Entry Of C pneumoniae Into The Nervous System

Infection of the oral and nasal mucosae of the respiratory tract by C. pneu-

moniae is considered to be the normal route of entry for this obligate, intra-

cellular pathogen into the body.(30) However, the exact mechanisms by which the organism enters the systemic circulation are not well defined. Two routes by which C. pneumoniae may enter the CNS are through the intravascular and olfactory pathways (Fig. 1). Evidence for these routes has been obtained in our studies of the association of this organism with AD.(20,31) C. pneumoniae-

infected glial cells, perivascular macrophages, and monocytes have been identi fied around blood vessels in the AD brain.(20,32) As the monocyte may be the prin cipal peripheral blood cell in which C. pneumoniae is harbored(33) and through which the organism gains initial entry to the circulation,(34) the monocyte is likely to be the vehicle for trafficking C. pneumoniae across the blood-brain barrier (BBB).(32)

There is precedence for chronic persistent infection of monocytes with

C. pneumoniae/33 and this could facilitate systemic and CNS infection with this organism. Recent evidence implicates monocytes and human brain microvas cular endothelial cells (HBMECs) in the entry of C. pneumoniae through an in vitro model of the blood-brain barrier.(32) C. pneumoniae infection of HBMECs

FIGURE 1. Hypothetical routes ofinfection with C. pneumoniae. (1) Olfaction, entry of bacteria into nasal and/or oral mucosae. From this site, C. pneumoniae trafficks to the (2) brain and/or to the (3) lungs. Following lung infection, C. pneumoniae gains access to the systemic circulation. From the circulation, distant sites such as the (4) heart and brain are susceptible to establishment of infection.

FIGURE 1. Hypothetical routes ofinfection with C. pneumoniae. (1) Olfaction, entry of bacteria into nasal and/or oral mucosae. From this site, C. pneumoniae trafficks to the (2) brain and/or to the (3) lungs. Following lung infection, C. pneumoniae gains access to the systemic circulation. From the circulation, distant sites such as the (4) heart and brain are susceptible to establishment of infection.

increased the expression of the surface adhesion molecules, intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule-1 (VCAM-1). In a similar manner, C. pneumoniae infection of THP-1 monocytes resulted in increased surface expression of the pintegrinsLFA-1 andMAC-l,theligandsfor ICAM-1, and the a4f51 integrin VLA-4, the ligand for VCAM-1. With increased expression of the surface adhesins on the endothelial cells and the integrins on the monocytes, there was a 3-fold increase in transmigration of the mono-cytes through the in vitro barrier relative to the transmigration of uninfected monocytes through an uninfected endothelial barrier. Thus, brain microvascular endothelia and peripheral monocytes could play a major role in promoting the entry of C. pneumoniae into the CNS.

In conjunction with these studies, junctional protein expression was examined to determine how the zonula adherens and zonula occludens junctions were affected following endothelial and monocyte infection with C. pneumoniae.(35) Analysis of surface-to-junction cross-talk examined the role of cadherins, catenin, and occludin in maintaining the endothelial junctional integrity following infection. VE-cadherin, which is specific to the intercellular junctions of endothelial cells, communicates with the actin cytoskeleton through (5-catenin. Perturbations of the cytoskeleton can directly affect the endothelial junctional complex assembly. Likewise, N-cadherin, important to the junctional assembly of the zonula adherens, is present on the entire brain endothelial cell surface. This study demonstrated that infection of HBMECs with C. pneumoniae led to upregulation ofVE-cadheren, N-cadheren, and p-catenin. In contrast, infection of the HBMECs with C. pneumoniae resulted in the downregulation of the tight junctional protein, occludin, at 36-48 h postinfection, with recovery of occludin expression at 72 h postinfection. These data suggest that a compensatory response occurred at the level of the adherens junction to maintain barrier integrity during the downregulation of tight junctional proteins at the time when barrier permeability increased. Occludin expression returned to control levels at 72 h postinfection, which suggests that the permeability changes were transient. These transient changes increase the likelihood that transmigration of monocytes through the HBMEC barrier would occur.(35) The alteration in the blood-brain barrier transport mechanism could therefore lead to increased immune cell infiltration and pathogen entry into the brain. Thus, these in vitro studies suggest that infection with C. pneumoniae of monocytes and brain endothelial cells could trigger the entry of infection into the brain, thereby setting the stage for neuroinflammation and eventual neurodegeneration characteristic of AD.

Another route of entry for C. pneumoniae into the CNS is through the olfactory pathway. Since C. pneumoniae readily infects epithelial cells and has direct access to the olfactory neuroepithelium of the nasal olfactory system, this route of infection would be likely, given that C. pneumoniae is a respiratory pathogen. Examination of the olfactory bulbs obtained at autopsy from two AD cases revealed by PCR and RT-PCR that C. pneumoniae genetic material was present in these structures.(31) Some of the earliest pathology observed in AD occurs in the olfactory and entorhinal cortices, in particular layers II and III of the entorhinal cortex of the parahippocampal gyrus from which neural projections of the perforant pathway arise to innervate the hippocampal formation.(36) Our earlier studies found evidence of the organism in the entorhinal cortex, hippocampus, and temporal cortex.(20) These findings bring into question how infection, inflammation, and/or damage of the olfactory bulbs could lead to damage in deeper cortical and limbic structures in the AD brain. Whether infection of the olfactory system with C. pneumoniae can ultimately establish inroads for more extensive infection in the brain remains to be determined.


Immunopathogenesis from inflammation is a hallmark of Chlamydia-induced disease. Chlamydial infections in vivo typically result in chronic inflammation characterized cellularly by the presence of activated monocytes and macrophages.(37) For example, in reactive arthritis associated with chlamydial infection, systemic chronic disease is manifested with activation of TH1/TH2 CD4+ cells and macrophages at sites of inflammation/38' In addition, at sites of chlamydialinfections,proinflammatory cytokines (IL-lp,IL-6,TNFa) and TH1-associated cytokines (IFNy and IL-12) have been identified.(37) Promotion of any or all of these responses could be evoked by chronic or persistent infection with C. pneumoniae as well as by chlamydial products such as lipopolysaccharide (LPS), heat shock proteins, and outer membrane proteins. The expression of LPS alone by this organism could account for numerous aspects of AD pathology. Previous work by others demonstrated that E. coli LPS injected at low dose directly into the brains of rats resulted in inflammation characterized by increased cytokine production and microglial activation.(39) In addition, pathology comparable to that observed in AD was observed in the rat temporal lobe, as demonstrated by the induction of the amyloid precursor protein. Thus, these studies suggest that products of infection that are either produced by the infectant, or by the host in response to infection, may stimulate the inflammatory process in the brain, resulting in neurodegeneration characteristic of AD.

In the AD brain, inflammation is thought to arise as a result of deposition, and has been advanced as a major mechanism in the overall patho-genesis of AD.(40) Clinical trials investigating the effects of nonsteroidal antiin-flammatory drugs in older populations also implicate inflammation as a factor in AD, as some of these trials have shown that use of these drugs can delay the onset of sporadic AD.(41) The resident cells in the brain responsible for inflammation are typically the microglia and to a lesser extent, the astroglia. Microglia and astroglia have been shown to be activated in the AD brain, and often are identified in and around amyloid plaques.(42) Microglia are the tissue macrophages in the brain and respond to insult with the production of proin-flammatory cytokines, and the generation of reactive oxygen species, among numerous other products. Identification of C. pneumoniae in the CNS has led us to speculate on the role of this infection in the pathology observed in the AD brain.

A distinct superimposition of the inflammation induced by C. pneumoniae infections and that documented in AD is apparent. Data on the association of C. pneumoniae with AD demonstrated that microglia, astroglia, and perivas-cular macrophages were the cells principally infected in the AD brain with C. pneumoniae,(20) and these infected cells were observed often in areas of amyloid deposition. The influx of activated monocytes infected with C. pneumoniae through the blood-brain barrier could have dire consequences in the brain. In diseases associated with other infectants such as human immunodeficiency virus-1 (HIV-1), perivascular monocytic infiltration with subsequent symptoms of dementia has been documented.(43) Activation of microglia and astroglia(44) in response to the presence of infected, activated monocytes could promote increased production of a variety of cytokines and chemokines such as interleukins IL-lp, IL-6,TNFa , and IFNy among others.(45-47) As perivascular macrophages, pericytes, microglia, and astroglia were shown to be infected with C. pneumoniae,(20) this infection could account for a significant proportion of the neuroinflammation and underlying pathology in the AD brain. In other neurological disorders in which neuroinflammation is a primary factor in pathogenesis,(48) C. pneumoniae has been implicated. Thus, infection with C. pneumoniae is likely to play a role in neuroinflammation.

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