An Overview of Peripheral Blood Mononuclear Cells as a Model for Immunological Research of Toxoplasma gondii and Other Apicomplexan Parasites

MINI REVIEW published: 08 February 2019 doi: 10.3389/fcimb.2019.00024 An Overview of Peripheral Blood Mononuclear Cells as a Model for Immunological Research of Toxoplasma gondii and Other Apicomplexan Parasites John Alejandro Acosta Davila* and Alejandro Hernandez De Los Rios GEPAMOL, Centro de Investigaciones Biomédicas, Universidad del Quindío, Armenia, Colombia Edited by: Kamal El Bissati, University of Chicago, United States Reviewed by: Yang Zhang, University of Pennsylvania, United States Juan Carlos Sepúlveda-Arias, Technological University of Pereira, Colombia *Correspondence: John Alejandro Acosta Davila Specialty section: This article was submitted to Clinical Microbiology, a section of the journal Frontiers in Cellular and Infection Microbiology Received: 30 June 2018 Accepted: 22 January 2019 Published: 08 February 2019 Citation: Acosta Davila JA and Hernandez De Los Rios A (2019) An Overview of Peripheral Blood Mononuclear Cells as a Model for Immunological Research of Toxoplasma gondii and Other Apicomplexan Parasites. Front. Cell. Infect. Microbiol. 9:24. doi: 10.3389/fcimb.2019.00024 In biology, models are experimental systems meant to recreate aspects of diseases or human tissue with the goal of generating inferences and approximations that can contribute to the resolution of specific biological problems. Although there are many models for studying intracellular parasites, their data have produced critical contradictions, especially in immunological assays. Peripheral blood mononuclear cells (PBMCs) represent an attractive tissue source in pharmacogenomics and in molecular and immunologic studies, as these cells are easily collected from patients and can serve as sentinel tissue for monitoring physiological perturbations due to disease. However, these cells are a very sensitive model due to variables such as temperature, type of stimulus and time of collection as part of posterior processes. PBMCs have been used to study Toxoplasma gondii and other apicomplexan parasites. For instance, this model is frequently used in new therapies or vaccines that use peptides or recombinant proteins derived from the parasite. The immune response to T. gondii is highly variable, so it may be necessary to refine this cellular model. This mini review highlights the major approaches in which PBMCs are used as a model of study for T. gondii and other apicomplexan parasites. The variables related to this model have significant implications for data interpretation and conclusions related to host-parasite interaction. Keywords: PBMCs (peripheral blood mononuclear cells), immunologic research, toxoplasma gondii, model of study, apicomplexa INTRODUCTION The phylum Apicomplexa consists of approximately 6,000 species of intracellular protozoan parasites, including various important human and animal pathogens such as Plasmodium, the causative agent of malaria; Cryptosporidium, the causative agent of cryptosporidiosis; Theileria, Babesia and Eimeria, which are important pathogens in cattle and fowl; and T. gondii, which is responsible for toxoplasmosis in birds, marsupials and mammals including humans (Tenter et al., 2000; Dubey, 2010). T. gondii has emerged as a model system for the study of intracellular parasitism; it is one of the most studied parasites due to its medical and veterinary importance, its wide range of distribution and its suitability as a model of study in pharmacogenomics, cell biology, molecular genetics and immunology. T. gondii infections are generally subclinical in Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 1 February 2019 | Volume 9 | Article 24 Acosta Davila and Hernandez De Los Rios An Overview of PBMCs as a Model for Apicomplexan Parasites et al., 2010). In chronic asymptomatic individuals, the PBMCs’ immune responses against total lysate antigen and against peptides derived from T. gondii are predominantly characterized by high levels of interferon gamma (IFN-γ) (Prigione et al., 2006; Bayram Delibaş et al., 2009; Cong et al., 2011; Cardona et al., 2015; Meira et al., 2015); in ocular toxoplasmosis and Toxoplasma-seronegative individuals, however, the level of this cytokine is much lower (Alfonzo et al., 2005; Meira et al., 2014; Maia et al., 2017). PBMCs have also been useful in studying the immune response of HIV-infected individuals and of pregnant women with toxoplasmosis. In one study on HIV patients who had been coinfected with T. gondii, researchers measured the IFN-γ expression of stimulated total lysate antigen using PBMCs, both before and after treatment with antiparasitic drugs (sulfadiazine, pyrimethamine, folinic acid, trimethoprim-sulfamethoxazole, and corticosteroids); the infection’s evolution was correlated with the restoration of the IFN-γ response and with decreased inflammation (Meira et al., 2015). In another study, researchers showed that, during pregnancy, tumor necrosis factor alpha (TNF-α) and interleukin (IL)-12 had decreased expression when cells were stimulated with live tachyzoites (Rezende-Oliveira et al., 2012). Interestingly, the addition of the prolactin hormone to the cells seemed to restrict the parasite’s proliferation (Dzitko et al., 2012). In similar works, researchers have shown the importance of IFN-γ production in the congenital transmission of T. gondii through the upregulation of intercellular adhesion molecular 1 (ICAM-1) (Pfaff et al., 2005). Stimulating PBMCs with complete or partial antigens of T. gondii seems to reveal important aspects of the host’s immune response. However, T. gondii and other apicomplexans secrete proteins in a highly regulated manner that is involved in the parasite’s immune evasion mechanisms (Tosh et al., 2016). These processes are not seen when parasite antigens are used, so we recommend the use of live parasites to stimulate PBMCs (Figure 1). On the other hand, the vaccine candidates for T. gondii are typically parasite proteins or the peptides that elicit protective immune responses in mice. However, vaccine candidates that are effective in mice are not necessarily effective in humans. PBMCs are potentially very useful tools for identifying and characterizing novel vaccine candidates for T. gondii. Cells from individuals with varied genetic and immunological backgrounds can be easily isolated and stimulated with the antigens of interest, thus allowing measurement of the desired cytokine profile or cell response. However, to our knowledge, few researchers have used this strategy (Tan et al., 2010; Cong et al., 2012; Cardona et al., 2015). The studies mentioned above have identified novel parasite derived peptides that induce strong production of IFN-γ in people who express one of the most common human leukocyte antigen (HLA) supertypes (HLA-A02, HLA-B07, and HLA-A11), making those peptides attractive vaccine candidates. PBMCs have also been used to evaluate the efficacy of two phytoecdysteroids (α-ecdysone and 20-hydroxyecdysone) in cont (...truncated)