Chlamydia pneumoniae

Associations With Chronic Disease

Infection and Atherosclerosis Development
Archives of Medical Research Journal, 2015.
Abstract- Atherosclerosis is a chronic disease hallmarked by chronic inflammation, endothelial dysfunction and lipid accumulation in the vasculature. Although lipid modification and deposition are thought to be a major source of the continuous inflammatory stimulus, a large body of evidence suggests that infectious agents may contribute to atherosclerotic processes. This could occur by either direct effects through infection of vascular cells and/or through indirect effects by induction of cytokine and acute phase reactant proteins by infection at other sites. Multiple bacterial and viral pathogens have been associated with atherosclerosis by seroepidemiological studies, identification of the infectious agent in human atherosclerotic tissue, and experimental studies demonstrating an acceleration of atherosclerosis following infection in animal models of atherosclerosis. This review will focus on those infectious agents for which biological plausibility has been demonstrated in animal models and on the challenges of proving a role of infection in human atherosclerotic disease

Dr. Wilmore Webley of UMASS breaks down the microbiology, features and impact of Chlamydia pneumoniae infection. It’s important to note that this video is a clip from a longer presentation in which Dr. Webley later discusses biofilms. The discussion of Chlamydia is distinct from the discussion on biofilm.

Chlamydia pneumoniae infection and cerebrovascular disease: a systematic review and meta-analysis
BMC Neurology, 2013.
Background- A wealth of published studies have been published on association between Chlamydia pneumoniae (C.pneumoniae) infection and cerebrovascular (CV) disease, but the results were inconsistent. This meta-analysis provides a systematic review of the available evidence from all serological and pathological studies of CV disease and C.pneumoniae.
Conclusion-Association between C.pneumoniae infection and CV disease depends on the analytical method adopted, which seems stronger with stroke due to large artery atherosclerosis. Establishing a causal relationship between C.peumoniae infection and CV disease will require more prospective studies with combination of techniques and stratified by etiological subtypes.

Association of Chlamydia pneumoniae (strain TWAR) infection with wheezing, asthmatic bronchitis, and adult-onset asthma.
Prospective clinical, bacteriologic, and serologic study, also a matched comparison of patients with and without evidence of CpN infection.  , n = 365, JAMA, 1991.
Methods- adult male patients (serologic titers greater than or equal to 1:64 and less than 1:16, respectively). Association of acute C pneumoniae infection with signs and symptoms of respiratory illness and the relationship of C pneumoniae antibody titer with wheezing at the time of enrollment in the study, and with the diagnosis of asthmatic bronchitis.
Results- Nine (47%) of 19 patients with acute C pneumoniae infection had bronchospasm during respiratory illness, and there was a strong quantitative association of C pneumoniae titer with wheezing at the time of enrollment in the study (P = .01).
In the matched study, C pneumoniae antibody was significantly associated with asthmatic bronchitis after, but not before, respiratory illness (odds ratio, 7.2; 95% confidence interval, 2.2 to 23.4). Four infected patients had newly diagnosed asthma after illness, and four others had exacerbation of previously diagnosed asthma.
Conclusions- Some C pneumoniae antibody titers, although not diagnostic of chlamydial infection by present criteria, probably represent acute reinfection or ongoing chronic infection. Repeated or prolonged exposure to C pneumoniae may have a causal association with wheezing, asthmatic bronchitis, and asthma.

Chlamydia pneumoniae infection and lung cancer risk: A meta-analysis
European Journal of Cancer, 2011.
Abstract- Chlamydia pneumoniae (C. pneumoniae) is a common cause of acute respiratory infection and has been hypothesised to cause several chronic diseases, including lung cancer. Numbers studies were conducted to analyse the association between C. pneumoniae infection and risk of lung cancer, but no clear consensus had been found. To assess this relationship more precisely, a meta-analysis was performed. The electronic databases PubMed, Embase, Web of Science and CNKI were searched; Data were extracted and analysed independently by two investigators. Ultimately, 12 studies, involving 2595 lung cancer cases and 2585 controls from four prospective studies and eight retrospective studies were included. Overall, people exposed to C. pneumoniae infection had an odds ratio (OR) of 1.48 (95% confidence interval (CI), 1.32-1.67) for lung cancer risk, relative to those not exposed. C. pneumoniae infection was clearly identified as a risk factor for lung cancer in both prospective studies (OR, 1.16; 95% CI, 1.00-1.36) and retrospective studies (OR, 2.17; 95% CI, 1.79-2.63) and in both IgA ≥ 16 cutoff group (OR, 1.22; 95% CI, 1.06-1.41) and the IgA ≥ 64 cutoff group (OR, 2.35; 95% CI, 1.88-2.93). In conclusion, C. pneumoniae infection is associated with an increased risk for lung cancer, higher titre may be a better predictor of lung cancer risk.

Infections Caused by Chlamydia pneumoniae Strain TWAR
Clinical Infectious Diseases, 1992.
Chlamydia pneuomoniae (the TWAR strain) is described by Dr. Thomas Grayston in this article which highlights acute respiratory illness with C. pneumoniae, the microbiology of the organism, and reviews the associated illnesses, laboratory diagnostics, treatment, epidemiology.

C. pneumoniae life cycle-05-05

Chlamydophila Pneumoniae and the Etiology of Late-Onset Alzheimer’s Disease
Journal of Alzheimer’s Disease, 2008.
Abstract- Sporadic, late-onset Alzheimer’s disease (LOAD) is a non-familial, progressive neurodegenerative disease that is now the most common and severe form of dementia in the elderly. That dementia is a direct result of neuronal damage and loss associated with accumulations of abnormal protein deposits in the brain. Great strides have been made in the past 20 years with regard to understanding the pathological entities that arise in the AD brain, both for familial AD (∼5% of all cases) and LOAD (∼95% of all cases). The neuropathology observed includes: neuritic senile plaques (NSPs), neurofibrillary tangles (NFTs), neuropil threads (NPs), and often deposits of cerebrovascular amyloid. Genetic, biochemical, and immunological analyses have provided a relatively detailed knowledge of these entities, but our understanding of the “trigger” events leading to the many cascades resulting in this pathology and neurodegeneration is still quite limited. For this reason, the etiology of AD, in particular LOAD, has remained elusive. However, a number of recent and ongoing studies have implicated infection in the etiology and pathogenesis of LOAD. This review focuses specifically on infection with Chlamydophila (Chlamydia) pneumoniae in LOAD and how this infection may function as a “trigger or initiator” in the pathogenesis of this disease.

International Reviews of Immunology, 2015.
Abstract- Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease of the central nervous system (CNS). Although the etiology of MS is unknown, genetic and environmental factors play a role. Infectious pathogens are the likely environmental factors involved in the development of MS. Pathogens associated with the development or exacerbation of MS include bacteria, such as Mycoplasma pneumoniae and Chlamydia pneumoniae, the Staphylococcus aureus-produced enterotoxins that function as superantigens, viruses of the herpes virus (Epstein-Barr virus and human herpesvirus 6) and human endogenous retrovirus (HERV) families and the protozoa Acanthamoeba castellanii. Evidence, from studies with humans and animal models, supporting the association of these various pathogens with the development and/or exacerbation of MS will be discussed along with the potential mechanisms including molecular mimicry, epitope spreading and bystander activation. In contrast, infection with certain parasites such as helminthes (Schistosoma mansoniFasciola hepaticaHymenolepis nanaTrichuris trichiuraAscaris lumbricoidesStrongyloides stercolarisEnterobius vermicularis) appears to protect against the development or exacerbation of MS. Evidence supporting the ability of parasitic infections to protect against disease will be discussed along with a brief summary of a recent Phase I clinical trial testing the ability of Trichuris suis ova treatment to improve the clinical course of MS. A complex interaction between the CNS (including the blood-brain barrier), multiple infections with various infectious agents (occurring in the periphery or within the CNS), and the immune response to those various infections may have to be deciphered before the etiology of MS can be fully understood.

Association of Chlamydia pneumoniae with Chronic Human Diseases
Antimicrobics and Infectious Diseases Newsletter, 2000.

A review of Chlamydia pneumoniae by Dr. Charles Stratton implicating this bacterium in more than acute lower respiratory tract infections.  This paper covers pathogenesis in chronic diseases, chronic lung diseases, chronic otolaryngeal diseases, asthma, atherosclerosis, neurologic diseases, chronic rheumatological diseases, cancer and other miscellaneous conditions like Interstitial Cystitis.

Elsevier Medical Hypothesis, 2005.
Summary- In the decade from 1980 to 1990, anamnestic data were amassed from 746 animal breeders on 31 farms, suffering from similar health problems and at the same time, 146 people from various professions outside agriculture were chosen as a control sample. A randomly selected group of 20 people from the 746 animal breeders were serologically tested for a wide range of infectious diseases (mycoplasmosis, tularaemia, leptospirosis, boreliosis, toxoplasmosis, listeriosis, and others). The analyses of these tests showed comparable figures in the majority of the tested people only in their serological response to chlamydial infection. Then, another randomly selected group of 157 people were serologically tested specifically for chlamydial infection. In 96% of these people a serological chlamydial response to a general chlamydial antigen and Chlamydia trachomatis antigen were diagnosed.

Serological Responses to C pneumoniae-01

Microbiology & Pathogenesis

FEMS Pathogens and Disease, 2015.

Summary- Chlamydiae are obligate intracellular bacteria that share a unique but remarkably conserved biphasic developmental cycle that relies on a eukaryotic host cell for survival. Although the phylum was originally thought to only contain one family, the Chlamydiaceae, a total of nine families are now recognized. These so-called Chlamydia-like organisms (CLOs) are also referred to as ‘environmental chlamydiae’, as many were initially isolated from environmental sources. However, these organisms are also emerging pathogens, as many, such as Parachlamydia sp., Simkania sp. and Waddlia sp., have been associated with human disease, and others, such as Piscichlamydia sp. and Parilichlamydia sp., have been documented in association with diseases in animals. Their strict intracellular nature and the requirement for cell culture have been a confounding factor in characterizing the biology and pathogenicity of CLOs. Nevertheless, the genomes of seven CLO species have now been sequenced, providing new information on their potential ability to adapt to a wide range of hosts. As new isolation and diagnostic methods advance, we are able to further explore the richness of this phylum with further research likely to help define the true pathogenic potential of the CLOs while also providing insight into the origins of the ‘traditional’ chlamydiae.

Chlamydia cell biology and pathogenesis
Nature Reviews Microbiology, 2016.
Abstract- Chlamydia spp. are important causes of human disease for which no effective vaccine exists. These obligate intracellular pathogens replicate in a specialized membrane compartment and use a large arsenal of secreted effectors to survive in the hostile intracellular environment of the host. In this Review, we summarize the progress in decoding the interactions between Chlamydia spp. and their hosts that has been made possible by recent technological advances in chlamydial proteomics and genetics. The field is now poised to decipher the molecular mechanisms that underlie the intimate interactions between Chlamydia spp. and their hosts, which will open up many exciting avenues of research for these medically important pathogens.

Chlamydia pneumoniae Multiply in Neutrophil Granulocytes and Delay Their Spontaneous Apoptosis
The Journal of Immunology, 2004.
Abstract- In the present study we investigated the interactions of neutrophil granulocytes with Cp. We monitored the uptake of Cp by PMN and demonstrated that intracellular chlamydiae survive and multiply within PMN. Coincubation with Cp resulted in a delay of neutrophil apoptosis up to 3 days, which was associated with a decrease in caspase-3 activity and was mediated by both Cp LPS and the autocrine production of IL-8 by PMN. Up to 42 h after Cp-PMN coincubation, Cp LPS has the strongest antiapoptotic effect, whereas Cp-induced IL-8 mediates apoptosis inhibition at longer time intervals.

The pathogenesis of Chlamydia species
Elsevier Antimicrobics and Infectious Disease Newsletter, 1996.
Introduction- Chlamydia species have long been recognized as pathogens. However, the recent association of Chlamydia pneumoniae with coronary artery disease has returned these microorganisms to the forefront of clinical medicine. Members of the Chlamydia species are unusual microorganisms in comparison to either viruses or bacteria; many physicians may be unaware of some of their unique characteristics. Therefore, this brief review of the pathogenesis of Chlamydia species is offered as an introduction to this interesting pathogen.

Comparative genomic analysis of human Chlamydia pneumoniae isolates from respiratory, brain and cardiac tissues
Genomics, 2015.
Abstract- Chlamydia pneumoniae is an obligate intracellular bacterium implicated in a wide range of human diseases including atherosclerosis and Alzheimer’s disease. Efforts to understand the relationships between C. pneumoniae detected in these diseases have been hindered by the availability of sequence data for non-respiratory strains. In this study, we sequenced the whole genomes for C. pneumoniae isolates from atherosclerosis and Alzheimer’s disease, and compared these to previously published C. pneumoniae genomes. Phylogenetic analyses of these new C. pneumoniae strains indicate two sub-groups within human C. pneumoniae, and suggest that both recombination and mutation events have driven the evolution of human C. pneumoniae. Further fine-detailed analyses of these new C. pneumoniae sequences show several genetically variable loci. This suggests that similar strains of C. pneumoniae are found in the brain, lungs and cardiovascular system and that only minor genetic differences may contribute to the adaptation of particular strains in human disease.

The pathogenesis of systemic chlamydial infections: Theoretical considerations of host cell energy depletion and its metabolic consequences
Elsevier Antimicrobics and Infectious Disease Newsletter, 1997.
Introduction- The recent observation that Chlamydia pneumoniae can infect human endothelial cells in vivo has led to speculation that such chronic infections might play a role in the pathogenesis of atherosclerosis. Regardless of any role in atherosclerosis, the fact that this pathogen can chronically infect endothelial cells, monocytes, smooth muscle cells, and perhaps other cells raises a number of theoretical considerations related to chlamydial energy requirements and their subsequent effects on the host cell. The following discussion addresses host-cell energy depletion and its possible metabolic consequences as these metabolic consequences could be important in the pathogenesis of systemic chlamydial infections.

Interaction of Chlamydiae with human macrophages
The FEBS Journal, 2015.
Abstract- The phylum Chlamydiae contains several members that are well‐known human pathogens, like Chlamydia trachomatis and C. pneumoniae. Establishing a chronic bacterial infection requires the active evasion of the host immune response. A major arm of the innate immune defence is constituted by macrophages, which fight infections by removing bacteria and triggering an adaptive immune response. However, some pathogenic Chlamydia infect and survive in macrophages at least for a certain period of time. Therefore, macrophages can serve as vehicles for the dissemination of bacterial infections from the primary infection site via the urogenital or respiratory tract to distant sites in the body. The capacity to infect macrophages seems to depend on the chlamydial strain and the source of macrophages. In vitro infections of macrophages with C. trachomatis, C. psittaci and C. pneumoniaereveal low efficiency of infection and progeny formation, as well as failure to develop mature inclusions. In contrast, the emerging pathogen, Simkania negevensis, actively replicates in macrophages. Here we summarize the current knowledge of the intracellular and molecular key mechanisms of C. trachomatis, C. pneumoniae and S. negevensis infections in human macrophages.

A retrospective seroepidemiologic survey of Chlamydia pneumoniae infection in patients in Beijing between 2008 and 2017
Retrospective seroepidemiologic study, n=12,050 serum specimens, PloS One, 2018.
Methods- “Anti-Cpneumoniae IgG and IgM antibodies were detected using micro-immunofluorescence test in serum samples of patients visiting Peking Union Medical College Hospital between 2008 and 2017 for routine medical purposes, and the aim of this retrospective study was to analyze the test results.”
Results- anti-Cpneumoniae IgG and IgM antibodies, the overall prevalence of anti-Cpneumoniae IgG antibodies was overall 86.6%.  Men – 87.2% Women- 86.0%.  Interestingly young patients, ages 3-5 years had a much lower incidence of anti-Cpneumoniae IgG, 42.8%. It increased with age, reaching the highest level of 98.6% in patients >70 years old.
Conclusion- “Based on our experience during the study, we suggest it is advisable that both anti-Cpneumoniae IgG and IgM antibodies should be tested for serological diagnosis of acute infection of Cpneumoniae. If anti-Cpneumoniae IgG antibody is tested alone, the incidence of acute infection of Cpneumoniae will be underestimated owing to the by missing of specimens with anti-Cpneumoniae IgM antibodies but with IgG antibodies that do not reach the criteria for acute infection, as in the report from Liu et al. On the other hand, if anti-Cpneumoniae IgM antibody is tested alone, the incidence will be dramatically underestimated due to the exclusion of specimens without anti-Cpneumoniae IgM antibodies but with IgG antibodies that do meet the criteria for acute infection.”

Safe haven under constant attack- The Chlamydiacontaining vacuole
Review article, Cellular Microbiology, 2018.
Abstract- “Chlamydia belong to the group of obligate intracellular bacteria that reside in a membrane bound vacuole during the entire intracellular phase of their life cycle. This vacuole called inclusion shields the bacteria from adverse influences in the cytosol of the host cell like the destructive machinery of the cell-autonomous defence system. The inclusion thereby prevents the digestion and eradication in specialised compartments of the intact and viable cell called phagolysosomes or autophagolysosomes. It is becoming more and more evident that keeping the inclusion intact also prevents the onset of cell intrinsic cell death programmes that are activated upon damage of the inclusion and direct the cell to destruct itself and the pathogen inside. Chlamydia secrete numerous proteins into the inclusion membrane to protect and stabilise their unique niche inside the host cell. We will focus in this review on the diverse attack strategies of the host aiming at the destruction of the Chlamydia-containing inclusion and will summarise the current knowledge on the protection mechanisms elaborated by the bacteria to maintain the integrity of their replication niche.”


Growth Cycle-Dependent Pharmacodynamics of Antichlamydial Drugs
Antimicrobial Agents and Chemotherapy, 2005.
Abstract- Chlamydiae are obligate intracellular pathogens that exhibit an extensive intracellular developmental cycle in vivo. Clinical treatment of chlamydial infection is typically initiated upon occurrence of symptomatology and is directed against an asynchronous population of different chlamydial developmental forms. Pharmacodynamics of antichlamydial drugs are predominantly characterized by MICs; however, in vitro determinations of MIC may not reflect differential susceptibilities of the developmental cycle. In this study, we correlated the antichlamydial effect of erythromycin, rifampin, doxycycline, and ciprofloxacin with the developmental stage of a fast-replicating and a slow-replicating chlamydial species. In addition, we describe the influence of concentration on killing. Extracellular elementary bodies and very-early-phase and late-phase chlamydiae were refractory to all tested antibiotics except rifampin, which was very effective against early-cycle chlamydiae. Rifampin was the most effective antibiotic overall, killed in a dose dependent matter, and exhibited moderate synergism with erythromycin. These considerations provide important information on chlamydial biology and antimicrobial susceptibility. A combinational therapy of rifampin and a macrolide should be considered in therapy-refractory infections.

Effect of Prolonged Treatment with Azithromycin, Clarithromycin, or Levofloxacin on Chlamydia pneumoniae in a Continuous-Infection Model
Antibiotic activity assay of continuous C. pneumoniae infection in vitro,  Antimicrobial Agents and Chemotherapy, 2002.Methods- investigating the effect of higher concentrations and a longer duration of treatment with azithromycin, clarithromycin, or levofloxacin on the growth of C. pneumoniae ( 4 μg of azithromycin/ml, 16 μg of levofloxacin/ml, or 64 μg of clarithromycin/ml.Results- The results of this study demonstrated that prolonged treatment with azithromycin, clarithromycin, and levofloxacin at concentrations achieved in the epithelial lining fluid reduced but did not eliminate C. pneumoniae from continuously infected host cells.Conclusions- 1) The dosages of azithromycin being used in coronary artery disease secondary prevention are 500 or 600 mg/day for 3 and 6 days followed by weekly doses of 500 to 600 mg for periods of 3 months to 1 year. Based on the data presented here, it would appear unlikely that these dosage regimens would eliminate C. pneumoniae from an intravascular focus.  2) Existence of persistence also raises a separate important issue for the treatment of C. pneumoniae-associated diseases. Persistent forms generally do not replicate or have reduced activity and therefore may not be susceptible to antibiotics. It is quite possible that the 20 to 30% rate of microbiologic failures in reported C. pneumoniae treatment studies and the ability of C. pneumoniae to survive antibiotic treatment in our experiments may be directly related to the persistent state.

Diagnostic Methods

Laboratory diagnosis of persistent human chlamydial infection
Frontiers in Cellular and Infection Microbiology, 2013.
Abstract – Diagnostic assays for persistent chlamydial infection are much needed to conduct high-quality, large-scale studies investigating the persistent state 
in vivo, its disease associations and the response to therapy. Yet in most studies the distinction between acute and persistent infection is based on the interpretation of the data obtained by the assays developed to diagnose acute infections or on complex assays available for research only and/or difficult to establish for clinical use. Novel biomarkers for detection of persistent chlamydial infection are urgently needed. Chlamydial whole genome proteome arrays are now available and they can identify chlamydial antigens that are differentially expressed between acute infection and persistent infection. Utilizing these data will lead to the development of novel diagnostic assays. Carefully selected specimens from well-studied patient populations are clearly needed in the process of translating the proteomic data into assays useful for clinical practice. Before such antigens are identified and validated assays become available, we face a challenge of deciding whether the persistent infection truly induced appearance of the proposed marker or do we just base our diagnosis of persistent infection on the presence of the suggested markers. Consequently, we must bear this in mind when interpreting the available data.

Pathogenic Potential of Novel Chlamydiae and Diagnostic Approaches to Infections Due to These Obligate Intracellular Bacteria
Clinical Microbiology Reviews, 2006.
Abstract- Novel chlamydiae are newly recognized members of the phylum Chlamydiales that are only distantly related to the classic Chlamydiaceae, i.e., Chlamydia and Chlamydophila species. They also exhibit an obligate biphasic intracellular life cycle within eukaryote host cells. Some of these new chlamydiae are currently considered potential emerging human and/or animal pathogens. Parachlamydia acanthamoebae and Simkania negevensis are both emerging respiratory human pathogens, Waddlia chondrophila could be a novel abortigenic bovine agent, and Piscichlamydia salmonis has recently been identified as an agent of the gill epitheliocystis in the Atlantic salmon. Fritschea spp. and Rhabdochlamydia spp. seem to be confined to arthropods, but some evidence for human exposure exists. In this review, we first summarize the data supporting a pathogenic potential of the novel chlamydiae for humans and other vertebrates and the interactions that most of these chlamydiae have with free-living amoebae. We then review the diagnostic approaches to infections potentially due to the novel chlamydiae, especially focusing on the currently available PCR-based protocols, mammalian cell culture, the amoebal coculture system, and serology.