**2.** *Chlamydia pneumoniae*

The most important discovery related to the classification of *Chlamydia* was made by Moulder et al. in 1964. *Chlamydia* spp. were initially perceived as viruses because they were smaller than normal bacterial size and had life cycles in the host cell. However, they were included in the bacteria class because they have the ability to survive outside the cell. As such, they are defined as "compulsory intracellular bacteria" [3]. *Chlamydia* are generally larger than the average virus, but smaller than bacteria and human cells [3].

The genus *Chlamydia* is in the family Chlamydiaceae of the order Chlamydiales. Based on their antigenic structures, intracellular inclusions, and diseases they cause, the genus consists of four species: *C. pecorum*, *C. psittaci*, *C. trachomatis*, and *C. pneumoniae*. Except for *C. pecorum*, all can cause disease in humans. *C. trachomatis* is sexually transmitted and causes ocular trachoma, lymphogranuloma venerum, and neonatal infections. Infection is common in homosexuals [7]. *C. psittaci* causes a systemic disease often characterized by pneumonia. *C. psittaci* is also seen in birds and pets. Infection is common in occupational groups that come into contact with birds.

*C. pneumoniae*, previously known as TWAR, causes respiratory tract infections such as pneumonia, bronchitis, sinusitis, and pharyngitis [8]. It was first isolated from the conjunctival swab of a child with trachoma in Taiwan in 1965 and was named TW-183. The role of *C. pneumoniae* as a human pathogen was definitively determined in 1983 with the first respiratory tract isolate, named AR-39, obtained from a throat swab sample of a patient with pharyngitis in the USA. The name TWAR (TW+AR) comes from these first conjunctival and respiratory strains. In 1989, *C. pneumoniae* was identified as a unique species by electron microscopy morphological studies and DNA sequence analysis of TWAR [9]. Unlike *C. trachomatis*, *C. pneumoniae* is not sexually transmitted but is spread through respiratory secretions. Unlike *C. psittaci*, it does not cause disease in birds or animals. In addition to respiratory tract infections, *C. pneumoniae* is associated with atherosclerosis and cardiovascular diseases.

One in ten cases of community-acquired pneumonia is caused by *C. pneumoniae*, and studies have shown that the seroprevalence of *C. pneumonia* in adults is 80%. It has also been shown to cause diseases marked by chronic inflammatory processes, such as chronic obstructive pulmonary disease, asthma, lung cancer, Alzheimer's disease, arthritis, and atherosclerosis [10–15]. *Chlamydia* have a biphasic life cycle and are obligate intracellular bacteria. They are morphologically and structurally similar to gram-negative bacteria, with a three-layered, lipopolysaccharide-rich outer membrane. They require ATP from the host cell to develop and proliferate. *Chlamydia* were classified as bacteria because they contain both DNA and RNA, reproduce by division, have a cell membrane similar to gram-negative bacteria, and are susceptible to antibiotics [16].

Bacteria of the genus *Chlamydia* reproduce by forming incubation bodies in the cytoplasm of the cells they infect. The life cycle of *C. pneumoniae* is divided between two forms, the elementary body (EB) and reticulate body (RB). The EB form is metabolically inactive and is the extracellular form that is transmitted between hosts. It infects the respiratory tract through inhalation and attaches to the mucosal surfaces. The EB enters the host cell via endocytosis, where it transforms into the RB form. EBs are approximately 350 nanometers in diameter. After entering the host cell and becoming activated, they increase in size to a diameter of 800–1000 nm.

The RB form is metabolically active and exploits the host cell's metabolism. This transformation takes place within the first 24 hours after infection. It replicates within the host cell and then lyses that cell, spreading as newly formed EBs and propagating transmission. The RB form is protected from the endocytic-lysosomal degradation system of the host cell and can remain there for years. This feature enables it to persist in the body and cause a chronic inflammatory process [17, 18]. Its intracellular location enhances its ability to transform into a resistant and recurrent form [8, 19]. The bacteria infects the lung tissue and is taken up by monocytes and macrophages. However, instead of being eliminated they continue to thrive there and spread to the rest of the body via the circulation. *Chlamydia* that invades the arterial wall as a result of endothelial dysfunction contributes to the atherosclerosis process [20]. Its demonstrated presence in atheromatous plaques and smooth muscle cells, as well as in macrophage and foam cells, is the main feature that distinguishes *C. pneumoniae* from other microorganisms [21, 22].
