The genus, Chlamydophilia, as obligate intracellular pathogens, induce chronic scarring in humans. Chlamydia pneumoniae, a common cause of pneumonia, infects endothelial cells and circulating macrophages. Evidence that C. pneumoniae is an opportunistic pathogen in chronic skin ulcers and other inflammatory skin conditions analogous to its role in atherosclerosis is reviewed.
Keywords
Abbreviations
CPChlamydia pneumoniae
Chronic skin ulcers have common characteristics that include intermittent or persistent inflammation, infection, and the failure to heal (
Lazarus et al., 1994
;Mostow, 1994
;Philips, 1994
;Margolis et al., 1996
,Margolis et al., 1999a
;Eaglstein and Falanga, 1997
). A nonhealing wound may be due to genetic, environmental, or idiopathic factors, or an imbalance of bacteria (Robson, 1997
). Bacterial colonization of stage 2–4 skin ulcers is assumed to be present irrespective of etiology, so infection is a potential source of inflammation in all ulcers such as pressure sores. How and if such inflammation sustains the most common types of chronic skin ulcers is controversial and needs further clarification. The possible role(s) of Chlamydia pneumoniae in initiating or sustaining chronic skin conditions, including skin ulcers, has not been extensively investigated.Abrams et al., 1999
claimed that 12 of 27 patients with cutaneous T cell lymphoma had a C. pneumoniae-associated protein that activated Sezary T cells.Vannucci et al., 2000
detected C. pneumoniae serologically in a diabetic patient with pyoderma gangrenosum-like lesions that responded dramatically to antibiotics directed against Chlamydia.Sams et al., 2001
identified by serologic, immunohistochemical, and culture methods C. pneumoniae in a patient with pyoderma gangrenosum that responded to prolonged antichlamydial antibiotic therapy with decreases in anti-C. pneumoniae antibody titers. Serologic evidence of C. pneumoniae was retrospectively detected by PCR and anti-C. pneumoniae IgG and IgM methods in 13 of 20 patients with a clinical diagnosis of pyoderma gangrenosum (King et al, unpublished observations).King et al., 2001
also cultured C. pneumoniae from foot ulcer specimens from four of nine diabetic patients. We therefore propose that C. pneumoniae is present in chronic skin conditions both as an “innocent bystander” and as an opportunistic pathogen capable of maintaining inflammation.Chlamydia pneumoniae – “innocent bystander”, indicator of prior infection, or persistent intracellular pathogen?
Numerous studies have detected the presence of C. pneumoniae in endovascular structures as well as peripheral blood mononuclear cells (
Maass et al., 1998
;Boman et al., 1998
;Blasi et al., 1999
). The presence of viable C. pneumoniae in peripheral blood mononuclear cells suggests that C. pneumoniae may accompany these white blood cells to inflamed tissue sites and cause a secondary infection in the inflamed tissue; however, these studies do not in and of themselves prove a direct pathogenic role for C. pneumoniae in atherosclerosis, stroke, or other vasculopathies. For example, the prevalence rate of C. pneumoniae in cardiovascular atheroma differing human populations varies from very low (0%;Weiss et al., 1996
;Lindholt et al., 1998
) to very high (>90%;Jackson et al., 1997
) in selected populations. Recent approaches focus on finding reliable prognostic tests such as immunoreactive proteins and lipopolysaccharide (LPS) or PCR detectable DNA and RNA from C. pneumoniae that would be indicative of active infection that is pathogenetically highly relevant (Blasi et al., 1999
;Shor and Phillips, 1999
;Russell, 1999
). The data variability is due to the multiple difficulties in culturing C. pneumoniae (Maass and Dalhoff, 1995; Maass and Harig, 1995
) and technical problems with immunohistochemical methods (Taylor-Robinson and Thomas, 1998
). Maximizing the detection of reaction product by antigen retrieval strategies using immunochemical methods may be necessary in some anti- C. pneumoniae antibody staining procedures in formalin-fixed tissues as fixation can denature antigenic epitopes of C. pneumoniae.Microbiologic features of chlamydia
The genus, Chlamydophilia, Chlamydiaceae is rapidly expanding and now includes nine species, five of which were recently been added in 1999 (see below). The various Chlamydia species are readily distinguished by analysis of signature sequences in the 16S and 23S ribosomal genes (
Everett et al., 1999
;- Everett K.D.
- Bush R.M.
- Andersen A.A.
Emended description of the order Chlamydiales, proposal of Parachlamydiaceae fam.nov. & Simkaniaceae fam.nov., each containing one monotypic genus, revised taxonomy of the family Chlamydiaceae, including a new genus and five new species, and standards for the identification of organisms.
Int J System Bacteriol. 1999; 49: 415-440
Kalman et al., 1999
). Two species of Chlamydia are pathogenic in humans (C. pneumoniae, C. trachomatis) and seven are primarily pathogenic in other vertebrates (four species of C. psittacci, C. pecorum, C. muradarum sp. nov, and C. suis sp. nov) (Everett et al., 1999
). Chlamydia trachomatis induces conjunctivitis, keratitis and is the most common preventable cause of blindness worldwide (- Everett K.D.
- Bush R.M.
- Andersen A.A.
Emended description of the order Chlamydiales, proposal of Parachlamydiaceae fam.nov. & Simkaniaceae fam.nov., each containing one monotypic genus, revised taxonomy of the family Chlamydiaceae, including a new genus and five new species, and standards for the identification of organisms.
Int J System Bacteriol. 1999; 49: 415-440
Ward, 1995
). These organisms also cause pelvic inflammatory disease, endometrosis, vaginitis, urethritis, and infertility. Chlamydia pneumoniae is a common pathogen in acute human upper and lower respiratory infections worldwide (Ward, 1995
).As a genus the Chlamydia are obligate intracellular microorganisms that cause chronic and relapsing diseases in humans and other animals. Chlamydia have a unique biphasic life cycle with functionally and morphologically distinct dimorphic forms. The extracellular form, the elementary body, is infectious but metabolically inactive. After endocytosis, elementary bodies differentiate into the metabolic active reticulate body that replicates by binary fission. Chlamydiae have been thought to be intracellular ATP scavengers as they contain nucleotide transport proteins and lack many enzymes of the electron transport chain necessary for de novo ATP biosynthesis (
Stratton and Mitchell, 1997
); however, recent data indicate that enough glucose-catabolizing enzymes are present in Chlamydia that have the functional capacity to produce some of their own ATP and reducing power (Tjaden et al., 1999
;Iliffe-Lee and McClarty, 1999
). The pathogenic significance of this recent finding is unclear as Chlamydiae are known to stimulate glucose transport into the host cell to compensate for the extra energy load on the infected cell (Ojcius et al., 1998
). Moreover, cells infected with C. pneumoniae have depleted energy and thus may be dysfunctional (Shemer-Arni and Lieberman, 1995
).Pathobiology of chlamydial infections
Chlamydia pneumoniae is a common cause of pneumonia in humans (
Grayston et al., 1986
) and is associated with inflammatory arthritis and atherosclerosis (see below). The antibody response to C. pneumoniae increases with age as measured in otherwise unselected human populations (Grayston, 1992
). Since its discovery just over a decade ago, C. pneumoniae has been associated with a number of chronic diseases including some presumed to be autoimmune, such as multiple sclerosis (Sriram and Stratton Mitchell, 1998
,Sriram et al., 1999
;Stratton et al., 2000
) and Reiter's disease (Stratton, 1998
;Gerard et al., 1999
). Chlamydial infections including those caused by C. pneumoniae are remarkable because of their persistence in tissues. This feature has been best studied in humans with trachoma that has periodic exacerbations and remissions with progressive conjunctival inflammation and corneal scarring (Beatty et al., 1994
). Chlamydia trachomatis is detected in the quiescent phase of trachoma even in the absence of histologic and immunologic features of inflammation. The mechanism(s) of chlamydial-induced tissue injury is unclear but likely is relatively unique compared with gram(+) and gram(–) bacteria. Its lipopolysaccharide, lipid A, has unique structural features that induce only minimal endotoxin effects (Kosma, 1999
;Rund et al., 1999
). Chlamydia induce inflammation and clotting abnormalities, but no known chlamydial toxins have been positively identified likely to be responsible for their tissue injury-inducing effects.Read et al., 2000
reported a potential type III secreted toxin with homology to the Shiga toxin produced by E. coli 0157:H7. Chlamydia have type III secretion mechanisms that enable it to secrete and inject pathogenicity proteins into the cytosol of eukaryotic host cells, although the identity of the proteins secreted into the cytosol are unknown (Hackstadt et al., 1997
;Braavoil and Hsia, 1998
;Hueck, 1998
). Whether the in vivo activation of the immune system by Chlamydia in vivo is due to heat shock proteins (Kol et al., 1998
;LaVerda et al., 1999
), type III secreted proteins (see above,Braavoil and Hsia, 1998
), or other T cell activation mechanisms (Igieseme, 1996
) is unknown.Chlamydia pneumoniae and inflammation
Signal transduction pathways are activated in endothelial cells following infection with C. pneumoniae (
Krull et al., 1999
). Infection of human endothelial cells with C. pneumoniae stimulates transendothelial migration of neutrophils and monocytes (Moazed et al., 1998
;Molestina et al., 1999
). Chlamydia pneumoniae infection of vascular smooth muscle and endothelial cells activates NF-ĸB and induces tissue factor and plasminogen activator inhibitor 1 (PAI-1) expression (Dechend et al., 1999
). Other pathogenic mechanisms that may be involved include chlamydial heat shock proteins (Kol et al., 1998
;LaVerda et al., 1999
) and Toll receptors that are involved in the innate immune responses (Muzio and Polentanrutti, Bosisio, 2000
). Endothelial cytotoxicity immune reactions mediated by serum antibodies to heat shock proteins of Escherichia coli and C. pneumoniae and other outer membrane proteins, were proposed as a possible link between infection and atherosclerosis (Christiansen et al., 1999
;Mayr et al., 1999
). Chlamydial heat shock protein 60, and potentially outer membrane proteins (- Mayr M.
- Metzler B.
- Kiechl S.
- Willeit J.
- Schett G.
- Xu Q.
- Wick G.
Endothelial cytotoxicity mediated by serum antibodies to heat shock proteins of Escherichia coli and Chlamydia pneumoniae: immune reactions to heat shock proteins as a possible link between infection and atherosclerosis.
Circ. 1999; 99: 1560-1566
Christiansen et al., 1999
), are involved in the localization to and in human atheromas and regulates macrophage tumor necrosis factor-α and matrix metalloproteinase expression (Kol et al., 1998
;Christiansen et al., 1999
). A specific C. pneumoniae lipopolysaccharide, lipid A, induces macrophage foam cell formation (Kalayoglu and Byrne, 1998
). A plausible explanation for the chronic and relapsing nature of C. pneumoniae infection despite antibiotic therapy was lacking until recently. Chlamydia pneumoniae antigens remain accessible to immunocytes for at least 4 wk and are capable of sustaining inflammation when no viable C. pneumoniae are present (Wyrick et al., 1999
).Chlamydia pneumoniae, vascular inflammation, and atherosclerosis
Atherosclerosis is now classified as an inflammatory disease (
Ross, 1999
) so potentially it could be induced or modulated by an infectious agent. The association of C. pneumoniae with vascular disease was first demonstrated serologically in a Finnish population (Saikku et al., 1988
). Chlamydia pneumoniae was first identified as a respiratory pathogen byGrayston et al., 1986
, It was confirmed as a common cause of respiratory disease that was commonly detected in asymptomatic healthy adults (Hyman et al., 1995
). This organism was first directly associated with atherosclerotic lesions in South African patients (for a review seeShor and Phillips, 1999
). Recent evidence indicates that C. pneumoniae and potentially other microbes are associated with atherosclerosis in cardiovascular and cerebrovascular diseases (for reviews seeDanesh et al., 1997
;Cheng and Rivera, 1998
;Epstein et al., 1999
;Chiu, 1999
;Grayston and Campbell, 1999
;Leinonen and Saikku, 1999
;Bartels et al., 2000
). Convincing data that other infectious agents such as Mycoplasma pneumoniae and Helicobacter pylori may be involved are not available (Blasi et al., 1996
). In contrast, culture, serologic, immunocytochemical, polymerase chain reaction (PCR), in situ hybridization, and transmission electron microscopy data combined with epidemiologic data show that C. pneumoniae is detected in a statistically significant number of samples from human arterial tissues including peripheral vessels (Shor and Phillips, 1999
). Chlamydia pneumoniae infection is detectable in patients with cerebrovascular accidents (stroke) (Cook et al., 1998
) as well as Alzheimer's disease (Balin et al., 1998
) and diabetic nephropathy (Kanuchi et al., 2000
). Therefore, C. pneumoniae is likely to be widely prevalent in the vasculature.Pathogenetic significance of atherosclerosis and c. pneumoniae in diabetics
It has been claimed that the endovascular presence of C. pneumoniae DNA is a generalized phenomenon in atherosclerotic vascular disease (
Maass et al., 1998
). These data are intriguing as atherosclerosis is the underlying cause of chronic limb ischemia and often is the cause of chronic ulcers in many patients. The progression of atherosclerosis is accelerated by the coexistence of hypertension, lipoprotein abnormalities, tobacco addiction, and diabetes mellitus (Kempczinski and Bernhard, 1995
). Although atherosclerosis is not qualitatively different in diabetics, it appears at an earlier age and progresses more rapidly. Peripheral vascular disease (PVD) in diabetics most commonly affects the tibial, popliteal, and profunda femoris arteries rather than the aorta and iliac arteries (Kempczinski and Bernhard, 1995
). Atherosclerosis is generally assumed to be the cause of chronic ischemia of the lower extremities, including diabetic foot ulcers (Chait and Bierman, 1994
). There are very few collateral vessels in the lower leg so even nonsegmental occlusion of the distal and proximal tibial arteries may result in gangrene or severe ischemia requiring arterial reconstruction (Kempczinski and Bernhard, 1995
).Is c. pneumoniae likely to be the only pathogen involved in atherosclerosis?
Multiple infections of atherosclerotic plaques may be present (
Epstein et al., 1999
;Chiu, 1999
;Zhu et al., 2000
). Serum levels of high-sensitivity C reactive protein (hs-CRP), an acute phase reactant, correlated well with the total pathogen burden or number of chronic endogenous pathogens and coronary artery risk (Zhu et al., 2000
). In a much larger study, the levels of hs-CRP were as accurate a predictor of coronary artery disease in a long-term study of the coronary risk factors as cholesterol and lipid profile in a population of nurses (Ricker et al., 2000
).Detecting c. pneumoniae in chronic leg and diabetic foot ulcers
The previous inability to detect these organisms may be due to the difficulty of recovering viable C. pneumoniae organisms that require special methods for their isolation and propagation (). Studies on C. pneumoniae were aided by the discovery of a human lung cancer cell line, HL, that allowed isolation and propagation of the TWAR strain of C. pneumoniae (
Kuo and Grayston, 1990
). Chlamydia pneumoniae persistently infects and replicates in epithelium, endothelium, smooth muscle cells, macrophages (Sriram et al., 2000
), and neural tissue in vivo and in vitro (Balin et al., 1998
;Sriram and Stratton Mitchell, 1998
,Sriram et al., 1999
;Stratton et al., 2000
). The ability to isolate and propagate these organisms in HL cells (Kuo and Grayston, 1990
;Pruckler et al., 1999
;Sriram et al., 2000
) requires additional centrifugation steps and a 7 d culture time, resulting in a 500–5000-fold increase in the number of detectable inclusion-forming units. As punch or excisional biopsies are relatively contraindicated in patients with evolving or resolving diabetic foot ulcers, routine curettage samples of diabetic foot ulcers are especially helpful as a standard source for culture.Source of c. pneumoniae in chronic skin ulcers
If C. pneumoniae is to be considered as a source of infection for chronic skin ulcers, then the origin of the C. pneumoniae infection is germane. Chlamydia pneumoniae is common in the environment (“innocent bystander”), difficult to eradicate, and may be spread by contact with seemingly healthy humans (
Hyman et al., 1995
). Alternatively and, we believe, most likely, C. pneumoniae in chronic skin ulcers may be initiated by parasitized mononuclear cells (Airenne et al., 1999
). In a mouse model, C. pneumoniae infectivity was demonstrated to be mediated by parasitized monocytes (Moazed et al., 1998
). A possibility that has not been previously considered is that extracellular elementary bodies may be noncovalently bound or attached to circulating RBC via interaction with membrane molecules such as heparin.Is a specific skin type cell the source of c. pneumoniae in chronic skin ulcers?
Chlamydia pneumoniae was detected in human keratinocytes, endothelial cells, and histiocytes that contained intracellular inclusions stained with anti-MOMP (outer membrane protein) and anti-LPS (
Abrams et al., 1999
). These authors confirmed the presence of C. pneumoniae DNA and RNA in skin by PCR and RT-PCR and productively infected keratinocytes in vitro with C. pneumoniae (Abrams et al., 1999
). Recently, we detected C. pneumoniae serologically and by PCR in chronic cutaneous ulcers in a diabetic who responded dramatically to appropriate antibiotic therapy (Vannucci et al., 2000
). We cultured C. pneumoniae from chronic skin wounds in diabetic and nondiabetic patients such as those with pyoderma gangrenosum (King et al., 2001
;Sams et al., 2001
).Does c. pneumoniae infection predipose patients to develop chronic skin ulcers?
This is the fundamental question that underlies the debate over whether C. pneumoniae is an “innocent bystander” or an opportunistic pathogen (see reviews cited above). As demonstrated by the conflicting data and opinions over the role of C. pneumoniae in atherosclerosis and coronary artery disease, it is important to first document that an active infection by C. pneumoniae is unequivocally present at the site of tissue damage. Similarly, the ability to document the evolving pathologic responses or nonresponses to C. pneumoniae is critical to interpretation of epidemiologic data. Studies on the vasculopathy of coronary arteries, the aorta, and the abdominal aorta are severely limited by their accessibility for definitive biopsies and long-term follow-up. Epstein Barr virus, Cytomegalovirus, Herpes simplex type I and II, and potentially other members of the herpes virus family as well as Hepatitis A virus were proposed as opportunistic agents or copathogens for chronic vasculopathies (
Zhu et al., 2000
). Antibody titers, PCR titers, and culture results do not always directly correlate especially with patients receiving high doses of immunosuppresants (Sams and King, unpublished data). No published data are currently available to document the presence of chronic C. pneumoniae skin infections in diabetics or other causes of chronic leg ulcers so more study is required to evaluate this possibility.Chlamydia pneumoniae, skin infections, or ulcerations and diabetes
No direct data are available to confirm that there is an increase in C. pneumoniae skin infections in the chronic leg ulcer population; however, there are known associations between DM and atherosclerosis as well as between C. pneumoniae and atherosclerosis (
Muhlestein, 1998
;Shor and Phillips, 1999
). Indirect evidence suggests that increased blood glucose due to DM may help sustain persistent C. pneumoniae infections to compensate for the extra energy load on infected cells (Ojcius et al., 1998
). Chlamydial infections increase glucose consumption, lactate production, glutamate synthesis, glycogen accumulation, and an associated increase expression of the glucose transporter, GLUT-1, in vitro (Ojcius et al., 1998
). Conversely, diabetics are assumed to be very susceptible to infections so that it is not unreasonable to assume that C. pneumoniae are among the unusual and/or opportunistic pathogens that might be detected in some diabetics with chronic ulcers. There may be an association, moreover, between chronic C. pneumoniae infections and diabetic nephropathy based upon anti-C. pneumoniae serum IgG antibody titers in an ELISA (Kanuchi et al., 2000
).Chlamydia pneumoniae, serum lipids, dm, and atherosclerosis
Abnormal cholesterol and lipoproteins are major risk factors associated with atherosclerosis in diabetic as well as and nondiabetic patients. Atherosclerotic plaques contain foam cells and evidence of altered lipid composition (
Ross, 1999
). Animal models (Moazed et al., 1997
;Saikku et al., 1998
;Muhlestein et al., 1998
;Fong et al., 1999
) show that C. pneumoniae can induce atheromas and mimic inflammatory processes present in human atherosclerosis. Elevated C. pneumoniae antibody titers were associated with altered serum lipid profile in humans (Laurila et al., 1998
). In vitro cellular oxidation of low-density lipoproteins (LDL) is induced by C. pneumoniae (Kalayoglu et al., 1999
). The atherogenic effects of Chlamydia are claimed to be dependent on serum cholesterol and specific to C. pneumoniae (Hu et al., 1999
).Therapy
Published data to confirm the efficacy of chronic antibiotic therapy in the treatment of coronary artery disease to eliminate chronic infection are inconclusive. Chlamydia pneumoniae use monocytes as a transport for systemic dissemination and enter a persistent state not covered by an otherwise effective antichlamydial treatment, so prevention of vascular infection by such treatment may be problematic (
Gieffers et al., 2001
). Which antibiotic(s) to use in treating atherosclerosis is a moot point as multiple infectious agents may be involved and induce an unacceptably high pathogen burden (Chiu, 1999
;Zhu et al., 2000
). Chlamydia pneumoniae infected cells also may be more resistant to apoptosis than cells infected with other pathogens (Geng et al., 2000
). Although chronic antibiotic therapy did alter the clinical course of multiple skin ulcers with serologically documented C. pneumoniae infection with (Vannucci et al., 2000
) and without diabetes (Sriram et al., 2000
), it is not clear how many other patients would respond. Standard treatment of chronic venous ulcers or diabetic foot ulcers may not heal them within 12 wk (Margolis et al., 1999b
so long-term, cost-effective therapy may be required. The efficacy and cost-effectiveness of specific regimens for chronic skin ulcers will likely be a productive research area.References
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Article info
Publication history
Accepted:
June 8,
2001
Received in revised form:
May 18,
2001
Received:
February 14,
2001
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Copyright
© 2001 The Society for Investigative Dermatology, Inc. Published by Elsevier Inc.
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