Genes and Immunity (2010) 11, 363–373 & 2010 Macmillan Publishers Limited All rights reserved 1466-4879/10 www.nature.com/gene REVIEW Congenital toxoplasmosis: candidate host immune genes relevant for vertical transmission and pathogenesis LB Ortiz-Alegrı´a1, H Caballero-Ortega1, I Can˜edo-Solares1, CP Rico-Torres1, A Sahagu´ n-Ruiz2, ME Medina-Escutia3 and D Correa1 1Laboratorio de Inmunologı´a Experimental, Subdireccio´n de Medicina Experimental, Instituto Nacional de Pediatrı´a, SSA, Me´xico DF, Mexico; 2Departamento de Microbiologı´a e Inmunologı´a, Facultad de Medicina Veterinaria y Zootecnia, UNAM, Me´xico DF, Mexico and 3Laboratorio de Anticuerpos Monoclonales, Instituto de Diagno´stico y Referencia Epidemiolo´gicos, SSA, Me´xico DF, Mexico Toxoplasma gondii infects a variety of vertebrate hosts, including humans. Transplacental passage of the parasite leads to congenital toxoplasmosis. A primary infection during the first weeks of gestation causes vertical transmission at low rate, although it causes major damage to the embryo. Transmission frequency increases to near 80% by the end of pregnancy, but the proportion of ill newborns is low. For transmission and pathogenesis, the parasite genetics is certainly important. Several host innate and adaptative immune response genes are induced during infection in adults, which control the rapidly replicating tachyzoite. The T helper 1 (Th1) response is protective, although it has to be modulated to avoid inflammatory damage. Paradoxical observations on this response pattern in congenital toxoplasmosis have been reported, as it may be protective or deleterious, inducing sterile abortion or favoring parasite transplacental passage. Regarding pregnancy, an early Th1 microenvironment is important for control of infectious diseases and successful implantation, although it has to be regulated to support trophoblast survival. Polymorphism of genes involved in these parallel phenomena, such as Toll-like receptors (TLRs), adhesins, cytokines, chemokines or their receptors, immunoglobulins or Fc receptors (FcRs), might be important in susceptibility for T. gondii vertical transmission, abortion or fetal pathology. In this study some examples are presented and discussed. Genes and Immunity (2010) 11, 363–373; doi:10.1038/gene.2010.21; published online 6 May 2010 Keywords: congenital toxoplasmosis; host genetics; immune response; polymorphisms; Toxoplasma gondii Introduction likely to influence outcome. Recent investigations have shown surprising phenomena; that is, molecules and The protozoan parasite Toxoplasma gondii, an obligate cells that protect the mother might favor vertical intracellular eukaryotic pathogen of the phylum Api- transmission.6,7 Few direct data are available, but indirect complexa, may cause toxoplasmosis in many warm- evidence points to several candidate polymorphic host blooded animals, including humans.1 Transplacental immune response genes that may influence fetal infec- passage of the parasite causes congenital toxoplasmosis. tion or clinical outcome of the product. Transmission frequency and severity of disease vary with gestation time: during the first weeks, vertical Immune response in acquired toxoplasmosis transmission is of low rate, although if it occurs, it causes The key immune system molecules and cells related to major damage to the embryo. The transmission fre- control acquired (noncongenital) toxoplasmosis have quency increases to near 80% by the end of pregnancy, been studied extensively. It can be summarily said that 2 but the proportion of ill newborns is low. The changes in professional phagocytes and natural killer (NK) cells are endocrine phenomena occurring during pregnancy, as main effectors during the innate phase. Human Toll-like well as the size and maturity of the placenta and of the receptors (TLRs) of importance are TLR2 and TLR4. embryonic/fetal immune response certainly affect the Their ligands induce the production of inflammatory ability to be protected from invasion or to fight chemokines and cytokines (that is, CCL3, CCL5, inter- 3–5 infection. The size of the inoculum is also relevant leukin (IL)-6, IL-8 and IL-12) that mediate recruitment of for congenital infection risk and disease severity. Besides, professional phagocytes and dendritic cells.8–10 Crucial the genetic background of the mother and the product is adaptative responses include CD8 þ cytotoxicity of infected cells, antibody-mediated phagocytosis and NK cell antibody-mediated cytotoxicity (NK-ADCC). Correspondence: Dr D Correa, Lab. Inmunologı´a Experimental, A T helper 1 (Th1) profile (that is, IL-12 and interferon-g Instituto Nacional de Pediatrı´a, SSA, Av. Insurgentes Sur 3700-C, (IFN-g)) is essential to induce these mechanisms.11 Th17 Torre de Investigacio´n, Mexico DF, 04530, Mexico. E-mail: [email protected] cells are also involved in acute polymorphonuclear- Received 10 November 2009; revised and accepted 16 March 2010; mediated resistance to Toxoplasma.12 Some chemokines published online 6 May 2010 and their receptors have a determinant role for NK and Congenital toxoplasmosis LB Ortiz-Alegrı´a et al 364 dendritic cell recruitment; in addition, polarization to promote fetal growth and to inhibit allorejection by a Th1 profile depends on CCR5 stimulation by T. gondii maternal immune response. By the end of pregnancy, a cyclophilin 18, CCL3, CCL4 or CCL5.13,14 Other CCRs, Th1 inflammatory response arises again, promoting rup- such as CCR1, CCR2 and CXCR2, have important roles ture of membranes, placental detachment and partum.4,36 in neutrophil proliferation and monocyte recruitment, which are essential for parasite control.15–18 An early Th2 Candidate immune genes with a role in T. gondii vertical phenotype (driven by IL-4) is associated with bad transmission or fetal pathology outcome.19,20 HLA. The major histocompatibility complex (MHC) Antibodies and their Fc receptors (FcRs) have im- antigens have an important role in acquired toxoplasmosis portant roles as well.21,22 Antibodies of the immunoglo- for both CD8 þ lymphocyte-mediated cytolysis and for bulin (Ig)A, IgM and IgG1 (equivalent to murine IgG2a) CD4 þ -mediated regulation of the immune response. classes protect through neutralization, complement acti- Many studies using the murine model have described the vation, opsonization of phagocytes or NK-ADCC. IgG2 role of these antigens in the control of parasite replication and IgG4 are poor complement fixative subclasses and of or generation of inflammatory disease.11 Thus, MHC low affinity for FcRs, and thus they are not expected to antigens are thought to have a major role in fetus suscep- relate to protection. Similarly, IgE antibodies are related tibility to develop clinical problems. In this regard, Mack to lymphadenopathy in the acute phase.22 et al.37 showed that among congenitally infected Caucasian Once the parasite encysts, the Th1/Th17 response- children, the DQ3 allele frequency was significantly higher driven inflammatory reactions are downregulated, avoid- in infants with hydrocephalus than in those without it. In ing inflammatory damage. This is mediated by IL-10, transgenic chimerical mice they also showed that the transforming growth factor-b (TGF-b) and IL-27.11,23,24 human DQ3 allele protected less than the DQ1 against brain necrosis.37 Immune response and pregnancy Immunohistochemically, HLA-G and a small amount Thereissomeparallelismbetweentheresponsethat of HLA-C are the only molecules that can be detected in controls T. gondii infection and that related to pregnancy extravillous chorionic cytotrophoblasts.25 Its low poly- success. During implantation, a Th1-type inflammatory morphism ensures that paternal HLA-G expressed in the environment is essential for invasion of the endometrium trophoblast does not induce a maternal alloresponse by by trophoblasts; it is also necessary during the first month the class I MHC-restricted CD8 þ cells. Conversely, of pregnancy to favor spiral arteries growth and protection activation of NK cells depends on the lack of MHC from infection.25,26 Implantation is induced by IFN-g, expression in the target cells, but extravillous cytotro- which activates NK cells and regulates colony stimulation phoblast HLA-G expression induces IL-10 and other factors, promoting trophoblast growth. Chemokine and cytokines, which build a favorable milieu for pregnancy chemokine receptor signaling processes mediate leukocyte maintenance.38 Thus, the trophoblast resists NK cell and recruitment and controlled trophoblast invasion and thus CD8 þ lysis by disturbed antigen recognition through implantation and placentation.27 CCR1 is present on HLA-G, although low diversity peptides are presented invading human trophoblasts and promotes their migra- by HLA-G to cytotoxic T lymphocytes.38 Nothing is tion. Its ligand, CCL14, is expressed in endometrial known about T. gondii antigen presentation through vasculature, as well as in epithelial and decidual cells HLA-G, but it would induce limited CD8 þ lysis of during early pregnancy. CCR2 and CCL2 are coexpressed infected cells and Th1-type inflammation during early by human first-trimester decidual tissue and the latter is pregnancy, which would partially favor local parasite upregulated by pregnancy-associated hormones, such as control and implantation success. estrogen, progesterone and human chorionic gonadotro- phin.28 CCL5 promotes a Th1 profile and an adequate pro- Cytokines, chemokines, adhesion molecules and receptors implantatory microenvironment, influencing