*2.3.1 Neutrophils*

Neutrophils are the first immune cells to reach the site of infection [32]. Although they cannot clear the infection on their own, it is predicted that they have effects that reduce the burden of Chlamydia and limit the spread in the initial period of the infection [33]. Studies reporting that neutrophils inactivate *C. trachomatis in vitro* support this view [34]. Some studies do not confirm this assumption. In one study, *C. muridarum* load in the genital tract of neutrophil-depleted mice was 10 times higher than in wild-type mice, while *C. trachomatis* was shown to be eliminated in the same time period in both groups [33]. It has been found to increase chlamydial replication through MYD88-dependent signaling [35].

The relationship of neutrophils with pathology has also been the subject of research. In animal model studies, neutrophils are found to be associated with the development of tissue damage as well as contributing to the development of adaptive immune response [36, 37].

Neutrophils are very short-lived cells compared to other immune cells. They survive for about 5 hours before spontaneous apoptosis. How Chlamydia can persist in such a short-lived cell has been the subject of research. Although uninfected granulocytes become apoptotic within 10 hours, survival of infected granulocytes for up to 90 hours has revealed that Chlamydia can delay neutrophil apoptosis [38]. In a study in which primary human neutrophils were infected with *C. pneumoniae in vitro*, it was reported that the infection activates the ERK1/2 and PI3K/Akt survival signaling pathway, delaying neutrophil apoptosis, and thus prolonging their survival [39]. It has also been shown that granulocyte-macrophage colony-stimulating factor, which supports neutrophil activation and survival, is secreted from epithelial cells infected with *C. trachomatis* [40].

It is thought that the prolongation of neutrophil lifespan may have a negative effect on the outcome of chlamydial infection due to the cytokines they secrete causing tissue damage [41]. In a study performed with human fallopian tube tissue culture, the addition of an IL-1 receptor antagonist prevented tissue damage due to *C. trachomatis*. This study provides evidence that IL-1, a cytokine released mainly by neutrophils and monocytes, causes tissue damage in the genital tract [42].

One of the many mechanisms that Chlamydia spp. uses to break innate immune responses and ensure their persistence is that it causes neutrophil dysfunction. The chlamydial protease-like activity factor (CPAF) affects defense mechanisms such as oxidative burst and formation of extracellular traps by targeting the neutrophil surface receptor formyl peptide receptor 2 [43]. As a result, it is suggested that neutrophils with prolonged lifespans but weakened functions contribute to the pathogenesis of chronic chlamydial infections.

#### *2.3.2 Natural killer cells*

Natural killer (NK) cells are a group of innate cells involved in the response against cancer, viral infections, and intracellular bacteria [44]. Their role during chlamydial infection has been studied in various studies [32]. In mice inoculated intravaginally with *C. muridarum*, Tseng and Rank determined that NK cells reached the site of infection within 12–24 hours after inoculation [32, 45].

NK cells produce high levels of interferon-γ (IFN-γ). Hook and colleagues showed that interleukin-18 released from human epithelial and IL-12 produced by dendritic cells after being stimulated by *C. trachomatis* cell (DC) stimulate IFN-γ production in NK cells *in vitro* [46]. IFN-γ is important for the inhibition of Chlamydia growth, as well as one of the main cytokines important for the induction of a Th1 immune response. Animal studies in which NK cells have been experimentally destroyed highlight the importance of these cells. In the study by Tseng and Rank, antibody responses were investigated after intravaginal *C. muridarum* inoculation in mice and wild-type mice treated with anti-NK-cell antibody. In the humoral response to Chlamydia in NK cells depleted mice, Th2-associated antibody IgG1 was found to be significantly higher, while Th1-associated IgG2a antibodies were dominant in mice that did not receive anti-NK-cell antibody treatment. In conclusion, the absence of NK cells was associated with decreased TH1 response and exacerbation of the course of infection [32, 45]. In another study, it was shown *in vitro* that IL-12 secretions were decreased and their CD4 T cell-stimulating capacity decreased in DC obtained after

#### *Immune Response to Chlamydia DOI: http://dx.doi.org/10.5772/intechopen.110799*

intranasal inoculation of *C. muridarum* in mice with NK cells depleted. In addition, DC cells transferred from NK cell-depleted mice to naive mice failed to induce Th1 mediated immune response against intranasal *C. muridarum* infection [47]. These findings indicate that IFN-γ secreted by the NK cell in the early stages of infection shifts the immune response toward Th1 instead of Th2.

## *2.3.3 Macrophages*

Studies show that macrophages migrate to sites of chlamydial infection [48]. They are attracted to the infection site by chemokines and cytokines secreted from infected epithelial cells [49, 50]. They recognize chlamydial PAMPs through the PRRs they carry, primarily TLR and NOD-like receptors. Chlamydia enters macrophages *via* phagocytosis or receptor-mediated endocytosis [51, 52] and proinflammatory cytokines are secreted [22, 53]. Degradation of ingested bacteria with lysosomes ensures the elimination of bacteria. M66 Host cell autophagy, a process by which cells degrade cytoplasmic proteins and organelles, also makes bacteria the target of lysosomes. There are studies showing that autophagy is important for the clearance of *C. trachomatis* [54, 55]. Far fewer forms of chlamydial RB have been detected in macrophages compared to epithelial cells. Although chlamydia infects macrophages, it does not create a niche for intracellular replication. The reasons for this may be the failure of *C. trachomatis* to inhibit phagosome-lysosome fusion and autophagy [54, 56]. Furthermore, autophagy indirectly enhances cell-mediated and humoral responses against Chlamydia by increasing antigen presentation to T cells as supports [57, 58]. It is also important to note that IFN-γ both enhances autophagy and causes upregulation of MHC class II molecules [59].
