are also slight differences in TLR expression by HPV type. For example, the TLR4 expression was higher in SiHa (HPV16+) cells than in HeLa (HPV18+) cells and lower in C33A (HPV-) cells than in HeLa (HPV18+) cells [23].

Most HPV infections are transient and will be cleared by the immune system over time. The relationship between HPV clearance and the expression of TLRs is intimate. Daud et al. [26] found that clearance of HPV16 was associated with increased expression of TLR2, TLR3, TLR7, TLR8, and TLR9 during clinical follow-up. TLR2 and TLR7 levels were significantly higher in women with the regression of CIN2; whereas, TLR2, TLR7, and TLR8 were significantly increased in women with HPV conversion [27]. This suggests that TLRs play an essential role in viral clearance. Furthermore, the signal transduction and secretion of a series of cytokines triggered by the upregulation of TLRs exert antiviral effects.

While HPV can disrupt innate immunity by evading TLR identification, it can also cause disease progression and, eventually, the emergence of aggressive malignancies. In general, activation of TLRs on immune cells can exert anti-tumor effects. TLR expression on the surface of tumor cells impedes immune cell infiltration and creates an immunosuppressive microenvironment for promoting tumorigenesis and progression.

Yu L et al. [28] found that TLR4 expression gradually decreases during cervical tumor development and that this appears to be associated with the expression of p16INK4a, a key marker of integration into host cells. Myeloid differentiation factor88 (MyD88), responsible for TLR pathway activation, was also downregulated in cervical cancer cell lines, but SARM1 expression levels were upregulated. SARM1 acted as a competitor for TLR binding and caused signaling disruption, inhibiting the innate immune response triggered by TLR [29]. Therefore, inactivation of the TLR pathway and SARM1-specific activation may be involved in HPV immune escape. Aggarwal et al. [30] discovered that TLR1 was elevated in squamous cervical cancer tissue whereas TLR3, 4, and 5 were downregulated. However, the opposite conclusion was reached by Li J et al. [31] and Xiao J et al. [32], namely that TLR3, TLR4, TLR7, and TLR8 showed an upward trend in samples from patients with squamous cell carcinoma of the cervix than in samples from normal subjects. In view of this, there is a dynamic process of TLR expression in cervical tumors. On the one hand, the organism exerts anti-tumor effects by upregulating TLRs-mediated immune responses.

On the other hand, tumors avoid TLR identification by interfering with innate immunity and downregulating TLR transcription to increase virus persistence. In addition, the development of cervical tumors is also influenced by genetic factors. TLR gene polymorphism has a close connection, and the polymorphisms in TLR2, TLR4, and TLR9 genes can increase the risk of cervical cancer [33].

HSV is a double-stranded DNA virus that primarily infects the skin mucosa of the genital tract and can also be latent in the spinal ganglia for a lifetime [34]. Herpes simplex virus 2 (HSV-2) mainly causes genital herpes, with an estimated 491.6 million infections worldwide. It is considered one of the most common sexually transmitted diseases [35]. Since HSV-2 often disrupts the mucosal barrier of the genital tract, HSV-2 infection is also an essential synergistic factor for HIV and HPV infection. Natural immune responses are critical in maintaining the integrity of the genital tract mucosa, and the TLR also plays an important role in responding to HSV-2 infection.

First, HSV-2 relies on glycoproteins for adsorption and penetration into the host cell, followed by microtubules with kinesin-mediated migration of the viral capsid to the nucleus and release of chromatin. The capsid protein then forms and wraps the viral DNA to leave the nucleus. Finally, it is processed in the cytoplasm to form progeny viruses and released outside the cell. TLR mediates the immune response during HSV-2 infection, and TLR expression shows a temporal correlation with infection. A study by Duan Q et al. [36] reported that TLR4, located on the cell surface and recognizes viral glycoproteins, was first expressed after HSV-2 infection of VK2/E6E7 cells. TLR3, TLR7, and TLR9, which are located in the cell and recognize viral nucleic acids, were expressed in a time-dependent manner.

TLR4 is a pattern recognition receptor for LPS, a product of gram-negative bacteria. Recent reports have revealed that TLR4 can also recognize viruses and related proteins as a signal to trigger downstream-related responses [4], among which HSV-2 can upregulate TLR4 expression. Medullary differentiation protein 2 (MD2) is an auxiliary protein of TLR4-mediated endotoxin/LPS signaling that helps TLR4 recognize pathogen-associated molecular patterns. In HSV-2-infected human cervical epithelial cells (HCE), MD2 overexpression was found to enhance HSV-2-mediated activator protein 1 (AP-1) activation, and thus the TLR4/MD2 complex plays a role in HSV-2 infection similar to that of TLR4 recognition of LPS. In addition, ICP0, the immediate early protein of HSV-2, induces a significant increase in AP-1-driven transcription and TLR4 promoter activation in HEC-1 cells. Furthermore, the accumulation of ICP0 allows host cell AP-1 activation, which in turn mediates TLR4 activation [37].

HSV-2 infection of HCE induces the expression of TLR4, which activates the NF-$\kappa$B pathway and induces the expression and secretion of downstream pro-inflammatory factors IL-6 and IFN-$\beta$, which are synergistically involved in the natural immune response [38]. Using gene knockdown and inhibitors, Liu H et al. [39] determined that activation of the NF-$\kappa$B pathway in HSV-2 infection is TLR4-dependent. The myeloid differentiation factor MyD88, the bridging adaptor Mal, and their key downstream protein IRAK1 are required for TLR4-dependent signaling in response to HSV-2. In conclusion, HCE can respond to HSV-2 infection via the TLR4-Mal/MyD88-IRAK1-NF-$\kappa$B axial pathway. In addition, TLR4-TRIF/TRAM signaling plays a synergistic role in the innate immune response to HSV-2 infection in cervical epithelial cells together with the TLR4-mediated MyD88-dependent pathway [40].

TLR9 recognizes bacterial and viral DNA and CpG oligonucleotide (CpG-ODN). Although TLR9 can be activated by the DNA sequence of CpG-ODN and the HSV-2 genome is rich in CpG, HSV-2 infection induces TLR9 activation in a viral replication-dependent rather than a CpG-dependent manner. Infection of human cervical epithelial cell line ME-180 with HSV-2 induces TLR9 activation through the binding of the JNK signaling pathway promoting transcription factor specificity protein 1 (SP1) to the TLR9 promoter, which in turn enhances TLR9 expression, and TLR9 activation exhibits a dose-dependent and time-dependent HSV-2 infection [41]. Malmgaard L et al. [42] also confirmed that although TLR9 is one of the TLRs activated by HSV-2, the production of interferon signals occurs mainly through TLR non-dependent pathways rather than those mediated by the TLR9 signaling pathway. In particular, TLR9 and plasmacytoid dendritic cells mediate the early IFN response, but later responses come from different cell types and are independent of TLR9 induction [43]. This suggests that HSV-2 has evolved a mechanism to antagonize the TLR9 signaling pathway.

HSV-2, which causes persistent infection, has evolved many strategies to evade the host’s intrinsic antiviral response. The virion host shutoff protein (VHS) of HSV-2 inhibits TLR2 and TLR3 expression in VK2 cells to facilitate immune evasion during HSV-2 infection [44]. In addition, TLR2 gene polymorphisms were associated with the severity of HSV-2 infection [45], and polymorphisms in the TLR3 gene were also a factor in susceptibility to HSV-2 [46].

By exploiting the vital role of the TLR family in recognizing pathogenic microorganisms to activate natural immunity, agonists targeting the activation of these pattern recognition receptors may be effective in preventing primary HSV-2 infection in vaginal cells. In the research, ligand treatment of TLR3, TLR5, and TLR9 significantly inhibited HSV-2 replication [47]. FSL-1, the TLR6 agonist, exerted antiviral effects on mouse and human vaginal endothelial cells [48].

Bacterial vaginosis is a condition brought on by dysbiosis of the vaginal microbiota, which results in an increase in anaerobium and facultative anaerobe and a decrease in lactobacilli that produce hydrogen peroxide [49]. Typical causative agents include Gardnerella vaginalis, Mobiluncus mulieris, Mycobacterium vaginalis, and bacterial vaginitis-associated bacteria 1-3 (BVAB-1, BVAB-2, and BVAB-3) [50]. BV can increase the risk of infection by other common pathogens of the female reproductive tract, leading to pelvic inflammatory disease, premature birth, and associated diseases such as postpartum endometritis [51].

TLR-recognized compounds in the BV-associated microbiome include peptidoglycans and LPSs [50]. In response to the body’s natural immune response, these ligands bind to the relevant receptors to produce various products, including the corresponding cytokines and chemokines. TLR4 can recognize gram-negative LPS. Peptidoglycan of Mycobacterium can be recognized by TLR2, and lipopeptide of Mycobacterium can be recognized by TLR6. Flagellin of flagellated bacteria can be recognized by TLR5, common to various bacteria, and bacterial lipopeptide and non-methylated CpG DNA can be recognized by TLR2 and TLR9, respectively [1]. In addition, anaerobic bacteria synthesize short-chain fatty acids (SCFAs) from incompletely digested carbohydrates, consisting mainly of acetic acid, butyric acid, and propionic acid, which have been shown to modulate immune responses broadly. In the lower genital mucosa of women with BV, there are high concentrations of SCFAs. SCFAs significantly increase the release of IL-8 and TNF$\alpha$, which are mediated by TLR2 and TLR7, as well as the production of pro-inflammatory cytokines IL-6 and IL-1$\beta$, which has an inflammatory effect [52].

It has been demonstrated that vaginal lavage solution from BV patients could induce TLR4 and TLR2 expression in vitro and induce IL-8 production from NF-$\kappa$B by stimulating TLR2 [53]. Mycobacterium vaginalis effectively induces the production of IL-6, IL-8, and $\beta$-defensins in vaginal epithelial cells through TLR2-mediated NF-$\kappa$B signaling. At the same time, Mobiluncus mulieris and BVAB1 stimulate TLR5 and induce NF-$\kappa$B-dependent pro-inflammatory responses [49].

In genomic studies, TLR polymorphisms are also strongly associated with the dysregulation of vaginal microecology. Gene polymorphisms in TLR2 and TLR7 were proven to cause a significant increase in the incidence of BV in African women [54]. BV is associated with TLR1, TLR9, and TLR2 variants in a non-pregnancy cohort study of 159 HIV-1-positive African Americans [50]. In a study examining the impact of genetic variants in the TLR gene on the different host immune responses that occur in HIV-1-infected adolescents facing BV, missense mutations in TLR4 were found to cause a 10-fold increase in Gardnerella vaginalis levels, and genetic variants in the TLR9 gene were also discovered to be strongly connected with BV diagnosis [55].

VVC is an inflammatory vaginal disease primarily due to Candida albicans infection, with 75% of women of childbearing age becoming infected at least once during their lifetime and 6% to 8% of women suffering from recurrent vulvovaginal candidiasis (RVVC) [56]. Candida albicans is a saprophytic parasite. As an opportunistic pathogen, its pathogenicity depends on the vaginal microecological environment, the host’s immune response, and the virulence of the fungus. Host-microbe interactions during the natural immune response play an essential role in the pathogenesis of VVC.

The cell wall of Candida albicans contains chitin, dextran, and mannans, as well as intracellular DNA and RNA molecules that are pathogen-associated molecular patterns that can be recognized by the host immune system and activate an immune response. TLR4 recognizes mannans, whereas TLR2 recognizes phospholipid mannans, prevents colonization and endogenous invasion of Candida albicans, and TLR7 recognizes single-stranded RNA of Candida albicans [57].

A clinical study has shown that TLR2 and TLR4 expression was significantly increased in vaginal endothelial cells obtained from vaginal swabs of VVC patients compared with samples obtained from normal subjects. In addition, this was accompanied by activation of c-fos and p38 signaling, and phosphorylation of p-38 occurred in close association with the presence of pseudohyphal/mycelia [58].

Animal studies have shown that the lack of TLR2-mediated signaling increases the fungal load in the vagina. Usually, the fungus adheres to keratinized epithelial cells. However, in TLR2-deficient animals, the epithelial barrier can be easily crossed by Candida albicans hyphae, which invade the deep mucosa and produce severe tissue damage [56]. This confirms that TLR2 is an important factor in controlling the progression of VVC disease.

In vitro studies revealed that Candida albicans could induce TLR2 and TLR6 expression in VK2 cells and activate related genes and cytokines to produce inflammatory signals such as IL6 and TNF$\alpha$ through the NF-$\kappa$B signaling pathway [59]. PGE2 plays a crucial role in the morphogenesis of Candida albicans and has been shown to stimulate the formation of Candida budding tubes. Candida albicans isolated from the vagina of VVC patients were significantly released by PGE2 when co-cultured with HeLa cells, in which TLR2 and TLR4 also played a role [60].

TV is an inflammation of the vagina caused by the production and reproduction of Trichomonas vaginalis. It is one of the most common infectious diseases, often accompanied by severe vulvar itching, increased discharge, and urinary tract infections. Numerous diseases are closely associated with TV, such as premature birth, infertility, and HIV infection [61]. Trichomonas vaginalis is a flagellated, extracellular parasitic protozoan often found in the female vagina, producing extracellular virulence factors by adhering to female vaginal epithelial cells and destroying the genital tract barrier. Therefore, local natural immunity of the vagina is crucial for Trichomonas vaginalis defense [62].

For parasitic protozoa, adherence to epithelial cells is a key link to infection and parasitism of the host. The surface of trichomonad contains a variety of complex carbohydrates, such as glycolipids, glycoproteins, and glycophosphatidylinositol, which play a significant role in host cell invasion and evasion of the host immune response. Lipophosphoglycan (LPG) is the primary cell surface glycoconjugate of Trichomonas vaginalis, assisting in adherence to epithelial cells and initiating the secretion of cytokines. IL-8 and macrophage inflammatory protein-3$\alpha$ (MIP-3$\alpha$) production can be induced by LPG in the immune response to Trichomonas vaginalis, and this regulation is associated with the MyD88 non-dependent pathway of TLR [61]. At the same time, IL-8 induces more IL-8 and other cytokine production by neutrophils in a cascade response, leading to a prolonged and persistent inflammatory response in the vagina.

As indicated by Chang [62], Trichomonas vaginalis infection of cervical cancer cells HeLa cells upregulated the expression of TLR2, TLR4, and TLR9 through the p38 MAPK signaling pathway, thereby regulating the release of the p38 MAPK-dependent prototype chemokine IL-8, as well as tumor necrosis factor-$\alpha$ (TNF-a) from the epithelium. Trichomonas vaginalis induces apoptosis by activating Bcl-2-like survival factor (Bcl-xl) and NF-$\kappa$B signaling in macrophages, reflecting the initial immune response generated by Trichomonas vaginalis-infected hosts.

Notably, TLR4 is vital in the inflammatory response triggered by Trichomonas vaginalis. In the study of Zariffard [63], vaginal irrigation fluid from TV patients stimulated cytokine production in mouse splenocytes through TLR4 response. Trichomonas vaginalis activates TLR4, MAPKs, and NF-$\kappa$B, leading to CXCL8 and CCL2 production, which induces the migration of neutrophils and monocytes and leads to an inflammatory response [64]. Furthermore, studies have reported that TLR4 gene polymorphisms are firmly linked with a high risk of TV-induced cervicitis [65].

Treponema pallidum (TP) is the causative agent of the sexually transmitted disease syphilis, which infects about 36 million people worldwide, with 12 million new cases per year [66]. TP, a pathogenic microorganism that infects only humans, is spiral shaped like a spring and is highly motile. TP generally invades the body through broken skin mucosa, spreads through lymphatic vessels and the bloodstream, penetrates systemic tissue and breaks the vascular barrier [67]. This induces the host to establish a rapid immune response, and produces an inflammatory response [68]. Symptoms subside into latency, and TP enters the blood and lymphatic circulation from the site of infection, spreading to organs and skin mucosa throughout the body and causing widespread lesions. TP possesses a mechanism to evade the natural immune response, and persistent infection is one of the characteristics of syphilis [69]. TP has a complex structure comprised of an exterior membrane, a full-length spiral flagellum, or axial filament, and a cylindrical bacterium from the outer to the inner part.

Outer membrane proteins bind to the fibronectin of the host’s extracellular matrix through adhesion. They are involved in the colonization of host tissues by TP and the disruption of tissue barriers to facilitate the spread of the organism in vivo. As antigens are directly exposed to the external environment, they are recognized rapidly by the innate immune response system, activating a series of immunopathological effects and immune escape mechanisms. Tp92, the only TP membrane protein with structural features similar to other gram-negative bacterial outer membrane proteins, can mediate cell death by being recognized by CD14 and or TLR2 on the surface of human monocytes. When Tp92 is recognized by CD14 and TLR2, the downstream MyD88 pathway is signaled, which activates NF-$\kappa$B-mediated IL-8 production. This causes neutrophils and lymphocytes to gather at the site of infection, increasing the infiltration of inflammatory cells and escalating the immunopathological damage [69]. Tp0136 is one of the few proteins produced by syphilitic syphilis spirochetes that bind and adhere to fibronectin. Tp0136 can increase MCP-1/CCR2 expression and promote fibroblast migration in vitro in a time-dependent and dose-dependent manner during wound self-healing. Furthermore, in Tp0136-stimulated fibroblasts, TLR4 could mediate the activation of ERK, JNK, PI3K, and NF-$\kappa$B signaling pathways. When TLR4 was inhibited, fibroblast migration would also be impaired [70]. Although Tp0136-induced fibroblast migration can promote self-healing of TP wounds, this pattern may favor the survival and spread of syphilis due to its anaerobic nature.

Flagellar axoneme proteins are mainly composed of two outer proteins (FlaA1 and FlaA2) and three core proteins (FlaB1, FlaB2, and FlaB3) [66], which are of great importance in the induction of immune responses. Flagellin is the only ligand for TLR5 in many bacteria and binds to TLR5 at the cell surface to stimulate downstream signaling through a MyD88-dependent pathway. TP flagellin stimulates monocytes to produce pro-inflammatory cytokines such as IL-6 and IL-8 in a TLR5-dependent manner. Three TP flagellar core proteins (FlaB1, FlaB2, and FlaB3) induce IL-6 and IL-8 production in human acute monocytic leukemia cells THP-1 by activating ERK, p38, and NF-$\kappa$B after TLR5 and MyD88 activation [68]. Furthermore, FlaA2 can further stimulate IL-6 and IL-8 expression in THP-1 cells through p38, NF-$\kappa$B signaling via the TLR2 pathway [71].

The flagellin molecule contains two to four structural domains, D0–D3. Among them, the D0 and D1 structural domains (N/C regions) are highly conserved among organisms, which are essential for the immunostimulatory activity of flagellin. The ND1 structural domain of TP flagellin was found to be one of the sites on flagellin in TP-mediated TLR5 activation [66].

In genetic polymorphism studies, TLR1, TLR2, and TLR6 were found to be associated with an increased risk of neurosyphilis [72], whereas loci in the TLR2 TIR structural domain helped prevent syphilis infection [73].

Chlamydia trachomatis infection is a common sexually transmitted infection (STI) and is asymptomatic in 60-80% of cases. Chlamydia trachomatis (CT) is a specialized intracellular gram-negative bacterium that can cause various diseases. There are nineteen serotypes of CT. Infections of serotypes A-C cause ocular disease and are currently the leading cause of visual impairment due to infection, whereas serotypes D–K infections cause genitourinary tract disease. Aggressive serotypes L1–L3 cause genital lesions, leading to lymphogranuloma venereum (LGV). Repeated or persistent CT infections of the reproductive tract can cause urethritis, pelvic inflammatory disease, infertility, and neonatal infections [74]. Repeated or persistent CT infections of the genital tract can cause urethritis, pelvic inflammatory disease, infertility, and neonatal infections. Early-stage infections are easily cured. However, because 75% to 90% of women with chlamydia are asymptomatic in clinical disease, opportunities for therapeutic intervention are often missed. Asymptomatic infections are a significant contributor to sexual transmission [75]. CT is an intracellular pathogen with a bidirectional developmental cycle. In the extracellular form of infection, it is manifested as a metabolically inert elementary body (EB). After infecting the host cell to form inclusion bodies, it is transformed into the replication-competent reticulate body (RB), which replicates through bifurcation.

Furthermore, RB recombines into infectious EB and then moves extracellularly [76]. The cell wall and outer membrane components of CT can be used as a PAMP for TLR recognition.

Major outer membrane protein (MOMP) is the most abundant protein in the cell membrane of chlamydia. MOMP induces TLR2-dependent IL-8 secretion and increases NF-$\kappa$B-dependent fluorophore activity in HEK cells, and purified MOMP proteasomes induce IL-8 and IL-6 secretion in End/E6E7 cells [77].

Heat shock proteins (HSPs) are present in the outer membrane complexes of protozoan EB and reticulon RB, which are expressed throughout the life cycle of Chlamydia trachomatis [76]. According to Jha [76], cHSP60 stimulation enhanced TLR2 and TLR4 mRNA expression, activated NF-$\kappa$B, downregulated I$\kappa$B, and triggered the release of IL-1 and IL-18 in epithelial cells. During persistent chlamydia infection in women, the release of extracellular HSP60 may lead to apoptosis and inflammatory response, resulting in fibrosis and scar formation in the female genital tract.

Macrophage infectivity potentiator (Mip), a classical bacterial lipoprotein, is present on the surface of chlamydia and induces the secretion of TNF-$\alpha$ and IL-8. Bas [78] treated primary human differentiated macrophages with recombination Mip and confirmed that their pro-inflammatory activity was significantly diminished, which involved TLR1, TLR2, TLR6, and CD14.

Chlamydial secretory protein GlgA, an enzyme related to glycogen metabolism, is found in chlamydial inclusion bodies. Sun et al. [79] proved that GlgA contributes to the secretion of inflammatory factors IL-8, IL-1$\beta$, and TNF-$\alpha$ during chlamydia trachomatis infection via the TLR2, TLR4, and MAPK/NF-$\kappa$B pathways. Zhou et al. [80] revealed that the secreted protein pORF5 protein contributes to the inflammatory process associated with chlamydia infection. pORF5 protein induces the production of tumor necrosis factor-$\alpha$ (TNF-$\alpha$), IL-1$\beta$ and IL-8 in the human monocyte cell line THP-1, which is closely associated with TLR2 and the p38/MAPK and ERK/MAPK signaling pathways.

Gram-negative bacterial LPS is a well-known inflammatory trigger, however, chlamydia LPS has low endotoxic action compared with other bacteria and depends on membrane CD14 for TLR4 activation [81].

TLR2 and TLR4 have a significant role in the process of CT infection. Yilma et al. [82] found enhanced expression of TLR2 and TLR4 on Chlamydia trachomatis-infected macrophages, producing a broad spectrum of inflammatory cytokines and chemokines. O’Connell et al. [81] identified that TLR2 and MyD88 were specifically recruited to the inclusion body membrane during productive infection with chlamydia and that TLR2 was actively involved in intracellular signaling. Webster et al. [83] discovered that Chlamydia trachomatis infection also resulted in TLR4-dependent and MyD88 signaling-dependent protein kinase RNA activation (PKR) was also efficiently activated.

In addition, TLR3 deficiency leads to enhanced chlamydial replication and increases the risk of reproductive tract morbidity during infection. In a study, Xu et al. [75] used the immortalized human oviductal epithelial cell line (HOE) OE-E6/E7 to assess the role of TLR3 in the immune response to L2 CT infection and found that TLR3 deficiency resulted in increased levels of LPS within the chlamydial inclusion body.

There is a robust relationship between single nucleotide polymorphisms and susceptibility and severity of CT infection. Among them, Verweij et al. [84] showed that specific TLR2 and TLR9 haplotype genes prevented the exacerbation of clinical infection; TLR4 genotype polymorphisms were associated with increased odds of Chlamydia trachomatis infection in women with pelvic inflammatory disease in a clinical study by Taylor et al. [85].