Parasite Immunology, 2015, 37, 105–107

DOI: 10.1111/pim.12177

Editorial

Immunity to Toxoplasma gondii – into the 21st century J. L. COOMBES1 & C. A. HUNTER2 1 Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool, UK, 2Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

Keywords Toxoplasma, Immunology, Encephalitis The history of studying the immune response to Toxoplasma gondii dates back to the 1940s. The first reports that this parasite was a cause of abortion and congenital disease in humans (1) led to the development of serological methods for diagnostic testing (2). Later, a role for T. gondii as an opportunistic infection and cause of toxoplasmic encephalitis in the immune-deficient host was appreciated: first in cancer patients, then with the increasing use of immune suppressants or whole-body irradiation in the context of transplantation and cancer, and then with the onset of the AIDS pandemic and most recently in the context of biological response modifiers used to manage inflammatory disease (3, 4). These patients, most notably those with acquired defects in T-cell-mediated immunity, highlighted the importance of the immune response in the ability to control this persistent infection. This in turn motivated scientists in this field to understand the complex relationship between the parasite and the immune system, and this area of research advanced rapidly, in part because the mouse was a natural host of this parasite. Consequently, T. gondii became an important model organism to help understand how cell-mediated immunity controlled intracellular pathogens. For example, seminal studies using this organism established the role of interferons in activating host cells to control nonviral pathogens and the role of IFN-c in activating the antimicrobial effector mechanisms required for resistance to infection (5). Subsequent work Correspondence: Christopher Hunter, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Room 313 Hill Pavilion, 380 South University Av., Philadelphia, PA 19104-453 (email: [email protected]) and Janine Coombes, Department of Infection Biology, Liverpool Science Park IC2, 146 Brownlow Hill, Liverpool, L3 5RF (email: [email protected]) Received: 21 January 2015 Accepted for publication: 21 January 2015 © 2015 John Wiley & Sons Ltd

highlighted the role of IL-12 in the activation of NK cell production of IFN-c, which is relevant to innate resistance to many intracellular pathogens (6). In recent years, there have been numerous reports of strain-dependent disease, including pulmonary and ocular manifestations, in healthy immune competent hosts (7, 8). This has led to a better appreciation that T. gondii is not always asymptomatic, and its ability to drive alterations in neurological function, and a proposed association with mental illness, is attracting more attention (9). In addition, while modern industrial farming methods appear to have resulted in a decrease in the contamination of meat products with T. gondii cysts, a recent upsurge in consumption of ‘free range’ or ‘pasture-raised’ meat could reverse this trend (10). Consequently, there is still a pressing need to better understand the basis of parasite virulence and disease with the long-term aim of developing better vaccines, improving strategies to prevent congenital disease and to manage patients with clinical toxoplasmosis.

MECHANISMS OF CELL-MEDIATED IMMUNITY IN T. GONDII INFECTION As noted above, T. gondii has become a prominent model pathogen to study basic mechanisms of cell-mediated immunity, and this special issue highlights key areas where T. gondii may provide new insights into how the immune system works. The review by Denkers et al. (11) focuses on how this natural enteric pathogen interacts with the immune system in the gut, and discusses the development of intestinal pathology in genetically susceptible mouse models, and the role of the commensal flora in the regulation of the host–parasite dialogue. Beyond furthering our understanding of the earliest interactions between the parasite and host, these studies have been informative in dissecting the regulatory networks that maintain immune homoeostasis in the gut. Several of the articles in this issue highlight that advances in the ability to image T. gondii in real time has provided a better

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understanding of how T. gondii disseminates, and its interaction with host immune cell populations. This theme is the focus of the article from Coombes et al. (12) that describes the advantages of using T. gondii for dynamic imaging studies, and how advances in imaging technologies, as well as the availability of numerous cell reporters, has led to new insights into the interaction of T. gondii with different immune cells that have also informed how we think more generally about how the immune system deals with pathogens.

Parasite Immunology

this previously neglected field offer the key to understanding how T. gondii, and related apicomplexan parasites, cross-biological barriers to cause disease in the foetus, eye and central nervous system (CNS). Understanding these processes may provide new opportunities to prevent transmission from mother to foetus.

TOXOPLASMA AND THE CNS

There is a growing appreciation that primary infection of immune competent individuals is not benign and can result in severe disease, and one of the largest variables that underlies development of disease is parasite strain. Several of the articles in this issue reference the complex population structure of T. gondii and its impact on virulence. The article by Boyle et al. (13) describes how basic genetic studies to map virulence determinants in T. gondii led to the identification of several novel immune evasion mechanisms. This work illustrates the principle that a major reason why this organism has been so successful is its ability to target key host immune cellular processes (14). Thus, it is now recognized that during invasion of host cells, T. gondii uses unique organelles (the rhoptries) to inject a range of proteins into the host cell cytosol, and genetic mapping has implicated several of these proteins in immune evasion in murine and human cells (15–19). Recent in vitro studies revealed that T. gondii rhoptry proteins can be injected into host cells without invasion, and it has been proposed that the injection of parasite proteins into bystander cells contributes to evasion of the immune response (20). Other studies have highlighted the conservation of rhoptry proteins between strains of T. gondii, and a picture is emerging that the existence of large numbers of these rhoptry proteins represents a strategy to allow T. gondii to subvert the immune response in many different hosts and cell types. One key way in which T. gondii is thought to subvert the host immune response is to utilize motile immune cell populations to travel from the site of infection in the intestine and onwards through the host to the brain (21). The article from Lodoen et al. (22) discusses both extracellular and intracellular modes of dissemination, detailing the molecular mechanisms through which T. gondii uses host immune cells as ‘Trojan horses’, or its own intrinsic motility, to breach stringent biological barriers. Recent developments in

The reactivation of chronic T. gondii infection, resulting in toxoplasmic encephalitis, is a concern in many patients with primary or acquired defects in T-cell-mediated immunity, and well-characterized murine models have provided clinically relevant insights into the pathogenesis of toxoplasmic encephalitis in human patients. In this issue, Schl€ uter et al. (23) review the relative contributions of resident and recruited immune cells to the control of T. gondii in the brain. They discuss how presentation of a C-terminal epitope of the dense granule protein, GRA6, on the protective Ld MHC-I molecule controls cyst burden in the brain (24, 25). Further, they highlight the need to better understand how brain resident cells such as astrocytes and microglia are involved in the recruitment of peripheral immune cells and how these glial populations might regulate local T cell responses during chronic infection. Dunay et al. (26) focus on the growing topic of neuro-immune interactions. They describe how both parasite and host immune factors can contribute to altered neuronal function and perhaps host behaviour during chronic infection. Work in this emerging field will be crucial to understand the molecular pathways that might underpin observed relationships between T. gondii seropositivity and schizophrenia, mood disturbances or personality traits. Together, these two articles outline how murine models of T. gondii infection may allow us to assess not only how the immune system functions in an immune privileged environment, but also how apparently local subclinical immune responses in the CNS might impact on neurologic function. Genetic screens based on virulence have been instrumental in identifying strain-specific determinants of virulence, but have not yet identified the common mechanisms used by all T. gondii strains to evade the immune system in different hosts. With the relative ease of generating T. gondii mutants across many strains, perhaps it is time to consider a ‘Manhattan Project’ to knockout all genes that are not essential for parasite growth in vitro and to develop systems biology approaches to describe phenotypic changes in the parasites, together with disease manifestations in an infected host.

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© 2015 John Wiley & Sons Ltd, Parasite Immunology, 37, 105–107

DETERMINANTS OF VIRULENCE AND THE MANIPULATION OF HOST IMMUNE FUNCTION

Volume 37, Number 3, March 2015

Immunity to Toxoplasma gondii

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19 Behnke MS, Khan A, Wootton JC, Dubey JP, Tang K & Sibley LD. Virulence differences in Toxoplasma mediated by amplification of a family of polymorphic pseudokinases. Proc Natl Acad Sci USA 2011; 108: 9631–9636. 20 Koshy AA, Dietrich HK, Christian DA, et al. Toxoplasma co-opts host cells it does not invade. PLoS Pathog 2012; 8: e1002825. 21 Weidner JM & Barragan A. Tightly regulated migratory subversion of immune cells promotes the dissemination of Toxoplasma gondii. Int J Parasitol 2014; 44: 85–90. 22 Harker KS, Ueno N & Lodoen MB. Toxoplasma gondii dissemination: a parasite’s Journey through the Infected Host. Parasite Immunol 2014; 3: 141–149. 23 Blanchard N, Dunay IR & Schl€ uter D. Persistence of Toxoplasma gondii in the central nervous system: a fine tuned balance between the parasite, the brain and the immune system. Parasite Immunol 2015; 3: 150–158. 24 Feliu V, Vasseur V, Grover HS, et al. Location of the CD8 T cell epitope within the antigenic precursor determines immunogenicity and protection against the Toxoplasma gondii parasite. PLoS Pathog 2013; 9: e1003449. 25 Blanchard N, Gonzalez F, Schaeffer M, et al. Immunodominant, protective response to the parasite Toxoplasma gondii requires antigen processing in the endoplasmic reticulum. Nat Immunol 2008; 9: 937–944. 26 Parlog A, Schl€ uter D & Dunay IR. Toxoplasma gondii induced neuronal alterations. Parasite Immunol 2014; 3: 159–170.

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Immunity to Toxoplasma gondii--into the 21st century.

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