Bacterial forms/stages

warning: Creating default object from empty value in /home/cpnhelp/www/www/modules/taxonomy/taxonomy.pages.inc on line 33.
The forms which Cpn can take on in it's life cycle.

Tryptophan depletion as a mechanism of gamma interferon-mediated chlamydial persistence

Abstract found Here<
Previous studies have shown that the immune-regulated cytokinei gamma interferon (IFN-gamma) activates host cells to restrict intracellulari growth of the bacterial pathogen Chlamydia trachomatis by induction of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). Recently, subinhibitory levels of IFN-gamma were used to generate an in vitro persistent chlamydial infection characterized by large aberrant, noninfectious reticulate bodies from which infectious progeny could be recovered following the removal of IFN-gamma. Studies were done to determine if the mechanism functioning to induce chlamydiae to enter a persistent state in the presence of low levels of IFN-gamma was similar to that reported to inhibit chlamydial growth. Host cells treated with levels of IFN-gamma required to induce persistence were assessed for IDO activity by high-performance liquid chromatography analysis of tryptophan and its catabolic products. Substantial tryptophan catabolism was detected in acid-soluble cellular pools, indicating that the intracellular availability of this essential amino acid was limited under these conditions. In addition, a mutant cell line responsive to IFN-gamma but deficient in IDO activity was shown to support C. trachomatis growth, but aberrant organisms were not induced in response to IFN-gamma treatment. Analyses of infected cells cultured in medium with incremental levels of exogenous tryptophan indicated that persistent growth was induced by reducing the amount of this essential amino acid. These studies confirmed that nutrient deprivation by IDO-mediated tryptophan catabolism was the mechanism by which IFN-gamma mediates persistent growth of C. trachomatis.

Evolution of Chlamydiaceae

From this location:
http://www.chlamydiae.com/docs/Chlamydiales/ev_persistence.asp
Here<

Part II. Evolution of Chlamydiaceae
Persistent infection

Life persists. Plants, animals, and micro organisms have all worked out ways of ‘toughing out’ the hard times and waiting for the good ones (Levin, 1997). Birds migrate, bears hibernate, bacteria sporulate. So it is not surprizing that the Chlamydiaceae produce low-grade, long-lasting infections in their natural hosts. This behavior, usually referred to as persistent infection, is the subject of intense current interest because of its possible involvement in human disease. Persistent infections have been discussed at length in many excellent reviews (Beatty et al., 1994; Brunham, 1999; Darville, 2000; Nataro et al., 2000; Ward, 1999). Early investigations were summarized by Moulder (1991). Here I will concentrate on a few evolutionary questions. The ability to engender persistent infections is so widespread among Chlamydiaceae that it was in all probability a capability already possessed by the familial LCA. Chlamydial persistence comes in many guises and no one model fits them all. However, since chlamydiae are closely related organisms with pared - down genomes, a large number of completely different persistence mechanisms should not be expected. Let us hope that, when regulation of chlamydial multiplication in both acute and persistent infections is better understood, there will emerge a general underlying mechanism whose variations will account for the many faces of persistence.

Cpn Slides

This link< for slides on the different life stages of Cpn.

CPn Epidemiology

Clin Microbiol Infect. 1998 Jan;4 Suppl 4:S1-S6. Related Articles, Links

Epidemiology of Chlamydia pneumoniae.

Blasi F, Tarsia P, Arosio C, Fagetti L, Allegra L.

Institute of Respiratory Diseasesi, University of Milan, IRCCS Ospedale Maggiore Milano, Italy.

Chlamydia pneumoniae is the most commonly occurring intracellulari bacterial pathogen. It is frequently involved in respiratory tract infections and to a lesser degree in extrapulmonary diseases. According to seroepidemiologic surveys, C. pneumoniae infection seems to be both endemic and epidemic. Such studies indicate that C. pneumoniae infection is widespread, with frequent reinfection during a lifetime. In Western countries the highest rate of new infections occurs between the ages of 5 and 15. The antibody prevalence worldwide is higher in adult males than in females. Currently available data suggest that C. pneumoniae is primarily transmitted from human to human without any animal reservoir. Transmission seems to be inefficient, although household outbreaks with high transmission rates are reported. Most reports rank C. pneumoniae among the three most common etiologic agents of community-acquired pneumonia, with an incidence ranging from 6% to 25%, and generally presenting a mild and, in some cases, self-limiting clinical course. Recent reports also indicate a possible role for C. pneumoniae in severe forms of community-acquired pneumonia and in respiratory infections in immunocompromised patients. C. pneumoniae infection has also been implicated in the pathogenesis of asthma in both adults and children. The hypothesis that C. pneumoniae infection could lead to asthma is based on clinical studies and on the evidence of specific IgE production, direct epithelial damage, induction of T-cell immunopathologic diseases, and vascular smooth cell infection. Chronic C. pneumoniae infection seems to be common in patients with chronic bronchitis whether exacerbated or not, and is characterized by a strong humoral immune response to this intracellular microorganism, which is present in the majority of patients with severe chronic bronchitis. More than 60% of subjects with chronic bronchitis have specific C. pneumoniae antibody titers, and the microorganism may be identified by culture or PCRi in almost 40% of these patients. This pathogen has also been recently associated with atherosclerosis and coronary heart disease (CHD). Seroepidemiological evidence indicates that the majority of patients with CHD present an anti-C. pneumoniae antibody pattern consistent with chronic infection. Furthermore, C. pneumoniae has been detected in atherosclerotic coronary plaques by several methods, including immunocytochemistry, transmission electron microscopy and molecular biology techniques. Recently, we detected C. pneumoniae DNA in a high percentage (51%) of aortic aneurysm plaques. Moreover, our serologic data support the hypothesis that a chronic C. pneumoniae antibody pattern may be a possible risk marker for atherosclerosis. Recently, C. pneumoniae has been isolated by culture from the coronary artery of a patient with coronary atherosclerosis, providing direct evidence of the presence of viable organisms in atheromatous lesions. Moreover, we recently demonstrated an association between C. pneumoniae reinfection and acute myocardial infarction.

Early events in chlamydial infection of host cells

Harefuah. 2004 Sep;143(9):669-75, 693.

[Early events in chlamydial infection of host cells]

[Article in Hebrew]

Israeli E, Friedman M.

Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva.

Chlamydiae, gram-negative, obligate intracellulari bacteria, are major pathogens worldwide, causing several diseases including trachoma, respiratory diseases and sexually transmitted disease. Penetration of chlamydiae to epithelial cells, the environment which supports their growth and survival, leads to various events that begin with changes to the bacteria-containing vacuole, allowing for its progression from the endosomal to the exocytic pathway. The changes include fusion with vesicles carrying glycerophospholipids and sphingolipids and originating in the endoplasmic reticulum (ER) and the Golgi apparatusi. The bacteria then reproduce in the inclusion vesicles. In this survey we describe the chlamydial life cycle and review recent reports on early intracellular events in chlamydial infection. While antibiotics currently recommended for treatment of chlamydial infections interfere with bacterial macromolecular synthesis, newer forms of treatment may be developed based on our increasing understanding of chlamydial manipulation of intracellular processes. This manipulation, described in this article on early intracellular events in chlamydial infection, enables these pathogens to escape destruction in the endosomal compartment and begin replication in the target cell.

The Basics Page

Hello and Welcome!

This site is focused on treatment of chronic disease like Multiple Sclerosis (MSi) Chronic Fatigue Syndromei (CFSi) and Fibromyalgia (FMSi) an many other diseasesi with antibioticsi. Recent research indicates that Chlamydia Pneumoniae (CPni) plays a role in these diseases.

Here are the basics that make it easier for people new to the site to get going (if your brain isn't ready for even this much right now-- we've all been there-- read Cpn Simple< first):

Is this a sexually transmitted disease? No. this is chlamydia pneumoniae, a bacteria that can cause pneumonia. It may soon be called chlamydiophilia (meaning in the family of).

Is chlamydia pneumoniae (CPn) rare?

Chlamydia pneumoniae: crossing the barriers?

Pubmed link: http://erj.ersjournals.com/cgi/content/full/23/4/499< Eur Respir J 2004; 23:499-500
Copyright ©ERS Journals Ltd< 2004

Chlamydia pneumoniae: crossing the barriers?

F. Blasi1, S. Centanni2 and L. Allegra1

1 Institute of Respiratory Diseasesi, University of Milan, IRCCS Ospedale Maggiore di Milano, and 2 Institute of Respiratory Diseases, University of Milan, Respiratory Unit, San Paolo Hospital, Milan, Italy

Correspondence: F. Blasi, Institute of Respiratory Diseases, University of Milan, Pad. Litta, IRCCS Ospedale Maggiore di Milano, via F. Sforza, 35, I-20122 Milano, Italy. Fax: 39 0250320628. E-mail: francesco.blasi@unimi.it

Chlamydia pneumoniae has been recognised as a cause of respiratory tract infectionsi and implicated as a potential risk factor or causative agent in different extrapulmonary diseases including atherosclerosis, multiple sclerosis, and Alzheimer's diseasei< 1<3<. Being an obligate intracellulari bacterium, C. pneumoniae has been detected in circulating monocytes and can activate inflammatory processes in epithelial, endothelial and smooth muscle cells in vitro 4<.

In the present issue of the European Respiratory Journal (ERJ), Gieffers et al. 5< report an animal model showing that intratracheal infection with C. pneumoniae is followed by systemic dissemination of the infection mediated by peripheral blood mononuclear cells (PBMCs). The authors, on the basis of both the animal model and in vitro study results, hypothesise a "cellular model" for C. pneumoniae dissemination. Infection of the lung is characterised by an early phase dominated by granulocytes, and a late phase dominated by alveolar macrophages. Alveolar macrophages, infected by granulocytes, would migrate through the mucosal barrier, using lymphatic tissue, and gain access to the systemic circulation as PBMCs reaching the spleen and the vasculature. The conclusions are mostly inferred on the basis of cell morphology in the absence of definitive determination of infected cell types in extra-pulmonary tissues. Nonetheless, the proposed "cellular model" hypothesis is intriguing and undoubtedly consistent with other recently published studies.

Wark et al. 6< analysed the relationship between airway inflammationi< and serological response to C. pneumoniae in acute severe asthmai. At presentation with acute asthma, the sputum total cell count was increased in C. pneumoniae antibody responders compared to nonresponders, and C. pneumoniae responders had significantly more sputum neutrophils compared to nonresponders. Moazed et al. 7< demonstrated that monocytes may act as vectors and systemically disseminate C. pneumoniae, and Blasi et al. 8< showed a good correlation between C. pneumoniae detection in PBMCs and in atherosclerotic plaques. However, in order to adhere and migrate through the vessel wall, monocytes have to go through a highly coordinated process, which requires the activation of different adhesion receptors in a cascade-like fashion. May et al. 9< report that C. pneumoniae infection induces rolling and adhesion of macrophages to the noninflamed vessel wall of noninfected, nonatherosclerotic mice. C. pneumoniae-infected monocytic cells show enhanced transmigration and attach to the endothelium via the activated integrins very late antigen 4 (VLA-4), and the activation of the two ß2-integrins lymphocyte function-associated antigen-1 (LFA-1) and macrophage antigen-1 (MAC-1), involving the urokinase receptor (uPAR). This study demonstrates that C. pneumoniae-infected monocytes may be armed to invade noninflamed subendothelium and initiate inflammatory processes. The data indicate that C. pneumoniae has the potential to induce a functionally active, adhesive state in monocytic cells by activation of the integrin adhesion receptor system. Therefore, C. pneumoniae is not just transported into the subendothelium by monocytes as an innocent bystander, but can actively contribute to the monocyte recruitment to the preferential sites of atherosclerotic lesions. Moreover, this study suggests that C. pneumoniae-infected circulating monocytes may have the capacity to induce an adhesive phenotype in adjacent, noninfected monocytes.

Monocytes perhaps also act as the vehicle for trafficking C. pneumoniae across the blood/brain barrier. PBMCs may function as a means by which C. pneumoniae enters the central nervous system (CNSi) to induce neuroinflammation in Alzheimer's disease and in multiple sclerosis 10<. C. pneumoniae infection has been shown to stimulate transendothelial entry of monocytes through human brain endothelial cells (HBMEC). This entry is facilitated by the upregulation of vascular cell adhesion molecule-1 and intercellulari adhesion molecule-1 on HBMECs and a corresponding increase of LFA-1, VLA-4, and MAC-1 on monocytes.

An association between C. pneumoniae and multiple sclerosis has been proposed, based on the higher frequency of its detection in the cerebrospinal fluid (CSF) of multiple sclerosis patients compared to neurological controls. Multiple sclerosis is an inflammatory demyelinating disease of the CNS of unknown etiology. Current knowledge supports a multifactorial aetiology in which both genetic and environmental factors (including microbial agents) may concur. Interestingly, experimental autoimmune encephalomyelitis (EAE), the experimental animal model of multiple sclerosis, has been successfully induced using a C. pneumoniae peptide analogue of rat myelin basic protein 11<. Although multiple sclerosis and EAE are obviously two different entities, this study provides the first indication of a possible direct contribution of C. pneumoniae to the pathophysiology of (experimental) demyelinationi. The presence of C. pneumoniae in human CSF does not actually prove that the organism causes or triggers multiple sclerosis: chlamydial infection of the CNS may just represent an opportunistic, secondary event in the disease. Even in this case, however, the presence of the organism may exacerbate/modulate a pre-existing pathogenic process. This is also supported by the finding that C. pneumoniae polymerase chain reaction (PCRi)-positive patients have more active lesions than C. pneumoniae PCR-negative/patients suggesting a role for C. pneumoniae in fostering chronic inflammatory stimulation within the CNS 2<. It can be hypothesised that C. pneumoniae might act as cofactor capable of fuelling previously established inflammatory and demyelinating processes and promote a more active disease.

Gieffers et al. 5< showed a good correlation between the presence of C. pneumoniae in PBMCs both in the lung and in the vasculature. These data are consistent with the results reported by Blasi and co-workers 8<, 12< who showed that C. pneumoniae DNA identification is similar in biopsy specimens (vascular and bronchial) and PBMCs, which suggests that blood PCR may be a useful tool for identifying patients with chronic C. pneumoniae infection.

Clinical persistencei is probably a key concept in C. pneumoniae infection pathogenesis. Microbial persistence is a state of infection during which the host immune response does not eliminate the pathogen, thereby resulting in continuing damage to the host. Persistent infection may amplify airway inflammation in asthma and chronic obstructive pulmonary disease (COPD), but also in extrapulmonary diseases such as atherosclerosis, multiple sclerosis and Alzheimer's disease.

Stephens 13< has recently revised the possible pathogenic mechanisms of C. pneumoniae infection. He underlines that C. pneumoniae can induce an inflammatory process elicited by infected host cells that is necessary and sufficient to account for chronic and intense inflammation and the promotion of cellular proliferation, tissue remodelling and scarring, the ultimate causes of disease sequelae.

The cellular responses of epithelial cells, the primary home for C. pneumoniae, can be reliably induced upon acute, chronic and persistent infection. The cellular processes of the epithelial cells, elicited by chlamydial infection, cause the influx of inflammatory neutrophils, T-cells, B-cells and macrophages that are stimulated by the pro-inflammatory cytokinei and chemokine environment. These cells become activated in both antigen-nonspecific and, for re-infection, antigen-specific responses to produce their own repertoire of cytokinesi and growth factors. The induction of host cell cytokines will promote foci of inflammatory responses in addition to promoting cellular proliferation, tissue remodelling and healing processes that, if persistent, result in scarring.

The possible role of chronic-persistent infection is suggested in asthmatic children where persistent clinical features are associated with C. pneumoniae infection, indicating that this infection should be investigated and treated in case of persistent asthmatic symptoms 14<15<. On the other hand, in adults with asthma, higher titres of antibodies directed against C. pneumoniae are associated with more severe clinical disease 16<. The intense neutrophil influx demonstrated in acute severe asthma is potentially a potent source of proteolytic enzymes with the ability to damage and activate the airway epithelium, whereas neutrophil elastase can cause eosinophil degranulation 6<. The inflammatory changes caused by infection with C. pneumoniae have the potential to amplify the inflammation and airway damage present in asthma. Furthermore, standard asthma treatment may potentially enhance this response, given the ability of corticosteroids to reactivate C. pneumoniae infection. These data suggest that C. pneumoniae infection may influence the clinical course of asthma.

In the same way, preliminary data on chronic infection with C. pneumoniae in patients with COPD and its interaction with host cells indicate that this agent may be implicated in the modulation of the natural history of chronic bronchitis and emphysema 12<.

The interesting finding of the study by Gieffers et al. 5< is the demonstration that granulocytes are one of the main target of C. pneumoniae infection and that these cells can act as "infecting" cells and reservoir of the pathogen. These data confirm the excellent capacity of C. pneumoniae to survive in different immune cells, use the immune cells as carriers for breaching the blood-tissue barriers, and potentially cause chronic/persistent infections.

Chronic infection is probably the real challenge in Chlamydia pneumoniae infection and we certainly need new studies addressing the question whether Chlamydia pneumoniae long-term survival within immune and nonimmune cells has a role in chronic pulmonary and extrapulmonary diseases.

References

 

    <
  1. < Neuman FJ. Chlamydia pneumoniae-atherosclerosis link: a sound concept in search for clinical relevance. Circulation 2002;106:2414–2416.[Free Full Text]<<
  2. < <
  3. < Grimaldi LM, Pincherle A, Martinelli-Boneschi F, et al. An MRI study of Chlamydia pneumoniae infection in Italian multiple sclerosis patients. Mult Scler 2003;9:467–471.[CrossRef]<[ISI]<[Medline]< [Order article via Infotrieve]<<
  4. < <
  5. < Blain BJ, Gerard HC, Arking EJ, et al. Identification and localization of Chlamydia pneumoniae in the Alzheimer's brain. Med Microbiol Immunol 1998;187:23–42.[CrossRef]<[ISI]<[Medline]< [Order article via Infotrieve]<<
  6. < <
  7. < Dechend R, Maass M, Gieffer J, et al. Chlamydia pneumoniae infection of vascular smooth muscle and endothelial cells activates NF-{kappa}B and induces tissue factor and PAI-1 expression: a potential link to accelerated arteriosclerosis. Circulation 1999;100:1369–1373.[Abstract/Free Full Text]<<
  8. < <
  9. < Gieffers J, van Zandbergen G, Rupp J, et al. Phagocytes transmit Chlamydia pneumoniae from the lung to the vasculature. Eur Respir J 2004;23:506–510.[Abstract/Free Full Text]<<
  10. < <
  11. < Wark PAB, Johnston SL, Simpson JL, Hensley MJ, Gibson PG. Chlamydia pneumoniae immunoglobulin A reactivation and airway inflammation in acute asthma. Eur Respir J 2002;20:834–840.[Abstract/Free Full Text]<<
  12. < <
  13. < Moazed TC, Kuo CC, Grayston JT, Campbell LA. Evidence of systemic dissemination of Chlamydia pneumoniae via macrophages in the mouse. J Infect Dis 1998;177:1322–1325.[ISI]<[Medline]< [Order article via Infotrieve]<<
  14. < <
  15. < Blasi F, Boman J, Esposito G, et al. Chlamydia pneumoniae DNA detection in peripheral blood mononuclear cells is predictive of vascular infection. J Infect Dis 1999;180:2074–2076.[CrossRef]<[ISI]<[Medline]< [Order article via Infotrieve]<<
  16. < <
  17. < May AE, Redecke V, Grüner S, et al. Recruitment of Chlamydia pneumoniae-infected macrophages to the carotid artery wall in noninfected, nonatherosclerotic mice. Arterioscler Thromb Vasc Biol 2003;23:789–794.[Abstract/Free Full Text]<<
  18. < <
  19. < MacIntyre A, Abramov R, Hammond CJ, et al. Chlamydia pneumoniae infection promotes the transmigration of monocytes through human brain endothelial cells. J Neurosci Res 2003;71:740–750.[CrossRef]<[ISI]<[Medline]< [Order article via Infotrieve]<<
  20. < <
  21. < Lenz DC, Lu L, Conant SB, et al. A Chlamydia pneumoniae-specific peptide induces experimental autoimmune encephalomyelitis in rats. J Immunol 2001;167:1803–1808.[Abstract/Free Full Text]<<
  22. < <
  23. < Blasi F, Damato S, Cosentini R, et al. Chlamydia pneumoniae and chronic bronchitis: association with severity and bacterial clearance following treatment. Thorax 2002;57:672–676.[Abstract/Free Full Text]<<
  24. < <
  25. < Stephens RS. The cellular paradigm of chlamydial pathogenesis. TRENDS Microbiol 2003;11:44–51.[CrossRef]<[ISI]<[Medline]< [Order article via Infotrieve]<<
  26. < <
  27. < Cunningham AF, Johnston SL, Julious SA, Lampe FC, Ward ME. Chronic Chlamydia pneumoniae infection and asthma exacerbations in children. Eur Respir J 1998;11:345–349.[Abstract/Free Full Text]<<
  28. < <
  29. < Thumerelle C, Deschildre A, Bouquillon C, et al. Role of viruses and atypical bacteria in exacerbations of asthma in hospitalized children: a prospective study in the Nord-Pas de Calais region (France). Pediatr Pulmonol 2003;35:75–82.[CrossRef]<[ISI]<[Medline]< [Order article via Infotrieve]<<
  30. < <
  31. < ten Brinke A, van Dissel JT, Sterk JT, Zwinderman AH, Rabe KF, Bel EH. Persistent airflow limitation in adult-onset nonatopic asthma is associated with serologic evidence of Chlamydia pneumoniae infections. J Allergy Clin Immunol 2001;107:449–454.[CrossRef]<[ISI]<[Medline]< [Order article via Infotrieve]<

Research Articles

These pages on research articles are now reorganized into separate pages for each category. Doing this has been needed for some time, but it is with some trepidation we do this because in some diseases the research is very equivocal and incomplete.

Dead Bugs Don't Mutate

Classic and important article on antibiotic resistance by Cpn researcher Charles Strattoni Dead Bugs Don't Mutate: Susceptibility Issues in the Emergence of Bacterial Resistance Charles W. Stratton www.cdc.gov/ncidod/EID/vol9no1/pdfs/02-0172.pdf<

Comments by David Wheldon in response to questions about choice of antibiotics in his protocal versus the Vanderbilt protocal:

I believe that Stratton and co-workers used a beta-lactam (penicillin, amoxycillin or similar) to attack the infectious stage
(elementary body) of the organism. They did some in vitro work to support this, which they should publish, because it's
fundamental. I reasoned that, as culture was so rare in persistent human infections, the numbers of elementary bodies would
be small. Also, any elementary body entering a phagosome in a cell containing bacterial protein-synthesis inhibitors would be
doomed, as the organism needs to fabricate proteins immediately to survive. Coupled with this was a native gut-reaction that
people would buy into the idea more readily if there were fewer antibiotics. And, further, that one is taught at med school
never to combine cidal and static agents. In the higher levels of microbiology that's not always true, but basically you just
want people to believe you and treat, as early as possible, and the more complications you put in their way the more difficult
that is.

Syndicate content