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Atherosclerotic cardiovascular diseases, chronic inflammatory diseases of multifactorial etiology, are the leading cause of death worldwide. In the last decade, more infectious agents, labeled as "infectious burden", rather than any single pathogen, have been showed to contribute to the development of atherosclerosis through different mechanisms. Some microorganisms, such as Chlamydia pneumoniae (C. pneumoniae), human cytomegalovirus, etc. may act directly on the arterial wall contributing to endothelial dysfunction, foam cell formation, smooth muscle cell proliferation, platelet aggregation as well as cytokine, reactive oxygen specie, growth factor, and cellular adhesion molecule production. Others, such as Helicobacter pylori (H. pylori), influenza virus, etc. may induce a systemic inflammation which in turn may damage the vascular wall (e.g., by cytokines and proteases). Moreover, another indirect mechanism by which some infectious agents (such as H. pylori, C. pneumoniae, periodontal pathogens, etc.) may play a role in the pathogenesis of atherosclerosis is molecular mimicry. Given the complexity of the mechanisms by which each microorganism may contribute to atherosclerosis, defining the interplay of more infectious agents is far more difficult because the pro-atherogenic effect of each pathogen might be amplified. Clearly, continued research and a greater awareness will be helpful to improve our knowledge on the complex interaction between the infectious burden and atherosclerosis.

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Chlamydia trachomatis is an obligate, intracellular pathogen responsible for the most common sexually transmitted bacterial disease worldwide, causing acute and chronic infections. The acute infection is susceptible to antibiotics, whereas the chronic one needs prolonged therapies, thus increasing the risk of developing antibiotic resistance. Novel alternative therapies are needed. The intracellular development of C. trachomatis requires essential nutrients, including iron. Iron-chelating drugs inhibit C. trachomatis developmental cycle. Lactoferrin (Lf), a pleiotropic iron binding glycoprotein, could be a promising candidate against C. trachomatis infection. Similarly to the efficacy against other intracellular pathogens, bovine Lf (bLf) could both interfere with C. trachomatis entry into epithelial cells and exert an anti-inflammatory activity. In vitro and in vivo effects of bLf against C. trachomatis infectious and inflammatory process has been investigated. BLf inhibits C. trachomatis entry into host cells when incubated with cell monolayers before or at the moment of the infection and down-regulates IL-6/IL-8 synthesized by infected cells. Six out of 7 pregnant women asymptomatically infected by C. trachomatis, after 30 days of bLf intravaginal administration, were negative for C. trachomatis and showed a decrease of cervical IL-6 levels. This is the first time that the bLf protective effect against C. trachomatis infection has been demonstrated.

Chlamydia pneumoniae, an obligate intracellular pathogen, is known as a leading cause of respiratory tract infections and, in the last two decades, has been widely associated with atherosclerosis by seroepidemiological studies, and direct detection of the microorganism within atheroma. C. pneumoniae is presumed to play a role in atherosclerosis for its ability to disseminate via peripheral blood mononuclear cells, to replicate and persist within vascular cells, and for its pro-inflammatory and angiogenic effects. Once inside the vascular tissue, C. pneumoniae infection has been shown to induce the production of reactive oxygen species in all the cells involved in atherosclerotic process such as macrophages, platelets, endothelial cells, and vascular smooth muscle cells, leading to oxidative stress. The aim of this review is to summarize the data linking C. pneumoniae-induced oxidative stress to atherosclerotic lesion development.

Accumulating evidence demonstrates that vascular oxidative stress is a critical feature of atherosclerotic process, potentially triggered by several infectious agents that are considered as risk co-factors for the atherosclerotic cardiovascular diseases (CVDs). C. pneumoniae has been shown to upregulate multiple enzymatic systems capable of producing reactive oxygen species (ROS) such as NADPH oxidase (NOX) and cyclooxygenase in vascular endothelial cells, NOX and cytochrome c oxidase in macrophages as well as nitric oxide synthase and lipoxygenase in platelets contributing to both early and late stages of atherosclerosis. P. gingivalis seems to be markedly involved in the atherosclerotic process as compared to A. actinomycetemcomitans contributing to LDL oxidation and foam cell formation. Particularly interesting is the evidence describing the NLRP3 inflammasome activation as a new molecular mechanism underlying P. gingivalis-induced oxidative stress and inflammation. Amongst viral agents, immunodeficiency virus-1 and hepatitis C virus seem to have a major role in promoting ROS production, contributing, hence, to the early stages of atherosclerosis including endothelial dysfunction and LDL oxidation. In conclusion, oxidative mechanisms activated by several infectious agents during the atherosclerotic process underlying CVDs are very complex and not well-known, remaining, thus, an attractive target for future research.

In the female genital ecosystem, the complex interplay between the host immune system and the resident microflora protects against urogenital pathogens, like Chlamydia trachomatis. C. trachomatis is responsible for urethritis and cervicitis; however, most chlamydial infections are asymptomatic and, thus, not treated, potentially leading to severe reproductive sequelae. Here we investigated the interaction between the levels of selected immune mediators and the community state types of the cervical microbiota in C. trachomatis-infected women. Cervical samples from 42 C. trachomatis-positive women and 103 matched healthy controls were analyzed through the metagenomic analysis of the hypervariable region v4 of the 16S rRNA gene and the determination of lactoferrin, interleukin 1α (IL-1α), IL-6, alpha interferon (IFN-α), IFN-β, and IFN-γ by ELISA. Overall, C. trachomatis infection was significantly associated with a microbiota dominated by anaerobic bacteria (P = 0.000002). In addition, a network of Gardnerella vaginalis, Prevotella amnii, Prevotella buccalis, Prevotella timonensis, Aerococcus christensenii, and Variovorax guangxiensis has been identified as a potential biomarker of C. trachomatis infection through multiple statistical approaches. Again, chlamydial infection was significantly correlated with an increased production of lactoferrin, IL-6, IL-1α, IFN-α, and IFN-β (P < 0.05), whereas very low levels of IFN-γ were observed in C. trachomatis-infected women, levels similar to those detected in healthy women. Our findings show a distinctive signature of C. trachomatis genital infection, characterized by a specific bacterial network, constituted by anaerobes, as well as by increased levels of lactoferrin and proinflammatory cytokines (IL-1α, IL-6, IFN-α, and IFN-β), accompanied by low levels of IFN-γ. IMPORTANCE To our knowledge, this is the first study that investigated the association of C. trachomatis with the cervical levels of lactoferrin and selected inflammatory mediators and their correlation with the different community state types characterizing the female genital ecosystem. C. trachomatis, known as the leading cause of bacterial sexually transmitted diseases, continues to be an important public health problem worldwide for its increasing incidence and the risk of developing severe reproductive sequelae, like pelvic inflammatory disease and infertility. Specifically, C. trachomatis tend to persist in the female genital tract, leading to a chronic inflammatory state characterized by increased production of immune mediators responsible for tissue damage. Therefore, our study may help to broaden the knowledge on the complex interplay between the female genital microbiota and the host immune system in response to C. trachomatis infection.

Chlamydia trachomatis genital infection continues to be an important public health problem worldwide due to its increasing incidence. C. trachomatis infection can lead to severe sequelae, such as pelvic inflammatory disease, obstructive infertility, and preterm birth. Recently, it has been suggested that the cervico-vaginal microbiota may be an important defense factor toward C. trachomatis infection as well as the development of chronic sequelae. Therefore, the investigation of microbial profiles associated to chlamydial infection is of the utmost importance. Here we present a pilot study aiming to characterize, through the metagenomic analysis of sequenced 16s rRNA gene amplicons, the cervical microbiota from reproductive age women positive to C. trachomatis infection. The main finding of our study showed a marked increase in bacterial diversity in asymptomatic C. trachomatis positive women as compared to healthy controls in terms of Shannon's diversity and Shannon's evenness (P = 0.031 and P = 0.026, respectively). More importantly, the cervical microbiota from C. trachomatis positive women and from healthy controls significantly separated into two clusters in the weighted UniFrac analysis (P = 0.0027), suggesting that differences between the two groups depended entirely on the relative abundance of bacterial taxa rather than on the types of bacterial taxa present. Furthermore, C. trachomatis positive women showed an overall decrease in Lactobacillus spp. and an increase in anaerobes. These findings are part of an ongoing larger epidemiological study that will evaluate the potential role of distinct bacterial communities of the cervical microbiota in C. trachomatis infection.