The Pathogenesis of Lyme Neuroborreliosis - from Infection to Inflammation -

Source: Molecular Medicine, Dec 19, 2007
by Hans-Walter Pfister, MD, et al.
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01-15-2008 [Note: The full text of this article may be accessed free at PubMed Central  [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18097481]. It includes illustrative figures and links to more than 100 footnoted references.

This review describes the current knowledge of the pathogenesis of acute Lyme neuroborreliosis (LNB), from invasion to inflammation of the central nervous system.

We describe current knowledge about the infiltration of leukocytes into the CSF in LNB.

In the final section, the mechanisms by which the spirochetal infection leads to the observed neural dysfunction will be discussed.

In conclusion, this review will construct a stringent concept of the pathogenesis of LNB.

Source: Molecular Medicine. 2007 Dec 19. PMID: 18097481, by Rupprecht TA, Koedel U, Fingerle V, Pfister HW. Departments of Neurology and Microbiology, Ludwig-Maximilians University, Munich, Germany  

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Excerpts:

Introduction

Lyme borreliosis is the most common human tick-borne disease in the Northern hemisphere. Its prevalence is estimated to range between 20 and 100 cases per 100,000 people in the US and about 100 to 130 cases per 100,000 in Europe (1;2). It is caused by the spirochete Borrelia burgdorferi (B.b.) sensu lato. B.b. can be divided into four human pathogenic species: B.b. sensu stricto (the only human pathogenic species present in the US), B. afzelii, B. garinii and B. spielmanii (3). The infection by B.b. is a complex process beginning with the translation from the gut to the salivary glands of the tick during the feeding process on the host. After invasion into the skin, B.b. can cause a local infection called erythema migrans (EM). During the second stage of Lyme disease, B.b. can spread from the tick bite on the skin to various secondary organs throughout the body, including the heart, joints, and the peripheral and central nervous system (CNS) (4). Major clinical findings of the neurological manifestation of acute Lyme neuroborreliosis (LNB) include painful meningoradiculitis with inflammation of the nerve roots and lancinating, radicular pain (Bannwarth’s syndrome), lymphocytic meningitis, and various forms of cranial or peripheral neuritis (5).

While the clinical picture of painful meningoradiculitis was first described in 1922 (6), the etiology was unknown till the description of the causative spirochetes by Willy Burgdorfer et al. in 1982 (7), and the isolation of spirochetes from the CSF of a patient with Bannwarth’s syndrome in 1984 (8). During the last 25 years we have gained some insight into the pathogenesis of LNB, but there are still many aspects that have not yet been clarified. One reason for our incomplete understanding of the mechanisms that lead to LNB is the limited availability of an adequate animal model. The induction of a reliable, clinically manifest LNB in an animal model so far was only successful in a nun-human primate model involving the rhesus macaque, where for example, spirochetes could be demonstrated at the nerve roots (9). Further insight has been gained either from human material or cell culture experiments: while for example the inflammatory response of the human host to B.b. has been measured in CSF samples (10�?2), the mechanisms of adherence of B.b. to endothelial cells, cytotoxicity on neural cells, or the induction of cytokines was analysed using primary cells or cell lines in vitro (13�?7). Though our knowledge of the pathogenesis is still incomplete, this review attempts to construct a stringent concept of the pathogenesis of LNB, from the first encounter of the spirochetes with the hostile immune system inside the tick up to the neuronal dysfunction evoked by B.b. as seen in patients with LNB.

Hiding from the immune system
Even before entering the host, the spirochete has to evade the hostile immune system. During the first 24�?8 hours of tick feeding, the borrelia are attached to the tick gut, mediated by the interaction of the borrelial outer surface protein A (OspA) with the tick receptor for OspA (TROSPA) (18). While the hostile blood flows into the tick gut, the spirochetes multiply and prepare for dissemination to the salivary glands (19). At that time, the borrelia are already faced with the different components of the mammalian immune system. An impressive example of this is the mechanism of action of OspA vaccination: anti OspA antibodies from the host are able to kill the borreliae already in the tick gut, thereby preventing infection of the host (20). In parallel, the borrelia are confronted with the hostile complement system. The complement system is a biochemical cascade which is not only potentially cytotoxic, but also opsonises the pathogen and attracts leukocytes (21). The leukocytes constitute another threat for B.b.: different borrelial surface lipoproteins are recognized by leukocytes, mainly by CD14 and the toll-like receptor 2 (TLR2) of the innate immune system (17;22�?4), and it has been shown in vitro that the spirochetes are rapidly taken up by polymorphonuclear cells, monocytes, and macrophages (25�?7). Once having entered the host, there are further hazards for B.b., especially when seroconversion has taken place, as mouse and human antibodies against different outer surface proteins (for example OspA or OspC) are borreliacidal in vitro (28;29). However, though the mammalian immune system possesses several means to defend itself against the borrelial invasion, the elimination might be incomplete. Without the application of antibiotics, B.b. might persist in the mammalian host, chronic infections have been reported in the literature (5;30) . But why is it so hard for the immune system to attack the borrelia? To achieve this, the borrelia possess several mechanisms which enable them to escape (Figure 1) by: (I) downregulation of immunogenic surface proteins, (II) inactivation of its effector mechanisms, or (III) hiding in less accessible compartments like the extracellular matrix. This will be depicted in detail below.

Downregulation of immunogenic surface proteins. To escape from the immune reaction of the host, the borrelia hide highly immunogenic surface proteins using the mechanism of antigenic variation (31). OspA, for example, is a potent stimulator of neutrophils (32) and induces the release of proinflammatory cytokines like Il-1β, TNF-α or IL-6 in vitro (33). To avoid such an inflammatory response, OspA, while abundantly expressed in the tick gut as an important adhesion protein (34), is rapidly downregulated during the feeding process on the host (35;36). Though OspA positive Borrelia are able to enter the host, they are unable to establish an infection (37) and B.b. isolated from mice four days after infection are all OspA negative (38). It can be concluded from these results that only OspA negative Borrelia are able to survive in the host and therefore, this surface protein does not appear to be expressed during the early phase of the infection. OspC, in contrast, is rapidly upregulated before dissemination to the salivary glands during the blood meal of the tick, most probably mediated by the increasing temperature and the pH shift as the blood of the host enters the tick gut (39�?1). The expression of OspC constitutes an important initial survival factor during transmission from the tick to the host: In a recent study, it has been shown that B.b. can bind the complement inhibiting protein Salp15 of the tick saliva via OspC, which protects the spirochete against the hostile complement system (42). Therefore, the expression of OspC appears essential for the first 48 hours of infection to escape the innate immunity (43) and OspC negative Borrelia are unable to disseminate and invade the host. However, a persistent infection of the host is only possible by downregulating OspC again 8�?1 days after infection (44). A constitutive expression of OspC, as for example, by a mutation of the respective regulatory element, leads to an efficient clearance of the borrelia once the humoral immune response is set (44;45). Therefore, the borrelia also hide this surface protein later during the course of infection to remain unrecognized from the immune system of the host. This is supported by the finding that Anti-OspC antibodies are found in the rhesus monkey up to 20�?0 days after infection, while they disappear in later stages (46). In parallel, neither OspA, nor OspC expression can be found in persistent borrelial infection in the rhesus monkey, and the rate of systemic inflammation in these animals is low (47). All in all, it appears that the borrelia suppress or hide several surface markers in order to minimize their immunogenic characteristics, but a transient expression can be used to utilize protective mechanisms.

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Furthermore, Borrelia lead to a local upregulation of the matrix metalloproteinase-9, that digests the surrounding extracellular matrix (65). In addition, the borrelia can attach to several proteins of the extracellular matrix, such as, for example, fibronectin (66), several integrins (67), or proteoglycans like decorin (68). Decorin is a collagen-binding proteoglycan that is produced as a component of the connective tissue. It facilitates both the dissemination and the survival of Lyme disease-spirochetes in decorin-rich tissues (69). As a consequence, the borrelia can hide in these extracellular structures, rendering them less subject to the circulating leukocytes.

Conclusion
The pathogenesis of LNB is a complex process with several fascinating aspects, such as, for example, how the borrelia manage to escape the immune system and the ability of the spirochetes to invade the carefully protected CNS. Insights into the pathophysiology of this disease help us to understand the principal microbiological mechanisms involved and these insights might even be transferable to infections with other spirochetes like Treponema or Leptospira. Therefore, further research on the pathophysiology of infection with B. b. would increase not only the knowledge of Lyme borreliosis but also of other spirochetal diseases, with an increasing incidence and higher morbidity and mortality, like syphilis or Weil’s syndrome.
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