s han nt Ec sanc¸ ity, G lege nive Keywords: Echinococcus multilocularis; Immune tolerance; Immunogenetics; HLA; Interferon alpha; Interleukin 10 alveolar echinococcosis (AE) is a good example of this survival strategy. Experimental studies in the past 30 years have helminth zoonotic diseases in humans. tion displayed by 55 disclosed some aspects of the survival strategy of E. multi- locularis in its hosts and the role of the host’s immune system. 1. Introduction ‘‘Invasion’’ (of the host) and ‘‘evasion’’ (of the host’s immune system) are the 2 key-events for the success of parasite infections. In fact, the survival of a parasite relies upon a mutual tolerance between the parasite and the host, and most parasites modulate and some even ‘‘use’’ the host’s immune system to ensure their survival. The pathological events occurring in intermediate hosts following ingestion of eggs of Echinococcus multilocularis and the resultant development of More than in other diseases, studies in mice may give appropriate insights into the mechanisms operating in the E. multilocularis/host relationship since rodents are actually the intermediate host in the life cycle of this parasite. However, any extrapolation from studies in mice to the situation occurring in humans is always questionable. Human clinical research is complementary to animal studies for obtaining a better understanding of host/parasite interactions and necessary for designing new approaches to the treatment of alveolar echinococcosis, one of the most severe and less curable Abstract As exemplified by ‘‘aborted’’ calcified liver lesions commonly found in patients from endemic areas, Echinococcus multilocularis metacestodes develop only in a minority of individuals exposed to infection with the papasite. Clinical research has disclosed some aspects of the survival strategy of E. multilocularis in human hosts. Clinical observations in liver transplantation and AIDS suggest that suppression of cellular/ Th1-related immunity increases disease severity. Most of the studies have stressed a role for CD8+ T cells and for Interleukin-10 in the development of tolerance. A spontaneous secretion of IL-10 by the PBMC seems to be the immunological hallmark of patients with progressive forms of alveolar echinococcosis (AE). IL-10-induced inhibition of effector macrophages, but also of antigen-presenting dendritic cells, may be operating and allowing parasite growth and survival. The genetic correlates of susceptibility to infection with E. multilocularis are clearer in humans than in the mouse model. A significant link between MHC polymorphism and clinical presentation of AE has been shown, and the spontaneous secretion of IL-10 in patients with a progressive AE is higher in patients with the HLA DR3+, DQ2+ haplotype. Clustering of cases in certain families, in communities otherwise exposed to similar risk factors, also points to immuno-genetic predisposition factors that may allow the larva to escape host immunity more easily. The first stage of larval development may be crucial in producing ‘‘danger signals’’ stimulating the initial production of cytokines. Therapeutic use of Interferon alpha is an attempt to foil the survival strategy of E. multilocularis. D 2005 Elsevier Ireland Ltd. All rights reserved. Available online 19 December 2005 Survival strategy of Echinococcu Dominique Ange`le Vuitton a,*, Shao Ling Z Isabelle Beurton a, Georges Ma a WHO Collaborating Centre for Prevention and Treatment of Human F-25030 Be b Sun Yat Sen Univers c Ningxia Medical Col d Queensland U Parasitology International 1383-5769/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.parint.2005.11.007 * Corresponding author. Tel.: +33 3 81 66 55 70; fax: +33 3 81 66 55 70. E-mail address:
[email protected] (D.A. Vuitton). multilocularis in the human host g a,b, Yurong Yang c,d, Ve´ronique Godot a, ion a, Solange Bresson-Hadni a hinococcosis, Universite´ de Franche-Comte´ and University Hospital, on, France uangzhou, PR China , Yinshuan, PR China rsity, Australia (2006) S51 – S55 www.elsevier.com/locate/parint 2. Susceptibility to E. multilocularis infec the human host The various susceptibilities of intermediate hosts to infec- tion with E. multilocularis provide information on the specific y In parasite/host interplay necessary to allow E. multilocularis sufficient survival time to develop protoscoleces for infection of definitive hosts. Most rodents (including experimental mice) and other small mammals such as Ochotona sp., are highly susceptible to infection with E. multilocularis but most domestic animals are more resistant to infection [1]. In humans, a range of severity in clinical presentations may be seen, from mild to severe; however, pathological features and the frequent absence of protoscoleces in AE lesions suggest that humans are generally ‘‘bad hosts’’ for E. multilocularis. In fact, the implementation of mass screenings in endemic areas has revealed that the number of established AE infections in humans was far fewer than the number of humans exposed to eggs of the parasite [2,3]. Positive serological results in individuals living in endemic areas (i.e., subjects with specific antibodies against E. multilocularis) have been shown to account for at least 4 different situations: 1) ‘‘patent’’, with overt disease symptoms, 2) ‘‘latent’’, non-apparent disease, 3) calcified dead lesions in the liver, and 4) no apparent lesions [3,4]. It is estimated that only 1 out of 10 subjects exposed to oncospheres of E. multilocularis will allow the metacestode to develop and will thus get AE lesions [5]. The conceptual consequences of these findings cover two complementary, albeit non-mutually exclusive, assessments: 1) natural (immu- nological) mechanisms of defence are at work in the majority of human hosts, which are able to stop the larval growth at the very first stages or during early development in the liver; 2) strategies have been evolved by the parasite to counteract the immune system of the host and/or take advantage of the host immune response for its own growth and survival. 3. Immune suppression and alveolar echinococcosis in humans In experimental animals various regimens of immune suppression have been shown to increase host’s susceptibility to infection and the rate of larval growth. [6,7]. First observations of the effect of immune suppression on E. multilocularis growth were made in the 1980s, when liver transplantation was recommended in very severe cases of AE. Following liver transplantation, rapid increase in the size of lung metastases, development of brain metastases and rapid re- invasion of the transplanted liver by parasitic cell remnants left in adjacent diaphragm or spleen tissue were reported and related to the therapeutic immunosuppression after liver transplantation [8]. One case of co-infection with E. multi- locularis and human immunodeficiency virus (HIV) has also been reported, with a rapid and irreversible growth of E. multilocularis larvae in a young patient [9]. Later, other cases of AE/HIV have been reported with a similar rapid and fatal outcome. More moderate levels of immune suppression may be associated with an accelerated course of development of alveolar echinococcosis, such as treatment with methotrexate or corticosteroids for chronic inflammatory diseases [10]. D.A. Vuitton et al. / ParasitologS52 Unusual increase in the size of alveolar echinococcosis lesions and/or occurrence of systemic metastases have also been observed in pregnant women ([11]; Bresson-Hadni, personal communication). This increased susceptibility of women to infection with AE during pregnancy together with their more frequent exposure to contamination, may account for the high prevalence of alveolar echinococcosis seen in women in high endemic areas, as observed in western China [1,4]. 4. E. multilocularis survival strategies to counteract immune mechanisms in human hosts Clinical observations in liver transplantation and AIDS strongly suggest suppression of cellular/Th1-related immunity increases disease severity and that immune stimulation may protect the human host and impair larval survival. How then do E. multilocularis larvae evade the efficient immune response? Immunological studies in patients with a progressive clinical course of alveolar echinococcosis may give some insights into the strategies employed by E. multilocularis in evading immune responses. 4.1. A progressive clinical course of AE is associated with a significant specific stimulation of T cells, and with a characteristic infiltration of CD8 T cells in the periparasitic granuloma In humans, a strong lymphocyte proliferative response can be elicited following stimulation of peripheral mononuclear cells (PBMC) with E. multilocularis antigens, especially in patients with abortive cases. Single T cells react specifically with unfractionated protein from E. multilocularis; and increased plasma level of IL-2 receptor alpha chain/CD25 is correlated with the volume of the lesions [12]. The relatively high number of CD4+ T cells within the granuloma is correlated with abortive or slow development of the larvae, while CD8+ T cells are predominant in inefficient granulomas in severe cases [12]. An increased activation and oligoclonality of peripheral CD8+ T cells is present in patients with AE [13]. Conversely, in all types of AE, the generation of Th1 CD4 T memory cells is impaired, especially those committed to Th1 cytokine secretion [14]. 4.2. A progressive clinical course of AE is associated with a Th2 profile and IL-10 secretion Studies of cytokine secretion by PBMC have shown that, in addition to a relatively low level of secretion of IFN-g, production of IL-5 was specifically induced by parasitic antigens in patients with AE [see Ref. [15] for a review]. This abnormal induction of Th2-related immune responses leads to high antibody response, including IgE and IgG4 specific antibodies in the more severe cases [15]. Spontaneous secretion of IL-10 by the PBMC is, however, the immunological hallmark of patients with progressive forms of the disease [15]. Conversely, IL-10 is significantly lower in patients with abortive lesions [16]. CD4 T lymphocytes are specifically ternational 55 (2006) S51–S55 involved in IL-5 secretion by stimulated PBMC. A variety of cell types are involved in the secretion of IL-10 by resting and stimulated PBMC, especially CD4 and CD8 T cells, but also y In non-T non-B cells [15]. The anti-inflammatory properties of IL-10 are well known, especially through the inhibition of macrophage activation and cytotoxic functions. IL-10-induced inhibition of effector macrophages, and also of antigen- presenting dendritic cells (DC), may be operating to protect parasitic growth and survival. Jenne et al. [17] have shown that immature DC did not mature in the presence of Em-Ag and their capacity to take up dextran was markedly reduced. However, further maturation of immature Em-Ag pulsed DC could be induced by proinflammatory cytokines. A preliminary report has confirmed that locally, in the periparasitic granulo- ma, T cells secrete IL-10 and the data also suggest IL-10 production is higher close to the parasitic vesicles [15]. Contact inhibition of effector macrophages could be induced either through this anti-inflammatory cytokine secretion or, more directly, through the contact between the parasitic cells and/or the laminated layer. Analysis of the cell surface markers of the epithelioid macrophages lining the parasitic vesicles in humans has shown a very unusual expression of these markers. In particular, there is a high expression of CD 25, the inducible a chain of the IL-2 receptor, a chain usually only expressed by activated T cells [12]. Such an abnormal expression of CD 25 has been shown in other granulomatous diseases and could be related to a particular functional state of the macrophages. High serum levels of CD-25 in severe cases of AE could also be related to this abnormal expression and be due to a direct influence of the larva. Two additional activators of immune subversion by the parasite, namely NO (highly suspected in the mouse model by Dai and Gottstein [18]) and TGF-beta (shown to be a potent immunoregulatory cytokine in several models of tolerance) have never been studied in humans with AE. Their role, if any, should certainly be the focus of further studies. 5. How does E. multilocularis provoke immune changes in the human host? From studies in patients with alveolar echinococcosis, we suspect the immune response of the host is modified by the parasite, but we know very little of the mechanisms E. multilocularis is using to induce the modifications which ensure its survival. However, the first stage of larval development might be crucial and the ‘‘danger signals’’ (recognized by ‘‘pattern receptors’’ such as Toll-like receptors) are likely to be involved. It may be hypothesized that they are shared by a variety of helminths, since hosts infected by these organisms share similar immunological profiles. Specific molecules of the parasites are assumed to be involved in triggering these ‘‘pattern receptors’’ directly or in inducing secondary signals. This crucial step is extremely difficult to study in humans, since diagnosis of AE is usually assessed several years after infection. Among potential ‘‘secondary signals’’, only expres- sion of MICA molecules (HLA-class I related molecules), which are considered to be ‘‘stress molecules’’ able to favour D.A. Vuitton et al. / Parasitolog cytotoxic immune responses, have been studied in humans infected with AE. Abnormal expression of MICA by the germinal layer of E. multilocularis, by ‘‘epithelioid’’ macro- phages lining the laminated layer, and by parenchymal liver cells might represent a long-lasting ‘‘secondary signal’’ involved in the persistent tolerance and/or liver invasion by the larva [19]. 6. Is E. multilocularis involved in the development of liver fibrosis and necrosis? Is this involvement part of its survival strategy? The diffusion of the fibrotic process even far from the parasitic lesions strongly suggests a major role for cytokines in collagen synthesis and cross-linking activation in humans as well as in the experimental models (see Ref. [12] for a review). However, parasitic cells could also be involved in the collagen cross-linking process, since a transglutaminase of parasitic origin has been shown to be strongly expressed in and at the border of the parasitic vesicles and is able to efficiently cross- link collagens of human origin in vitro [20]. Development of fibrosis has been shown to be either quantitatively or qualitatively correlated to host’s protection in experimental mice and is thus, usually, considered to be beneficial to the host. . . however, fibrosis, in addition to the laminated layer, could also be responsible for protection of the parasite against the cytolytic attacks by immune cells. Most of these cells with cytotoxic activity (either CD8 T-cells or TNF-containing macrophages) are located at the periphery of the granuloma, far from parasitic vesicles and close to liver parenchyma. Recent observations of MICA-expressing hepatic cells in close contact with CD8-T cells in infected human livers could represent another mechanism developed by E. multilocularis to invade the liver by using cytotoxic immune cells of the host to destroy autologous liver cells [19]. Such a mechanism should be further studied, including in the mouse model. 7. Immunogenetics of E. multilocularis susceptibility in humans or ‘‘why all humans do not react similarly when infected with E. multilocularis?’’ The infrequent occurrence of sustained E. multilocularis infection in humans without acquired immune suppression suggests that the parasite might find a more suitable environ- ment for its survival in only some of the individuals exposed to infection and that this suitable environment may be genetically determined. The genetic correlates of susceptibility to E. multilocularis are clearer in humans than in the mouse model. A European study with 150 AE patients has shown a significant association between HLA DR 11 and protection, HLA DPB1*0401 and susceptibility, and HLA DR3 and DQ2 and severe clinical evolution of the disease. The HLA B8, DR3, DQ2 haplotype is observed with an unusual frequency in patients with autoimmune disease and is characterised by an increased and inappropriate humoral immunity and a relatively inefficient cellular immune response [see Ref. [12] for a review of human immunogenetics in alveolar echinococcosis]. Studies ternational 55 (2006) S51–S55 S53 on cytokine secretion by PBMC from HLA DR3+, DQ2+ patients with AE compared with AE patients without this HLA haplotype have shown that the spontaneous secretion of IL-10 y In was much higher in the HLA DR3+, DQ2+ AE patients was much higher. [21]. AE cases observed in central China were shown to be associated with HLA DR4, but no immunological correlates have been reported in this population of patients [12]. Other genes within the MHC known to be related to the initiation and/or effector phase of the immune response could also be involved. No significant correlation has been observed between occurrence and/or severity of disease and polymor- phism in the TNF promoter gene. Sixty three percent of 94 patients with AE from the same European endemic area mentioned above had the homozygote Thr–Thr form of the TAP2 665 codon site, versus 45% of controls [12]. The association between TAP2 polymorphism and AE was partic- ularly significant in patients with severe disease and was not related to a linkage desequilibrium with HLA DR3. Its immunological significance is unknown, however, it could be related to the unexpected and characteristic infiltration of the lesions by CD8 T cells and to the possible role of these cells in immune suppression and IL-10 secretion around AE lesions. Clustering of cases in certain families, in communities exposed to similar risk factors, also points to immuno-genetic predis- position factors that may allow the larva to escape host immunity more easily [1,11,22]. More insight in the genetic characteristic of the patients with progressive AE could also help researchers to disclose the relevant mechanisms used by the parasite to survive in its human hosts. 8. How may immune modulation counteract the subversion of the immune response by E. multilocularis in susceptible humans? Specific cellular immunity is stronger in resistant strains of mice, and immune responses driven by the ‘‘Th1’’ profile of cytokine secretion that promotes effector cells may kill the parasite or prevent its development. After the reductive effect of Bacille Calmette Gue´rin (BCG) on the size and dissemina- tion of E. multilocularis larvae in experimental rodents had been reported [23], limited and unfortunately unpublished trials of its use in human AE were performed with encouraging results. A pilot study of the efficacy of another immunosti- mulating compound, Isoprinosine\, in patients with AE, showed a regression of the parasitic lesions in 2 patients (Vuitton and Bresson-Hadni, unpublished data). The mecha- nism of action of this drug, when tested in gerbils, was initially attributed to a direct interference with metacestode metabolism by acedobene, dimepranol and inosine, the 3 compounds present in Isoprinosine\. However, immunological data in those patients who responded to the drug suggested that it acted mainly through its capacity to increase cellular immunity and inhibit the Th2-type immune responses, such as IgE- dependent reactions. Isolated attempts of treatment with IFN-g in patients during the later stage of AE infection were no more successful than those performed in experimental mice and they did not significantly modify host’s cytokine profile [24]. The D.A. Vuitton et al. / ParasitologS54 logical use of IL-12 has proven to be extremely effective in the mouse model, by protecting the majority of the infected mice against secondary AE [25]. Because of potentially lethal side- effects in humans, IL-12 is unfortunately not available as a therapeutic agent in patients with AE and has thus not been evaluated. A unique observation in one patient with AE and chronic hepatitis C who had been treated with recombinant Interferon alpha-2a has suggested that this inducer of Th1 cytokines could be effective in AE, both limiting parasitic growth and reversing the abnormal cytokine profile [26]. Experiments in infected mice have confirmed the clinical observation. These studies have shown that Interferon alpha given at time of secondary infection in susceptible mice induced protection in a majority of mice against E. multi- locularis development, causing modification of the cytokine profile, especially reducing IL-10 secretion by both peritoneal and spleen cells and restoring the phagocytic and killing activity of macrophages [27]. A pilot clinical trial is planned to confirm the potential use of this new approach in the treatment of alveolar echinococcosis. Differential stimulation of human mononuclear cells by various extracts/molecules from E. multilocularis has been shown to induce different cytokines [12,15,16] and their sequential expression/secretion could be involved in the subtle sequence of events that lead to permanent establishment of the larva. This suggests that approaches based on specific antigenic components of Echinococcus sp. used as preventive or therapeutic vaccines might thus be considered, even if preliminary experimental reports suggest that the same antigenic compounds may act differently in models of primary versus secondary infection [28]. More sophisticated approaches such as the use of ex vivo generated E. multilocularis antigen- pulsed dendritic cells might also be of benefit for patients with AE [17]. Acknowledgements The authors wish to thank the European Commission (DG Research, DG Sanco and the InterReg II programme), the NIH and the NFS of the USA, the French Ministry of Health (PHRC grants) and the Re´gion de Franche-Comte´ for their financial support. 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Brain Survival strategy of Echinococcus multilocularis in the human host Introduction Susceptibility to E. multilocularis infection displayed by the human host Immune suppression and alveolar echinococcosis in humans E. multilocularis survival strategies to counteract immune mechanisms in human hosts A progressive clinical course of AE is associated with a significant specific stimulation of T cells, and with a characteristic infiltration of CD8 T cells in the periparasitic granuloma A progressive clinical course of AE is associated with a Th2 profile and IL-10 secretion How does E. multilocularis provoke immune changes in the human host? Is E. multilocularis involved in the development of liver fibrosis and necrosis? Is this involvement part of its survival strategy? Immunogenetics of E. multilocularis susceptibility in humans or why all humans do not react similarly when infected with E. multilocularis? How may immune modulation counteract the subversion of the immune response by E. multilocularis in susceptible humans? Acknowledgements References