Prematurity and Severity Are Associated With Toxoplasma gondii Alleles (NCCCTS, 1981–2009)

Congenital toxoplasmosis is usually diagnosed in the United States when there is fetal loss, prematurity, or severe disease at birth with damage to eyes and brain with lifelong consequences, especially if untreated. This disease also presents as recurrent active retinochoroiditis, loss of cognitive and motor function, and seizures later in life in persons who appeared normal at birth and whose initial disease went unrecognized. Of those who are congenitally infected with Toxoplasma gondii and did not receive treatment, 80%–90% are reported to have eye disease by adolescence [1]. Obstetrical serologic screening is mandated by law in France and Austria, virtually eliminating severe disease in these countries through early treatment of the fetus. In the United States, screening for acute acquired T. gondii infection during gestation is performed only occasionally. The National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS), which has been ongoing since 1981, has allowed careful evaluation of 2 cohorts of persons with congenital toxoplasmosis. There is one cohort of persons, most often diagnosed with substantial disease in the newborn period and treated in the first year of life, and another in which congenital toxoplasmosis was diagnosed after the first year of life. Sera have been collected from all the congenitally infected persons and almost all of their mothers. Genetically disparate parasites behave differently in animal models and tissue culture [2–4]. Type I parasites are more virulent, measured as causing death in mice. Type II parasites are less lethal in mice, produce more cysts in brains of mice, and grow more slowly in tissue culture. Type III parasites are intermediate for these phenotypes. Parasites may also be nonarchetypal, containing mixtures of II or I/III specific alleles, or altogether new alleles. In a small series of persons with substantial ophthalmologic disease, there was an unusual abundance of non-II or atypical parasites, suggesting that disease outcomes in humans infected with different parasite types may differ [3]. Immune responses, including production of interferon γ, dendritic cell responses, and numbers of activated T cells, also differ [3]. Effects of type I, II, and III parasites on transcriptomes of a human neuroepithelial cell line have been shown to differ [4]. In the United States there has been only limited study of distribution of parasite types and diseases they cause, with no analyses of substantial cohorts of congenitally infected persons as described herein. An enzyme-linked immunosorbent assay (ELISA) allows discrimination of infections caused by type II and non-II parasites using a serologic test identifying strain-specific antibodies induced by allelic peptide motifs in dense granule proteins GRA6 and GRA7 [5]. This assay allows us to distinguish strain type (II or not exclusively II [NE-II]) causing congenital toxoplasmosis in our cohorts and to correlate this with demographics of families, manifestations in infants at birth and later in life, and effects of treatment.