Update TRENDS in Microbiology Vol.12 No.2 February 2004 | Research Focus Variant Creutzfeldt – Jakob disease: between lymphoid organs and brain Markus Glatzel, Olivier Giger, Harald Seeger and Adriano Aguzzi Institute of Neuropathology, Schmelzbergstr. 12, CH – 8091 Zürich, Switzerland Prion diseases are often caused by peripheral uptake of the infectious agent. To reach their ultimate target, the central nervous system (CNS), prions enter their host, replicate in lymphoid organs and spread via peripheral nerves. Once the agent has reached the CNS disease progression is rapid, resulting in neurodegeneration and death. Many of these mechanisms have been uncovered using genetically modified mice. A recently published study has demonstrated the presence of pathological prion protein in sympathetic ganglia of patients suffering from variant Creutzfeldt–Jakob disease, suggesting that these mechanisms might apply to humans. A substantial subset of human prion diseases is caused by peripheral uptake of infectious prions [1]. Examples include certain instances of iatrogenic Creutzfeldt – Jakob disease (iCJD), attributed to exposure with material derived from deceased individuals who had suffered from an unrecognized human prion disease, such as recipients of prion-contaminated growth hormone or dura mater grafts. Variant Creutzfeldt – Jakob disease (vCJD) is a further example of a human prion disease that is believed to be initiated by peripheral uptake of prions. vCJD differs from iCJD because it is thought to be caused by transmission of bovine spongiform encephalopathy (BSE) prions to humans via the oral route [2]. The list of nonhuman prion diseases ascribed to peripheral prion uptake includes transmissible spongiform encephalopathies, such as scrapie, chronic wasting disease and BSE [3]. Neuroinvasion is not exclusive to prions. Many viruses are capable of invading the central nervous system (CNS), including rabies and several herpes viruses [4]. More recent additions to this list are emerging viral diseases, such as West Nile and Japanese encephalitis virus [5]. Although they do not appear to share any structural features with conventional viruses, prions possess several phenotypic attributes that are similar to those of the aforementioned agents when it comes to neuroinvasion. In all instances mentioned above, the infectious agent reaches the CNS from peripheral sites of entry. However, the methods used to accomplish this are diverse. Rhabdoviruses replicate in muscles and reach the CNS through motor end plates, whereas herpes viruses enter the body through mucosal surfaces and exploit retrograde axonal transport to reach ganglia cells [6]. By contrast, West Nile Corresponding authors: Markus Glatzel (markus.glatzel@usz.ch), Adriano Aguzzi (adriano@pathol.unizh.ch). www.sciencedirect.com virus travels in the blood stream and ultimately reaches the CNS by crossing the blood –brain barrier [5]. Prions, which are known to cause transmissible spongiform encephalopathies, are thought to be devoid of informational nucleic acids [7]. The idea that prions are entirely made up of proteins originates from the fact that the only molecule that consistently co-purifies with prion infectivity is a partially protease-resistant, abnormally folded protein. Subsequently it was shown that this protein, termed PrPSc, represents an isoform of the host-encoded prion protein, PrPC [8]. Furthermore, prion infectivity cannot be destroyed by methods that have been shown to inactivate infectious agents containing informational nucleic acids [9]. With this information in mind, one might predict that neuroinvasion of an infectious agent solely composed of a protein drastically differs from the mechanisms exploited by infectious agents containing nucleic acid. Surprisingly, this is not the case. Prion neuroinvasion has remarkable similarities to neuroinvasion by viral agents. A primary phase of prion accumulation and possibly also replication in organs of the lymphoreticular system (LRS) is followed by a secondary phase that is initiated once the agent has gained access to peripheral nerves [8]. Although this model might oversimplify the complex mechanisms of prion neuroinvasion, and studies have shown that both mechanisms can occur independently, the vast majority of experimental data can be explained on the basis of these two stages of neuroinvasion (Table 1). Prions accumulate in lymphoid organs A wealth of studies, some of which date back to 1960, point to the importance of prion replication in lymphoid organs [8]. Considerable progress has been made since then. Studies looking at the temporal and spatial distribution of prions within the LRS have demonstrated that prion infectivity can be detected as early as five days following peripheral prion challenge (Figure 1). Prions appear to reside on immobile, and to a lesser extent on mobile cells of the immune system [10]. Among the best candidates for the immobile cells that are responsible for prion accumulation are follicular dendritic cells (FDCs), which usually reside in germinal centers of secondary lymphoid follicles. In fact, depletion of FDCs blocks prion replication in lymphoid organs [11]. Furthermore, components of the complement system, particularly C3 and its receptor CD21/CD35, appear to play an important modulatory role in susceptibility to prion infection within lymphoid organs [12,13]. Update 52 TRENDS in Microbiology Vol.12 No.2 February 2004 Table 1. Distribution of PrPSc and prion infectivitiy in sporadic Creutzfeldt –Jakob disease (CJD), variant CJD and mouse or hamster scrapie Organ system Demonstration of PrPSc and prion infectivitya Compartment sCJD vCJD mouse or hamster scrapie PrPS Infectivity PrPSc Infectivity PrPSc Infectivity Gut-associated lymphoid tissue Tonsil Spleen Appendix Lymph node n.d. 2 þ n.d. 2 2 n.d. þ n.d. þ þ þ þ þ þ n.d. þ þ n.d. n.d. þ n.d. þ þ þ þ n.d. þ þ þ Sympathetic nervous system Parasympathetic nervous system þ 2 n.d. 2 n.d. n.d. n.d. þ n.d. n.d. n.d. n.d. þ þ n.d. þ n.d. n.d. Cortex Retina Optic nerve Olfactory bulb þ þ þ þ þ þ n.d. n.d. þ þ þ n.d. þ n.d. n.d. n.d. þ n.d. n.d. n.d. þ þ þ n.d. Lymphoreticular organs Peripheral nervous system Sensory-somatic nervous system Autonomous nervous system Central nervous system Eye a Abbreviations: þ , detected; 2, not detected; n.d., not done. Prions invade the CNS via peripheral nerves belonging to the autonomous nervous system Successful invasion of lymphoid organs does not automatically mean that prions will reach the CNS [14]. Moreover, prions can invade the CNS circumventing accumulation within the LRS [15]. This might indicate that a cell compartment distinct from the LRS is required, and might even be sufficient, for prion neuroinvasion. A prime candidate for this compartment is the peripheral nervous system (Figure 1). Studies suggesting an involvement of peripheral nerves date back to the early eighties [16]. From this time, essential insights have been obtained. We know that PrPC, produced in neurons, is transported via fast axonal transport and is organized in clusters on the outer cell membrane where it cycles between the cell surface and an endocytic compartment [17]. Peripheral nerves have to express PrPC to propagate the infectious Direct invasion via nerves Au to nom ous ner vou s sys tem Oral or i.p. infection with prions CNS Secondary invasion via nerves Replication of prions In lymphatic organs Secondary invasion via blood TRENDS in Microbiology Figure 1. Possible routes for prion neuroinvasion. Prions accumulate in lymphoreticular organs and invade the central nervous system (CNS) via peripheral nerves belonging to the autonomous nervous system. In some instances, direct neuroinvasion via the autonomous nervous system might occur. Neuroinvasion by the hematogenous route might play a role in some prion diseases. www.sciencedirect.com agent [14,18]. Furthermore, there are studies indicating that fast axonal transport does not appear to be involved in prion neuroinvasion [19]. The peripheral nervous system (PNS) is composed of several anatomically and functionally distinct subcompartments. Parts of the PNS, the autonomous nervous system, especially the sympathetic and parasympathetic portions, have been the focus of various studies on prion neuroinvasion [20,21]. Apart from enabling prion neuroinvasion, the autonomous nervous system is capable of transmitting and processing a variety of information and contains as many neurons as the entire spinal cord. Investigations of the temporal and spatial dynamics of neuroinvasion have shown that spread of orally administered prions occurs via nerves belonging to the autonomous nervous system [20]. Additional refinement of methods confirmed the physiological relevance of the autonomous nervous system in prion neuroinvasion [22]. In fact, both the vagal nerve and sympathetic nerve fibers contribute to this process. Surprisingly, sympathetic nerves, besides being involved in the transport of prions, might also accumulate and replicate prions in lymphatic organs [22]. Recently, these findings were validated by a study that investigated the involvement of the sympathetic nervous system in vCJD cases [23]. The authors found PrPSc in stellate and celiac ganglia of three individuals with confirmed vCJD, whereas stellate and celiac ganglia of patients succumbing to sporadic CJD were free of PrPSc. This supports the view that vCJD is caused by oral uptake of prions, presumably originating from BSE-contaminated material, and illustrates that neuroinvasion of prions in humans suffering from vCJD might occur via sympathetic nerves. However, the recent discovery of PrPSc in the spleen of sCJD patients [24] raises the question as to whether the pathogenesis of sCJD and vCJD might be more closely related than previously appreciated. Update TRENDS in Microbiology Open questions Although it is obvious that an intact LRS and intact PrPC-expressing autonomous nerves are essential components of prion neuroinvasion, many details of this process remain enigmatic. It is not known whether prions can be transferred directly from FDCs to sympathetic nerve-endings [8]. Although a recently published study demonstrates that the relative positioning of FDCs and sympathetic nerves controls the efficiency of prion neuroinvasion [25], it is still not clear if additional cell types are involved in this process. Moreover, it is unclear how prions are actually transported within peripheral nerves. Axonal and non-axonal transport mechanisms might be involved, and even non-neuronal cells (such as Schwann cells) might play a role. Some studies appear to indicate a non-axonal transport mechanism, resulting in periaxonal deposition of PrPSc. However, experiments that would provide us with an unambiguous answer to this problem, such as direct visualization of PrPSc transport in nerves, are non-existent [18,26]. 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Nature 425, 957 – 962 Hainfellner, J.A. and Budka, H. (1999) Disease associated prion protein may deposit in the peripheral nervous system in human transmissible spongiform encephalopathies. Acta Neuropathol. (Berl.) 98, 458 – 460 0966-842X/$ - see front matter q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.tim.2003.12.001 Horizontal gene transfer and microbial adaptation to xenobiotics: new types of mobile genetic elements and lessons from ecological studies Dirk Springael1 and Eva M. Top2 1 Laboratory of Soil and Water Management, Department of Land Management, Faculty of Agricultural and Applied Biological Sciences, Catholic University of Leuven, B-3001 Heverlee, Belgium 2 Department of Biological Sciences, 347 Life Sciences Building South, University of Idaho, Moscow ID 83844-3051, USA The characterization of bacteria that degrade organic xenobiotics has revealed that they can adapt to these compounds by expressing ‘novel’ catabolic pathways. Corresponding author: Dirk Springael (dirk.springael@agr.kuleuven.ac.be). www.sciencedirect.com At least some of them appear to have evolved by patchwork assembly of horizontally transmitted genes and subsequent mutations and gene rearrangements. Recent studies have revealed the existence of new types of xenobiotic catabolic mobile genetic elements,