To kill a tachyzoite: assault and battery.

Polymeric guanylate-binding proteins (GBPs) physically dismember the vacuole membrane formed by Toxoplasma gondii while nitric oxide (NO) poisons and inhibits parasite replication within interferon (IFN)-γ activated macrophages. Zhao et al. report a novel mechanism for synergy between these classical microbicidal and microbistatic effectors in cell-autonomous immunity to the intracellular parasites.

The intersection of host in vivo metabolism and immune responses to infection with kinetoplastid and apicomplexan parasites.

SUMMARYProtozoan parasite infection dramatically alters host metabolism, driven by immunological demand and parasite manipulation strategies. Immunometabolic checkpoints are often exploited by kinetoplastid and protozoan parasites to establish chronic infection, which can significantly impair host metabolic homeostasis. The recent growth of tools to analyze metabolism is expanding our understanding of these questions. Here, we review and contrast host metabolic alterations that occur in vivo during infection with Leishmania, trypanosomes, Toxoplasma, Plasmodium, and Cryptosporidium. Although genetically divergent, there are commonalities among these pathogens in terms of metabolic needs, induction of the type I immune responses required for clearance, and the potential for sustained host metabolic dysbiosis. Comparing these pathogens provides an opportunity to explore how transmission strategy, nutritional demand, and host cell and tissue tropism drive similarities and unique aspects in host response and infection outcome and to design new strategies to treat disease.

The Impact of Helminth Coinfection on Innate and Adaptive Immune Resistance and Disease Tolerance during Toxoplasmosis.

More than 2 billion people worldwide are infected with helminths. Thus, it is possible for individuals to experience concomitant infection with helminth and intracellular microbes. Although the helminth-induced type 2 response can suppress type 1 proinflammatory responses required for the immunity against intracellular pathogens in the context of a coinfection, conflicting evidence suggest that helminth infection can enhance antimicrobial immunity. Using a coinfection model with the intestinal helminth Heligmosomoides polygyrus followed by infection with Toxoplasma gondii in Mus Musculus, we showed that the complex and dynamic effect of helminth infection is highly suppressive during the innate phase (days 0-3) of T. gondii infection and less stringent during the acute phase (d10). Helminth coinfection had a strong suppressive effect on the neutrophil, monocytic, and early IFN-γ/IL-12 responses. The IFN-γ response was later restored by compensatory production from T cells despite decreased effector differentiation of T. gondii-specific CD8 T cells. In accordance with the attenuated IFN-γ response, parasite loads were elevated during the acute phase (d10) of T. gondii infection but were transiently controlled by the compensatory T cell response. Unexpectedly, 40% of helminth-coinfected mice exhibited a sustained weight loss phenotype during the postacute phase (d14-18) that was not associated with T. gondii outgrowth, indicating that coinfection led to decreased disease tolerance during T. gondii infection. Our work uncovers the dynamic nature of the helminth immunomodulatory effects on concomitant infections or immune responses and unveils a loss of disease tolerance phenotype triggered by coinfection with intestinal helminth.

A Role for Basigin in Toxoplasma gondii Infection.

The role of specific host cell surface receptors during Toxoplasma gondii invasion of host cells is poorly defined. Here, we interrogated the role of the well-known malarial invasion receptor, basigin, in T. gondii infection of astrocytes. We found that primary astrocytes express two members of the BASIGIN (BSG) immunoglobulin family, basigin and embigin, but did not express neuroplastin. Antibody blockade of either basigin or embigin caused a significant reduction of parasite infectivity in astrocytes. The specific role of basigin during T. gondii invasion was further examined using a mouse astrocytic cell line (C8-D30), which exclusively expresses basigin. CRISPR-mediated deletion of basigin in C8-D30 cells resulted in decreased T. gondii infectivity. T. gondii replication and invasion efficiency were not altered by basigin deficiency, but parasite attachment to astrocytes was markedly reduced. We also conducted a proteomic screen to identify T. gondii proteins that interact with basigin. Toxoplasma-encoded cyclophilins, the protein 14-3-3, and protein disulfide isomerase (TgPDI) were among the putative basigin-ligands identified. Recombinant TgPDI produced in E. coli bound to basigin and pretreatment of tachyzoites with a PDI inhibitor decreased parasite attachment to host cells. Finally, mutagenesis of the active site cysteines of TgPDI abolished enzyme binding to basigin. Thus, basigin and its related immunoglobulin family members may represent host receptors that mediate attachment of T. gondii to diverse cell types.

Microglia and astrocyte responses to neuropathogenic protozoan parasites.

Cerebral toxoplasmosis and cerebral malaria are two important neurological diseases caused by protozoan parasites. In this review, we discuss recent findings regarding the innate immune responses of microglia and astrocytes to Toxoplasma and Plasmodium infection. In both infections, these tissue-resident glial cells perform a sentinel function mediated by alarmin crosstalk that licenses adaptive type 1 immunity in the central nervous system. Divergent protective or pathogenic effects of type 1 activation of these astrocytes and microglia are revealed depending on the inherent lytic potential of the protozoan parasite.

Developmental IL-6 Exposure Favors Production of PDGF-Responsive Multipotential Progenitors at the Expense of Neural Stem Cells and Other Progenitors.

Interleukin-6 (IL-6) is increased in maternal serum and amniotic fluid of children subsequently diagnosed with autism spectrum disorders. However, it is not clear how increased IL-6 alters brain development. Here, we show that IL-6 increases the prevalence of a specific platelet-derived growth factor (PDGF)-responsive multipotent progenitor, with opposite effects on neural stem cells and on subsets of bipotential glial progenitors. Acutely, increasing circulating IL-6 levels 2-fold above baseline in neonatal mice specifically stimulated the proliferation of a PDGF-responsive multipotential progenitor accompanied by increased phosphorylated STAT3, increased Fbxo15 expression, and decreased Dnmt1 and Tlx expression. Fate mapping studies using a Nestin-CreERT2 driver revealed decreased astrogliogenesis in the frontal cortex. IL-6-treated mice were hyposmic; however, olfactory bulb neuronogenesis was unaffected. Altogether, these studies provide important insights into how inflammation alters neural stem cells and progenitors and provide new insights into the molecular and cellular underpinnings of neurodevelopmental disorders associated with maternal infections.