Immunological aspects of Giardia infections

Parasite 2014, 21, 55 Ó M.F. Heyworth, published by EDP Sciences, 2014 DOI: 10.1051/parasite/2014056 Available online at: www.parasite-journal.org OPEN REVIEW ARTICLE ACCESS Immunological aspects of Giardia infections Martin F. Heyworth1,2,* 1 2 Research Service, Department of Veterans Affairs (VA) Medical Center, Philadelphia, PA 19104, USA Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Received 27 August 2014, Accepted 16 October 2014, Published online 28 October 2014 Abstract – Immunodeficiency, particularly antibody deficiency, predisposes to increased intensity and persistence of Giardia infections. Giardia-infected immunocompetent hosts produce serum and intestinal antibodies against Giardia trophozoites. The number of Giardia muris trophozoites, in mice with G. muris infection, is reduced by intra-duodenal administration of anti-G. muris antibody. Giardia intestinalis antigens that are recognised by human anti-trophozoite antibodies include variable (variant-specific) and invariant proteins. Nitric oxide (NO) appears to contribute to host clearance of Giardia trophozoites. Arginine is a precursor of NO and is metabolised by Giardia trophozoites, possibly reducing its availability for generation of NO by the host. Work with mice suggests that T lymphocytes and interleukin-6 (IL-6) contribute to clearance of Giardia infection via mechanisms independent of antibodies. Key words: Giardia intestinalis, Giardiasis, NO. Résumé – Aspects immunologiques des infections à Giardia. L’immunodéficience, particulièrement la déficience en anticorps, prédispose à une augmentation de l’intensité et de la durée des infections à Giardia. Les hôtes immunocompétents infectés par Giardia produisent des anticorps sériques et intestinaux contre les trophozoïtes de Giardia. Le nombre de trophozoïtes de Giardia muris, chez la souris infectée par G. muris, est réduit par l’administration intra-duodénale d’anticorps anti G. muris. Les antigènes de Giardia intestinalis qui sont reconnus par des anticorps humains anti-trophozoïtes comprennent des protéines variables (spécifiques aux variants) et des protéines invariantes. L’oxyde nitrique (NO) semble contribuer à débarrasser l’hôte des trophozoïtes de Giardia. L’arginine est un précurseur de NO et est métabolisé par les trophozoïtes de Giardia, ce qui réduit peut-être sa disponibilité pour la production de NO par l’hôte. Les travaux sur la souris suggèrent que les lymphocytes T et l’interleukine-6 (IL-6) contribuent à éliminer Giardia par des mécanismes indépendants des anticorps. Giardia intestinalis (synonyms: G. duodenalis, G. lamblia) is a protozoan parasite that colonises the small intestinal lumen of vertebrate hosts. In human subjects, G. intestinalis infections range in clinical severity from asymptomatic colonisation to a debilitating syndrome that includes chronic diarrhoea and malabsorption. The two-stage life cycle of Giardia species comprises the motile trophozoite, with eight flagella and a ventral adhesive disc by which it adheres to the luminal surface of intestinal epithelial cells (and thereby resists peristaltic expulsion from the host’s intestine), and the thick-walled cyst, which is excreted from the host. Previously uninfected hosts become infected by oral ingestion of Giardia cysts. Giardia infections are increased in intensity and/or duration in human or non-human mammalian hosts with various forms of immunodeficiency, in comparison with their immuno*Corresponding author: competent counterparts [9, 14, 20]. This situation indicates that host immunological responses limit the intensity and/or duration of these infections. The extant literature suggests that impaired production of anti-Giardia antibodies is the main reason why immunodeficiency states predispose to severe/ prolonged Giardia infections [4]. From the 1980s onwards, it has been known that Giardia-infected human and non-human hosts generate serum and intestinal antibody responses against Giardia trophozoites [10, 28]. Anti-Giardia IgA is present in the intestinal lumen of Giardia-infected hosts and has also been detected in human milk [10, 32]. Colostrum from cows with G. intestinalis-infected calves contains anti-Giardia IgG [19]. Intraperitoneal or intraduodenal administration of anti-G. muris antibody leads to reduction in the number of intestinal G. muris trophozoites, in mice infected with this parasite [1, 3]. This result is consistent with a role for antibodies in clearing G. muris from the mouse intestinal lumen. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 2 M.F. Heyworth: Parasite 2014, 21, 55 Giardia trophozoite antigens that are recognised by antibodies of Giardia-infected hosts include heterogeneous ‘‘variant-specific surface proteins’’ (VSPs), and non-variable (structurally conserved) proteins [21]. Of a repertoire of approximately 150 (or more) VSPs in Giardia intestinalis, only one VSP appears to be expressed on an individual Giardia trophozoite at any one time, other than during antigenic ‘‘switching’’ [17, 18]. It has been speculated that antigenic switching by Giardia trophozoites, whereby expression of one VSP changes to that of a different VSP, might be an immune evasion strategy (an adaptation by the parasite to the presence of host antibodies directed against whichever VSP is initially expressed by a population of trophozoites in the intestinal lumen) [17]. The observation that G. intestinalis trophozoites switch from the expression of one VSP to another in the absence of antibodies, during in vitro culture [18], does not rule out the possibility that antibodies might select against the persistence of initially expressed VSP(s) in the host. The biological role, if any, of VSPs appears to be unknown, although it has been postulated that expression of a particular VSP might influence the relative ability of Giardia trophozoites to colonise a particular species of host [26]. Giardia trophozoites genetically engineered to express ‘‘numerous’’ VSPs simultaneously can act as a vaccine (whether given as live organisms, or as an inanimate mixture of antigens) to generate protective anti-Giardia immunity in a gerbil host [24]. The implications of this finding for understanding the ‘‘normal’’ mechanism(s) of host protective immunity against Giardia infection(s) are, however, unclear. Sera from G. intestinalis-infected human subjects contain antibodies directed against trophozoite VSPs [23]. Of possibly greater biological significance, antibodies against G. intestinalis trophozoite proteins that are structurally conserved (invariant) have also been identified in sera from Giardia-infected individuals. Trophozoite invariant proteins recognised by hu (...truncated)