Intraepithelial lymphocytes (IELs) are localized to epithelial barriers and are most abundant within the intestine. Approximately half of small intestinal IELs express the nonconventional γδ T-cell receptor, and are thought to bridge innate and adaptive immunity.¹ x 1 Goodman, T. and Lefrancois, L. Intraepithelial lymphocytes. Anatomical site, not T cell receptor form, dictates phenotype and function. J Exp Med. 1989; 170: 1569–1581 Crossref | PubMed | Scopus (315) | Google Scholar See all References Although the precise function of intestinal γδ IELs is incompletely understood, in their absence, translocation of both commensal bacteria and enteric pathogens, such as Salmonella typhimurium and Toxoplasma gondii, is enhanced.² x 2 Li, C., Mannoor, K., Inafuku, M. et al. Protective function of an unconventional gammadelta T cell subset against malaria infection in apoptosis inhibitor deficient mice. Cell Immunol. 2012; 279: 151–159 Crossref | PubMed | Scopus (7) | Google Scholar See all References ^{, 3} x 3 Dalton, J.E., Cruickshank, S.M., Egan, C.E. et al. Intraepithelial gammadelta+ lymphocytes maintain the integrity of intestinal epithelial tight junctions in response to infection. Gastroenterology. 2006; 131: 818–829 Abstract | Full Text | Full Text PDF | PubMed | Scopus (74) | Google Scholar See all References ^{, 4} x 4 Sheridan, B.S., Romagnoli, P.A., Pham, Q.M. et al. γδ T cells exhibit multifunctional and protective memory in intestinal tissues. Immunity. 2013; 39: 184–195 Abstract | Full Text | Full Text PDF | PubMed | Scopus (87) | Google Scholar See all References ^{, 5} x 5 Ismail, A.S., Severson, K.M., Vaishnava, S. et al. Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc Natl Acad Sci U S A. 2011; 108: 8743–8748 Crossref | PubMed | Scopus (142) | Google Scholar See all References Although responses to individual pathogens differ, γδ T cells secrete the antimicrobial protein RegIIIγ via intestinal epithelial MyD88-dependent signaling in response to commensal and pathogenic bacteria.⁵ x 5 Ismail, A.S., Severson, K.M., Vaishnava, S. et al. Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc Natl Acad Sci U S A. 2011; 108: 8743–8748 Crossref | PubMed | Scopus (142) | Google Scholar See all References These and other data indicate that γδ IEL interactions with intestinal epithelia are involved in host defense.

One third of humans are infected lifelong with the brain-dwelling, protozoan parasite,Toxoplasma gondii. Approximately fifteen million of these have congenital toxoplasmosis. Although neurobehavioral disease is associated with seropositivity, causality is unproven. To better understand what this parasite does to human brains, we performed a comprehensive systems analysis of the infected brain: We identified susceptibility genes for congenital toxoplasmosis in our cohort of infected humans and found these genes are expressed in human brain. Transcriptomic and quantitative proteomic analyses of infected human, primary, neuronal stem and monocytic cells revealed effects on neurodevelopment and plasticity in neural, immune, and endocrine networks. These findings were supported by identification of protein and miRNA biomarkers in sera of ill children reflecting brain damage andT. gondiiinfection. These data were deconvoluted using three systems biology approaches: “Orbital-deconvolution” elucidated upstream, regulatory pathways interconnecting human susceptibility genes, biomarkers, proteomes, and transcriptomes. “Cluster-deconvolution” revealed visual protein-protein interaction clusters involved in processes affecting brain functions and circuitry, including lipid metabolism, leukocyte migration and olfaction. Finally, “disease-deconvolution” identified associations between the parasite-brain interactions and epilepsy, movement disorders, Alzheimer’s disease, and cancer. This “reconstruction-deconvolution” logic provides templates of progenitor cells’ potentiating effects, and components affecting human brain parasitism and diseases.

Globally, congenital toxoplasmosis remains a significant cause of morbidity and mortality, and outbreaks of infection with T. gondii represent a significant, emerging public health burden, especial...

The human malaria parasite Plasmodium falciparum relies on the acquisition of host purines for its survival within human erythrocytes. Purine salvage by the parasite requires specialized transporters at the parasite plasma membrane (PPM), but the exact mechanism of purine entry into the infected erythrocyte, and the primary purine source used by the parasite, remain unknown. Here, we report that transgenic parasites lacking the PPM transporter PfNT1 ( P. falciparum nucleoside transporter 1) are auxotrophic for hypoxanthine, inosine, and adenosine under physiological conditions and are viable only if these normally essential nutrients are provided at excess concentrations. Transport measurements across the PPM revealed a severe reduction in hypoxanthine uptake in the knockout, whereas adenosine and inosine transport were only partially affected. These data provide compelling evidence for a sequential pathway for exogenous purine conversion into hypoxanthine using host enzymes followed by PfNT1-mediated transport into the parasite. The phenotype of the conditionally lethal mutant establishes PfNT1 as a critical component of purine salvage in P. falciparum and validates PfNT1 as a potential therapeutic target.