Infection with Toxoplasma gondii triggers coagulation at the blood-brain barrier and a reduction in cerebral blood flow.

Background: Immunothrombosis is the process by which the coagulation cascade interacts with the innate immune system to control infection. However, the formation of clots within the brain vasculature can be detrimental to the host. Recent work has demonstrated that Toxoplasma gondii infects and lyses central nervous system (CNS) endothelial cells that form the blood-brain barrier (BBB).

Toxoplasma gondii Infection of Alzheimer's Disease Mice Reduces Brain Amyloid Density Globally and Regionally.

Background: Toxoplasma gondii infection of Alzheimer's disease model mice decreases amyloid β plaques. We aimed to determine if there is a brain regional difference in amyloid β reduction in the brains of T. gondii-infected compared to control mice.

Role for Caspase-8 in the Release of IL-1β and Active Caspase-1 from Viable Human Monocytes during Toxoplasma gondii Infection.

Monocytes are actively recruited to sites of infection and produce the potent proinflammatory cytokine IL-1β. We previously showed that IL-1β release during Toxoplasma gondii infection of primary human monocytes requires the NLRP3 inflammasome and caspase-1 but is independent of gasdermin D and pyroptosis. To investigate mechanisms of IL-1β release, we generated caspase-1, -4, -5, or -8 knockout (KO) THP-1 monocytic cells.

Deficiency in astrocyte CCL2 production reduces neuroimmune control of Toxoplasma gondii infection.

Toxoplasma gondii is an obligate intracellular parasite that infects one-third of the world's human population and establishes infection in the brain. Cerebral immune cell infiltration is critical for controlling the parasite, but little is known about the molecular cues guiding immune cells to the brain during infection. Activated astrocytes produce CCL2, a chemokine that mediates inflammatory monocyte recruitment to tissues by binding to the CCR2 receptor.

A transcriptional network required for bradyzoite development in Toxoplasma gondii is dispensable for recrudescent disease.

Identification of regulators of Toxoplasma gondii bradyzoite development and cyst formation is the most direct way to address the importance of parasite development in long-term persistence and reactivation of this parasite. Here we show that a T. gondii gene (named Regulator of Cystogenesis 1; ROCY1) is sufficient for T.

Monocytes as primary defenders against Toxoplasma gondii infection.

Monocytes are recruited from the bone marrow to sites of infection where they release cytokines and chemokines, function in antimicrobial immunity, and differentiate into macrophages and dendritic cells to control infection. Although many studies have focused on monocyte-derived macrophages and dendritic cells, recent work has examined the unique roles of monocytes during infection to promote immune defense. We focus on the effector functions of monocytes during infection with the parasite Toxoplasma gondii, and discuss the signals that mobilize monocytes to sites of infection, their production of inflammatory cytokines and antimicrobial mediators, their ability to shape the adaptive immune response, and their immunoregulatory functions.

Capers with caspases: Toxoplasma gondii tales of inflammation and survival.

Intracellular pathogens strike a delicate balance between maintaining their survival within infected cells, while also activating host defense mechanisms. Toxoplasma gondii is a protozoan parasite that initiates a variety of host signaling pathways as it invades host cells and establishes residence in a parasitophorous vacuole. Recent work has highlighted the interplay between T.

Toxoplasma gondii Dissemination in the Brain Is Facilitated by Infiltrating Peripheral Immune Cells.

Despite recent advances in our understanding of pathogenic access to the central nervous system (CNS), the mechanisms by which intracellular pathogens disseminate within the dense cellular network of neural tissue remain poorly understood. To address this issue, longitudinal analysis of Toxoplasma gondii dissemination in the brain was conducted using 2-photon imaging through a cranial window in living mice that transgenically express enhanced green fluorescent protein (eGFP)-claudin-5. Extracellular T.

Nanos gigantium humeris insidentes: old papers informing new research into Toxoplasma gondii.

Since Nicolle, Manceaux and Splendore first described Toxoplasma gondii as a parasite of rodents and rabbits in the early 20th century, a diverse and vigorous research community has been built around studying this fascinating intracellular parasite. In addition to its importance as a pathogen of humans, livestock and wildlife, modern researchers are attracted to T. gondii as a facile experimental system to study many aspects of evolutionary biology, cellular biology, host-microbe interactions, and host immunity.

Toxoplasma gondii Extends the Life Span of Infected Human Neutrophils by Inducing Cytosolic PCNA and Blocking Activation of Apoptotic Caspases.

is an intracellular protozoan parasite that has the remarkable ability to infect and replicate in neutrophils, immune cells with an arsenal of antimicrobial effector mechanisms. We report that infection extends the life span of primary human peripheral blood neutrophils by delaying spontaneous apoptosis, serum starvation-induced apoptosis, and tumor necrosis alpha (TNF-α)-mediated apoptosis. blockade of apoptosis was associated with an inhibition of processing and activation of the apoptotic caspases caspase-8 and -3, decreased phosphatidylserine exposure on the plasma membrane, and reduced cell death.

Transcranial chronic optical access to longitudinally measure cerebral blood flow.

Background: The regulation of cerebral blood flow is critical for normal brain functioning, and many physiological and pathological conditions can have long-term impacts on cerebral blood flow. However, minimally invasive tools to study chronic changes in animal models are limited.

New Method: We developed a minimally invasive surgical technique (cyanoacrylate skull, CAS) allowing us to image cerebral blood flow longitudinally through the intact mouse skull using laser speckle imaging.

Toxoplasma gondii Dysregulates Barrier Function and Mechanotransduction Signaling in Human Endothelial Cells.

can infect and replicate in vascular endothelial cells prior to entering host tissues. However, little is known about the molecular interactions at the parasite-endothelial cell interface. We demonstrate that infection of primary human umbilical vein endothelial cells (HUVEC) altered cell morphology and dysregulated barrier function, increasing permeability to low-molecular-weight polymers.

Assessing Rhoptry Secretion in T. gondii.

Rhoptries are key secretory organelles for Toxoplasma gondii invasion. Here, we describe how to assess the ability of T. gondii tachyzoites to secrete their rhoptry contents in vitro.

Imaging the dynamic recruitment of monocytes to the blood-brain barrier and specific brain regions during infection.

Brain infection by the parasite in mice is thought to generate vulnerability to predation by mechanisms that remain elusive. Monocytes play a key role in host defense and inflammation and are critical for controlling However, the dynamic and regional relationship between brain-infiltrating monocytes and parasites is unknown. We report the mobilization of inflammatory (CCR2Ly6C) and patrolling (CX3CR1Ly6C) monocytes into the blood and brain during infection of C57BL/6J and CCR2CX3CR1 mice.

Toxoplasma gondii activates a Syk-CARD9-NF-κB signaling axis and gasdermin D-independent release of IL-1β during infection of primary human monocytes.

IL-1β is a potent pro-inflammatory cytokine that promotes immunity and host defense, and its dysregulation is associated with immune pathology. Toxoplasma gondii infection of myeloid cells triggers the production and release of IL-1β; however, the mechanisms regulating this pathway, particularly in human immune cells, are incompletely understood. We have identified a novel pathway of T.

Mechanisms of Human Innate Immune Evasion by .

is an intracellular protozoan parasite of global importance that can remarkably infect, survive, and replicate in nearly all mammalian cells. Notably, 110 years after its discovery, Toxoplasmosis is still a neglected parasitic infection. Although most human infections with are mild or asymptomatic, infection can result in life-threatening disease in immunocompromised individuals and in the developing fetus due to congenital infection, underscoring the role of the host immune system in controlling the parasite.

CD11a expression distinguishes infiltrating myeloid cells from plaque-associated microglia in Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of age-related neurodegeneration and is characterized neuropathologically by the accumulation of insoluble beta-amyloid (Aβ) peptides. In AD brains, plaque-associated myeloid (PAM) cells cluster around Aβ plaques but fail to effectively clear Aβ by phagocytosis. PAM cells were originally thought to be brain-resident microglia.

Correction to "Immunomodulation of the NLRP3 Inflammasome through Structure-Based Activator Design and Functional Regulation via Lysosomal Rupture".

[This corrects the article DOI: 10.1021/acscentsci.8b00218.

A Member of the Ferlin Calcium Sensor Family Is Essential for Toxoplasma gondii Rhoptry Secretion.

Invasion of host cells by apicomplexan parasites such as is critical for their infectivity and pathogenesis. In , secretion of essential egress, motility, and invasion-related proteins from microneme organelles is regulated by oscillations of intracellular Ca Later stages of invasion are considered Ca independent, including the secretion of proteins required for host cell entry and remodeling from the parasite's rhoptries. We identified a family of three proteins with homology to the ferlin family of double C2 domain-containing Ca sensors.

Immunomodulation of the NLRP3 Inflammasome through Structure-Based Activator Design and Functional Regulation via Lysosomal Rupture.

The NLRP3 inflammasome plays a role in the inflammatory response to vaccines, in antimicrobial host defense, and in autoimmune diseases. However, its mechanism of action remains incompletely understood. NLRP3 has been shown to be activated by diverse stimuli including microbial toxins, ATP, particulate matter, etc.

Evasion of Human Neutrophil-Mediated Host Defense during Infection.

Neutrophils are a major player in host immunity to infection; however, the mechanisms by which human neutrophils respond to the intracellular protozoan parasite are still poorly understood. In the current study, we found that, whereas primary human monocytes produced interleukin-1beta (IL-1β) in response to infection, human neutrophils from the same blood donors did not. Moreover, inhibited lipopolysaccharide (LPS)-induced IL-1β synthesis in human peripheral blood neutrophils.

disrupts β1 integrin signaling and focal adhesion formation during monocyte hypermotility.

The motility of blood monocytes is orchestrated by the activity of cell-surface integrins, which translate extracellular signals into cytoskeletal changes to mediate adhesion and migration. is an intracellular parasite that infects migratory cells and enhances their motility, but the mechanisms underlying -induced hypermotility are incompletely understood. We investigated the molecular basis for the hypermotility of primary human peripheral blood monocytes and THP-1 cells infected with Compared with uninfected monocytes, infection of monocytes reduced cell spreading and the number of activated β1 integrin clusters in contact with fibronectin during settling, an effect not observed in monocytes treated with lipopolysaccharide (LPS) or Furthermore, infection disrupted the phosphorylation of focal adhesion kinase (FAK) at tyrosine 397 (Tyr-397) and Tyr-925 and of the related protein proline-rich tyrosine kinase (Pyk2) at Tyr-402.

NLRP3 and Potassium Efflux Drive Rapid IL-1β Release from Primary Human Monocytes during Infection.

IL-1β is produced by myeloid cells and acts as a critical mediator of host defense during infection and injury. We found that the intracellular protozoan parasite induced an early IL-1β response (within 4 h) in primary human peripheral blood monocytes isolated from healthy donors. This process involved upregulation of , (IL-1R antagonist), and transcripts, de novo protein synthesis, and the release of pro- and mature IL-1β from infected primary monocytes.

Endothelial cells are a replicative niche for entry of Toxoplasma gondii to the central nervous system.

An important function of the blood-brain barrier is to exclude pathogens from the central nervous system, but some microorganisms benefit from the ability to enter this site. It has been proposed that Toxoplasma gondii can cross biological barriers as a motile extracellular form that uses transcellular or paracellular migration, or by infecting a host cell that then crosses the blood-brain barrier. Unexpectedly, analysis of acutely infected mice revealed significant numbers of free parasites in the blood and the presence of infected endothelial cells in the brain vasculature.