User:Dangermouse72/Cpn

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Chlamydia pneumoniae
Scientific classification
Kingdom: Bacteria
Phylum: Chlamydiae
Order: Chlamydiales
Family: Chlamydiaceae
Genus: Chlamydia
Species: C. pneumoniae

Chlamydia pneumoniae (also known as Chlamydophila pneumoniae or Cpn) is a recently discovered (1989) species of chlamydiae bacteria that infects humans and is a major cause of pneumonia worldwide (hence its name). Like other chlamyidae species, Cpn has a complex developmental cycle and must first infect another cell in order to reproduce. It is thus classified as an obligate intracellular parasite. Although Cpn causes roughly 10% of all community acquired pneumonia, perhaps its most significant clinical aspect is its proposed role in a whole host of chronic diseases. Although it initially presents as a respiratory tract infection there is a growing body of evidence associating Cpn with a range of chronic inflammatory conditions including Atherosclerosis[1] , Asthma [2], Multiple Sclerosis [3], Rheumatoid Arthritis [4], Alzheimer's disease [5] and Chronic Fatigue Syndrome[6] . The key features of Cpn are its chronicity (it is able to evade the immune system by entering into a persistent form) and the resulting inflammation it produces.

Contents

[edit] Cpn Timeline

1907 First Chlamydia discovered (Chlamydia trachomatis)

1965 TW-183 chlamydia isolate recovered from a child in Taiwan [7]

1986 Isolate found in acute respiratory patients in US and renamed TWAR [7][8]

1989 Chlamydia pneumoniae identified as a distinct species [7]

1999 Full genome sequence for Chlamydia pneumoniae published.[9]

[edit] Life cycle and method of infection

Life cycle of Chlamydia pneumoniae
Life cycle of Chlamydia pneumoniae

Chlamydia pneumoniae is a small bacterium (0.2 to 1 micrometer) that undergoes several transformations during its life cycle. It exists as an elementary body (EB) in between hosts. The EB is not biologically active but is resistant to most environmental stresses and can survive outside of a host for a limited time. The EB travels from an infected person to the lungs of a non-infected person in small droplets and is responsible for infection. Once in the lungs, the EB is taken up by cells in a pouch called an endosome by a process called phagocytosis. However, the EB is not destroyed by fusion with lysosomes as is typical for phagocytosed material. Instead, it transforms into a reticulate body and begins to replicate within the endosome. The reticulate bodies must utilize some of the host's cellular machinery to complete its replication. The reticulate bodies then convert back to elementary bodies and are released back into the host often after causing the death of the host cell. The EBs are thereafter able to infect new cells, either in the same organism or in a new host. Thus, the life cycle of Chlamydia pneumoniae is divided between the elementary body which is able to infect new hosts but can not replicate and the reticulate body which replicates but is not able to cause new infection.

[edit] Persistent (Cryptic) State

  • There is ample evidence showing that Chlamydiae species (in particular Cpn) enter into a cryptic form as a response to stress. [10] - e.g. when challenged with antibiotics or as a response to interferon-gamma.
  • Typically the size of the inclusion body is reduced and the Cryptic Bodies are much larger than the reticulate bodies.
  • Chlamydiae in this state are known to not to be susceptible to standard antibiotics. However there is evidence that they are susceptible to the Nitroimidazole family.

[edit] Acute Infection / Pneumonia

Cpn is a common cause of pneumonia around the world and is thought to cause between 5% and 15% of all community acquired pneumonia. Because treatment and diagnosis are different from historically recognized causes such as Streptococcus pneumoniae, pneumonia caused by Chlamydia pneumoniae is commonly categorized as an "atypical pneumonia." It may also be referred to as "walking pneumonia" because the initial infection is usually mild and even asymptomatic.

[edit] Symptoms and diagnosis

Symptoms of infection with Chlamydia pneumoniae are indistinguishable from other causes of pneumonia. These include cough, fever, and difficulties breathing. However Chlamydia pneumoniae does more often cause pharyngitis, laryngitis, and sinusitis than other causes of pneumonia.

Diagnosis of Chlamydia pneumoniae may be confounded by prior infections with this microorganism. Examination of sputum may reveal signs of the bacteria. Otherwise, examination of the blood may reveal antibodies against the bacteria. If there has been a prior infection, this may have resulting in pre-existing antibodies. Therefore, interpretation may require a period of six weeks in order to reanalyze the antibodies and to determine whether the infection was new or old. Examination of the blood may also show proteins (antigens) from Chlamydia pneumoniae, either through direct fluorescent antibody testing, enzyme-linked immunosorbent assay (ELISA), or polymerase chain reaction (PCR).

Chest x-rays of lungs infected with Chlamydia pneumoniae often show a small patch of increased shadow (opacity). However, many different patterns are common and there is no appearance which allows for a specific diagnosis.

[edit] Treatment

Whilst short term treatment with a single antibiotic may be sufficient to alleviate acute infections, there is much research showing that such treatments are ineffective for chronic infections. Indeed Cpn can be recovered from cell cultures even after 30 days of antibiotic treatment [11]. Also in animal models infection persists after monotherapy [12]. It is known that Cpn can enter into a persistent state for indefinite periods when placed under stress. Indeed [13] show that Cpn can infect monocytes where it is able to enter a persistent state which is unaffected by standard antibiotics. In general a single drug approach (e.g. a macrolide or tetracycline) only targets one phase of the organism's life-cycle. In order to be effective, a therapy needs to address multiple stages of the organism's life cycle.

  • talk about CAP
  • talk about alternatives to CAP - e.g. Calcium channel blockers proposed by Azenabor, using tryptophan to keep bacteria out of cryptic state etc.

[edit] Dissemination

How CPn disseminates throughout various cells/tissues.


[edit] Links between Chlamydia pneumoniae and chronic inflammatory diseases

[edit] Asthma

Repeated or prolonged exposure to C pneumoniae may have a causal association with wheezing, asthmatic bronchitis, and asthma. [14]

[edit] Atherosclerosis

Links between infection with Cpn, heart attacks (myocardial infarction) and atherosclerosis have also been found [1]. In fact Cpn has been found within plaques in the walls of coronary arteries supplying the heart [15] [16]. Antibody levels against Cpn are also higher in people with heart problems [17]. Although short-term prescription of anti-chlamydial antibiotics has not been shown to decrease incidence of myocardial infarction[18], this is entirely consistent with the chronic multi-phase life cycle characteristic of chlamydial infection and also the fact that the mechanisms involved in athersclerosis are likely to be complex and entrenched. Indeed in Cpn-induced animal models of atherosclerosis, antibiotic treatment only seems to have beneficial effects when carried out early after infection, but not later on. [19]

[edit] Multiple Sclerosis

Cpn has also been found in the cerebrospinal fluid of some patients diagnosed with multiple sclerosis [20].

Systemic Cpn infection is more frequent in MS patients than the healthy population and either occurs early in the course of the disease or before disease onset. [21]

[edit] Alzheimer's

Following inoculation of mice with Cpn, amyloid plaques consistent with those observed in the AD brain develop[22]. Cpn can sustain a chronic infection in neuronal cells by interfering with apoptosis[23]. In one study 20/27 of AD patients, but only 3/27 controls, were PCR-positive for Cpn[5]. Astrocytes, microglia, and neurons were all seen to serve as host cells for Cpn in the AD brain, and infected cells were found in close proximity to both neuritic senile plaques and neurofibrillary tangles[5]. It has also been found that the load of Cpn found in Alzheimer's brain varies with APOE genotype[24], an important risk factor in AD. Cpn is found in blood vessels and monocytes in AD brain tissues, and Cpn infection in these cell types may contribute to increased monocyte migration and promote inflammation within the CNS[25]. Cpn infection results in a pro-inflammatory milieu that ultimately results in neurodegeneration with prominent roles for both IL-6 and TNF-alpha.[26] Combination antibiotic therapy has been clinically tried in AD patients[27]. There was significantly less decline at 6 months in the antibiotic group than in the placebo group. The authors claim this can not be due to Cpn as tests were not significantly different between the 2 groups, however this conclusion fails to take into account the chronic and persistent nature of Cpn. Some studies however have failed to detect any Cpn in Alzheimer's[28].

[edit] Rheumatoid Arthritis

[edit] Research Difficulties

  • Cpn presents particular difficulties for researchers. Its an intracellular infection so does not culture without cells. Difficult to measure, detect. Has multi-phase life cycle.
  • Resistance within areas of clinical medicine for bacterial infection as the source of chronic disease. Situation is identical to that faced by Helicobacter Pylori in the 1980's.

To quote professor Grayston who discovered Cpn: "Our situation is somewhat similar to that of the investigators of Helicobacter pylori, who were faced with great skepticism concerning the role that microorganism played in ulcers of the stomach and duodenum" [7]

  • Biphasic life cycle makes Chlamydiae some of the most difficult organisms to study. No way of doing targeted gene disruption:

EB has tightly linked outer membrane with packed chromosome. RB has 3 membranes seperating its cytoplasm from the extracellular environment - host cell membrane, inclusion membrane, and bacterial cell wall.

[edit] Cause or Effect

In some cases Cpn will clearly be a 2ndary infection rather than a causative agent. However in some studies the rate of infection is just too high for Cpn to merely be opportunistic.

[edit] Testing

Antibody test is the best. PCR may be best for acute infections, but accuracy unknown and is likely to be low.[29]

[edit] Other Stuff

  • Briefly mention Cpn involvement in other species
  • Mention possibility for vaccination
  • Economic damage caused by Cpn likely to be significant

[edit] References

  1. ^ a b Blasi F et al. Detection of Chlamydia pneumoniae but not Helicobacter pylori in atherosclerotic plaques of aortic aneurysms. J Clin Microbiol. 1996 Nov;34(11):2766-9. PMID: 8897180
  2. ^ Johnston SL, Martin RJ. Chlamydophila pneumoniae and Mycoplasma pneumoniae: a role in asthma pathogenesis? Am J Respir Crit Care Med. 2005 Nov 1;172(9):1078-89. Epub 2005 Jun 16. Review. PMID: 15961690
  3. ^ Stratton CW, Wheldon DB. Multiple Sclerosis: an infectious syndrome involving Chlamydophila pneumoniae. Trends Microbiol. 2006 Nov;14(11):474-9. PMID: 16996738
  4. ^ Villareal C, Whittum-Hudson JA, Hudson AP. Persistent Chlamydiae and chronic arthritis. Arthritis Res. 2002;4(1):5-9. Epub 2001 Oct 8. Review. PMID: 11879531
  5. ^ a b c Gérard HC et al. Chlamydophila (Chlamydia) pneumoniae in the Alzheimer's brain. FEMS Immunol Med Microbiol. 2006 Dec;48(3):355-66. Epub 2006 Oct 18. PMID:17052268
  6. ^ Nicolson GL, Gan R, Haier J. Multiple co-infections (Mycoplasma, Chlamydia, hhv-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms. APMIS. 2003 May;111(5):557-66. PMID: 12887507
  7. ^ a b c d A New Bug That's Full of Surprises: Chlamydia pneumoniae http://www.washington.edu/research/pathbreakers/1989a.html
  8. ^ Kuo CC, Chen HH, Wang SP, Grayston JT. Identification of a new group of Chlamydia psittaci strains called TWAR. J Clin Microbiol. 1986 Dec;24(6):1034-7. PMID: 3097063
  9. ^ Kalman, S et al. 1999. Comparative genomes of Chlamydia pneumoniae and C. trachomatis. Nature Genetics 21:385-389
  10. ^ Beatty WL, Morrison RP, Byrne GI. Persistent chlamydiae: from cell culture to a paradigm for chlamydial pathogenesis. Microbiol Rev. 1994 Dec;58(4):686-99. PMID: 7854252
  11. ^ Kutlin A, Roblin PM, Hammerschlag MR. Effect of prolonged treatment with azithromycin, clarithromycin, or levofloxacin on Chlamydia pneumoniae in a continuous-infection Model. Antimicrob Agents Chemother. 2002 Feb;46(2):409-12. PMID: 11796350.
  12. ^ Bin XX, Wolf K, Schaffner T, Malinverni R. Effect of azithromycin plus rifampin versus amoxicillin alone on eradication and inflammation in the chronic course of Chlamydia pneumoniae pneumonitis in mice. Antimicrob Agents Chemother. 2000 Jun;44(6):1761-4. PMID: 10817751
  13. ^ Gieffers J, Füllgraf H, Jahn J, Klinger M, Dalhoff K, Katus HA, Solbach W, Maass M. Chlamydia pneumoniae infection in circulating human monocytes is refractory to antibiotic treatment. Circulation. 2001 Jan 23;103(3):351-6. PMID: 11157684
  14. ^ Hahn DL, Dodge RW, Golubjatnikov R. Association of Chlamydia pneumoniae (strain TWAR) infection with wheezing, asthmatic bronchitis, and adult-onset asthma. JAMA. 1991 Jul 10;266(2):225-30. PMID: 2056624
  15. ^ Ramirez JA. Isolation of Chlamydia pneumoniae from the coronary artery of a patient with coronary atherosclerosis. The Chlamydia pneumoniae/Atherosclerosis Study Group. Ann Intern Med. 1996 Dec 15;125(12):979-82. PMID: 8967709
  16. ^ Jackson LA, Campbell LA, Kuo CC, Rodriguez DI, Lee A, Grayston JT. Isolation of Chlamydia pneumoniae from a carotid endarterectomy specimen. J Infect Dis. 1997 Jul;176(1):292-5. PMID: 9207386
  17. ^ Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet. 1997 Aug 9;350(9075):430-6. Review. PMID: 9259669
  18. ^ M Stitzinger (2007). Lipids, inflammation and atherosclerosis (pdf). The digital repository of Leiden University. Retrieved on 2007-11-02.
  19. ^ H Friedman, Y Yamamoto, M. Bendinelli. Chlamydia pneumoniae Infection and Disease. Kluwer Academic. 2004.
  20. ^ Sriram S, Stratton CW, Yao S, et al (1999). "Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis". Ann. Neurol. 46 (1): 6–14. PMID 10401775. 
  21. ^ Parratt J, Tavondale R, O'Riordan J, Parratt D, Swingler R. Chlamydia pneumoniae-specific serum immune complexes in patients with multiple sclerosis. Mult Scler. 2008 Jan 21; [Epub ahead of print] PMID: 18208884
  22. ^ Itzhaki RF, Wozniak MA, Appelt DM, Balin BJ. Infiltration of the brain by pathogens causes Alzheimer's disease. Neurobiol Aging. 2004 May-Jun;25(5):619-27. Review. PMID: 15172740
  23. ^ Appelt DM, Roupas MR, Way DS, Bell MG, Albert EV, Hammond CJ, Balin BJ. Inhibition of apoptosis in neuronal cells infected with Chlamydophila (Chlamydia) pneumoniae. BMC Neurosci. 2008 Jan 24;9(1):13 [Epub ahead of print] PMID: 18218130
  24. ^ Gérard HC, Fomicheva E, Whittum-Hudson JA, Hudson AP. Apolipoprotein E4 enhances attachment of Chlamydophila (Chlamydia) pneumoniae elementary bodies to host cells. Microb Pathog. 2007 Oct 18; [Epub ahead of print]
  25. ^ MacIntyre A, Abramov R, Hammond CJ, Hudson AP, Arking EJ, Little CS, Appelt DM, Balin BJ. Chlamydia pneumoniae infection promotes the transmigration of monocytes through human brain endothelial cells. J Neurosci Res. 2003 Mar 1;71(5):740-50. PMID: 12584732
  26. ^ Boelen E, Steinbusch HW, Pronk I, Grauls G, Rennert P, Bailly V, Bruggeman CA, Stassen FR. Inflammatory responses following Chlamydia pneumoniae infection of glial cells. Eur J Neurosci. 2007 Feb;25(3):753-60. PMID: 17313571
  27. ^ Loeb MB et al. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease. J Am Geriatr Soc. 2004 Mar;52(3):381-7. PMID: 14962152
  28. ^ Ring RH, Lyons JM. Failure to detect Chlamydia pneumoniae in the late-onset Alzheimer's brain. J Clin Microbiol. 2000 Jul;38(7):2591-4. PMID: 10878049
  29. ^ Verkooyen RP, Willemse D, Hiep-van Casteren SC, Joulandan SA, Snijder RJ, van den Bosch JM, van Helden HP, Peeters MF, Verbrugh HA. Evaluation of PCR, culture, and serology for diagnosis of Chlamydia pneumoniae respiratory infections. J Clin Microbiol. 1998 Aug;36(8):2301-7. PMID: 9666010

[edit] External links

  • http://cpnhelp.org CPNhelp.org, A Clearinghouse for Information on Treatment of CPn Infections, especially those believed to be associated with chronic and disabling diseases such as MS and Chronic Fatigue Syndrome. Includes dozens of scientific papers, input from physicians who treat CPn infections, links to patents, and a forum to communicate with patients currently going through treatment of CPn infection through multi-antibiotic protocols.

Abstract by Nancy Humphrey http://www.asthmastory.com/a70.asp

Chlamydia Pneumoniae and chronic Diseases: http://books.google.com/books?id=kBtbytrAzYwC&pg=PA65&lpg=PA65&dq=%22respiratory+chlamydia%22&source=web&ots=NgK2ltCXvu&sig=xVTvuLkEXT7DfAeh1qUVNpFGvhc#PPP2,M1

Infections and the Cardiovascular System: New Perspectives: http://books.google.com/books?id=Dp6wRIuSP-sC&pg=PA159&lpg=PA159&dq=%22respiratory+chlamydia%22&source=web&ots=fex6Tw59dk&sig=Vi5YvNNaWXg1XL_IXpQfdSE84hY#PPA155,M1