**5. Immunological basis of** *Chlamydia* **persistence**

*Chlamydia* employs several mechanisms to interfere with the host innate immune response to persist within the host cell.

#### **5.1 Modulation of proinflammatory signaling pathways**

The epithelial cells of the urethra or vagina/endocervix represent the first contact and innate immune barrier against *Chlamydia*. The cells can recognize the pathogen through pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors or cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS), which induces the production of proinflammatory cytokines via nuclear factor-κB (NF-κB) or activator protein 1 (AP-1) signaling [Reviewed in 61]. The stimulation of cGAS by *Chlamydia spp*. DNA leads to the dimerization and activation of the IFN regulatory factor 3 (IRF3), which then translocates into the nucleus and promotes the transcription of type I IFN and IFN-inducible genes [60].

The NFκB pathway may be modulated by several different Chlamydial proteins and mechanisms, all of which can interfere with NFκB-mediated gene transcription and regulation. Some of these mechanisms include: (1) blocking the degradation of the NF-κB retention factor, IκBα via *C. trachomatis* deubiquitination (DUB) proteins ChlaDub1 and ChlaDub2 [61], (2) preventing the nuclear translocation of NF-κB, thus stopping or dampening NF-κB transcription, (3) sequestration of the NF-κB activator 1 (Act1) upon binding of the *C. pneumonia*-specific inclusion membrane protein (Inc) CP0236 [22], and (4) suppression of NF-κB signaling by *Chlamydia* secreted proteases (the tail-specific protease of *C. trachomatis*, CT441, and Chlamydial protease-like activity factor, CPAF) [62].

#### **5.2 Interference with proinflammatory cytokines**

Inflammation participates significantly not only in host defenses against *Chlamydia spp*., but it also contributes to the pathophysiology of infection. *Chlamydia*-infected host cells produce a number of cytokines and chemokines, including CXC-chemokine ligand 1 (CXCL1), CXCL8 (also known as interleukin-8, IL-8), TNF-α, and IL-1β and cause activation of various inflammasome pathways, including the NLRP3/ASC inflammasome [60]. These proinflammatory mediators recruit immune cells to the

*Persistence in* Chlamydia *DOI: http://dx.doi.org/10.5772/intechopen.109299*

site of infection and cause local inflammation and tissue damage. *Chlamydia* employs several mechanisms to interfere with inflammation, promoting Chlamydial persistence. For instance, the *C. trachomatis* inclusion membrane protein CpoS can inhibit host inflammasome responses [20]. Another mechanism is the overexpression of the anti-inflammatory cytokine IL-10 [63]. This *in vitro* study was confirmed by findings of an increased *in vivo* expression of IL-10 in the semen and serum of patients infected with *C. trachomatis* [64]. *Chlamydia* CPAF contributes to the anti-inflammatory state required for persistence by inhibiting the IL-1ß-dependent secretion of IL-8 through cleavage of the transcription factor p65/RelA [65]. CPAF is also involved in the inhibition of the complement activation by cleavage of the complement factors B and C3 and attenuating the production of proinflammatory cytokines [66].
