Macrophages are effector cells of the innate immune system that phagocytose bacteria and secrete both pro-inflammatory and antimicrobial mediators In addition, macrophages play an important role in eliminating diseased and damaged cells through their programmed cell death Generally, macrophages ingest and degrade dead cells, debris, tumor cells, and foreign materials They promote homeostasis by responding to internal and external changes within the body, not only as phagocytes, but also through trophic, regulatory, and repair functions Recent studies demonstrated that macrophages differentiate from hematopoietic stem cell-derived monocytes and embryonic yolk sac macrophages The latter mainly give rise to tissue macrophages Macrophages exist in all vertebrate tissues and have dual functions in host protection and tissue injury, which are maintained at a fine balance Tissue macrophages have heterogeneous phenotypes in different tissue environments In this review, we focused on the phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis for a better understanding of the role of tissue macrophages in several pathological conditions

https://www.mdpi.com/1422-0067/19/1/92/pdf

The Phagocytic Function of Macrophage-Enforcing Innate Immunity and Tissue Homeostasis

Reactive oxygen species (ROS) are deadly weapons used by phagocytes and other cell types, such as lung epithelial cells, against pathogens. ROS can kill pathogens directly by causing oxidative damage to biocompounds or indirectly by stimulating pathogen elimination by various nonoxidative mechanisms, including pattern recognition receptors signaling, autophagy, neutrophil extracellular trap formation, and T-lymphocyte responses. Thus, one should expect that the inhibition of ROS production promote infection. Increasing evidences support that in certain particular infections, antioxidants decrease and prooxidants increase pathogen burden. In this study, we review the classic infections that are controlled by ROS and the cases in which ROS appear as promoters of infection, challenging the paradigm. We discuss the possible mechanisms by which ROS could promote particular infections. These mechanisms are still not completely clear but include the metabolic effects of ROS on pathogen physiology, ROS-i...

Are reactive oxygen species always detrimental to pathogens

Homoacetogenesis during hydrogen production by mixed cultures dark fermentation: Unresolved challenge

Toxoplasma gondii is a protozoan parasite of global importance In the laboratory setting, T gondii is frequently used as a model pathogen to study mechanisms of T helper 1 (TH1) cell-mediated immunity to intracellular infections However, recent discoveries have shown that innate type 1 immune responses that involve interferon-γ (IFNγ)-producing natural killer (NK) cells and neutrophils, rather than IFNγ-producing T cells, predetermine host resistance to T gondii This Review summarizes the Toll-like receptor (TLR)-dependent mechanisms that are responsible for parasite recognition and for the induction of IFNγ production by NK cells, as well as the emerging data about the TLR-independent mechanisms that lead to the IFNγ-mediated elimination of T gondii

Innate immunity to Toxoplasma gondii infection

Leukocyte adhesion through L-selectin to peripheral node addressin (PNAd, also known as MECA-79 antigen), an L-selectin ligand expressed on high endothelial venules, has been shown to require a minimum level of fluid shear stress to sustain rolling interactions (Finger, E.B., K.D. Puri, R. Alon, M.B. Lawrence, V.H. von Andrian, and T.A. Springer. 1996. Nature (Lond.). 379:266–269). Here, we show that fluid shear above a threshold of 0.5 dyn/cm2 wall shear stress significantly enhances HL-60 myelocyte rolling on P- and E-selectin at site densities of 200/μm2 and below. In addition, gravitational force is sufficient to detach HL60 cells from P- and E-selectin substrates in the absence, but not in the presence, of flow. It appears that fluid shear–induced torque is critical for the maintenance of leukocyte rolling. K562 cells transfected with P-selectin glycoprotein ligand-1, a ligand for P-selectin, showed a similar reduction in rolling on P-selectin as the wall shear stress was lowered below 0.5 dyn/cm2. Similarly, 300.19 cells transfected with L-selectin failed to roll on PNAd below this level of wall shear stress, indicating that the requirement for minimum levels of shear force is not cell type specific. Rolling of leukocytes mediated by the selectins could be reinitiated within seconds by increasing the level of wall shear stress, suggesting that fluid shear did not modulate receptor avidity. Intravital microscopy of cremaster muscle venules indicated that the leukocyte rolling flux fraction was reduced at blood centerline velocities less than 1 mm/s in a model in which rolling is mediated by L- and P-selectin. Similar observations were made in L-selectin–deficient mice in which leukocyte rolling is entirely P-selectin dependent. Leukocyte adhesion through all three selectins appears to be significantly enhanced by a threshold level of fluid shear stress.

Threshold levels of fluid shear promote leukocyte adhesion through selectins (CD62L,P,E)

https://www.cell.com/trends/parasitology/pdf/S1471-4922(12)00085-2.pdf

Receptor-mediated phagocytosis of Leishmania: implications for intracellular survival.

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. The use of diverse transgenic parasites combined with reporter mice and intravital imaging demonstrated that replication in and lysis of endothelial cells precedes invasion of the central nervous system, and highlight a novel mechanism for parasite entry to the central nervous system. T. gondii crosses biological barriers using transcellular migration or within an infected migrating cell. Here, infection and lysis of endothelial cells in the brain vasculature is identified as a new route of access to the central nervous system.

/pdf/endothelial-cells-are-a-replicative-niche-for-entry-of-3nt9pagp08.pdf

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

Toxoplasma gondii is a highly successful global pathogen that is remarkable in its ability to infect nearly any nucleated cell in any warm-blooded animal. Infection with T. gondii typically occurs through the ingestion of contaminated food or water, but the parasite then breaches the intestinal epithelial barrier and spreads from the lamina propria to a large variety of other organs in the body. A key feature of T. gondii pathogenesis is the parasite's ability to cross formidable biological barriers in the infected host and enter tissues such as the brain, eye and placenta. The dissemination of T. gondii into these organs underlies the severe disease that accompanies human toxoplasmosis. In this review, we will focus on seminal studies as well as exciting recent findings that have shaped our current understanding of the cellular and molecular mechanisms by which T. gondii journeys throughout the host and enters organs to cause disease.

Toxoplasma gondii dissemination: a parasite's journey through the infected host.

Interleukin-1 (IL-1) functions as a key regulator of inflammation and innate immunity. The protozoan parasite Toxoplasma gondii actively infects human blood monocytes and induces the production of IL-1; however, the host and parasite factors that mediate IL-1 production during T. gondii infection are poorly understood. We report that T. gondii induces IL-1 transcript, processing/cleavage, and release from infected primary human monocytes and THP-1 cells. Treating monocytes with the caspase-1 inhibitor Ac-YVAD-CMK reduced IL-1 release, suggesting a role for the inflammasome in T. gondii-induced IL-1production. This was confirmed by performing short hairpin RNA (shRNA) knockdown of caspase-1 and of the inflam- masome adaptor protein ASC. IL-1induction required active parasite invasion of monocytes, since heat-killed or mycalolide B-treated parasites did not induce IL-1. Among the type I, II, and III strains of T. gondii, the type II strain induced substan- tially more IL-1mRNA and protein release than did the type I and III strains. Since IL-1transcript is known to be induced downstream of NF-B signaling, we investigated a role for the GRA15 protein, which induces sustained NF-B signaling in a parasite strain-specific manner. By infecting human monocytes with a GRA15-knockout type II strain and a type I strain stably expressing type II GRA15, we determined that GRA15 is responsible for IL-1 induction during T. gondii infection of human monocytes. This research defines a pathway driving human innate immunity by describing a role for the classical inflammasome components caspase-1 and ASC and the parasite GRA15 protein in T. gondii-induced IL-1 production. IMPORTANCE Monocytes are immune cells that protect against infection by increasing inflammation and antimicrobial activities in the body. Upon infection with the parasitic pathogen Toxoplasma gondii, human monocytes release interleukin-1 (IL-1), a "master regulator" of inflammation, which amplifies immune responses. Although inflammatory responses are critical for host defense against infection, excessive inflammation can result in tissue damage and pathology. This delicate balance underscores the importance of understanding the mechanisms that regulate IL-1during infection. We have investigated the molecular pathway by which T. gondii induces the synthesis and release of IL-1 in human monocytes. We found that specific proteins in the parasite and the host cell coordinate to induce IL-1production. This research is significant because it contributes to a greater understanding of human innate immunity to infection and IL-1regulation, thereby enhancing our potential to modu- late inflammation in the body.

/pdf/human-innate-immunity-to-toxoplasma-gondii-is-mediated-by-1hfos13g52.pdf

Norikiyo Ueno

Papers

Receptor-mediated phagocytosis of Leishmania: implications for intracellular survival.

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

Toxoplasma gondii dissemination: a parasite's journey through the infected host.

Human Innate Immunity to Toxoplasma gondii Is Mediated by Host Caspase-1 and ASC and Parasite GRA15

Characterization of acid-tolerant H2/CO2-utilizing methanogenic enrichment cultures from an acidic peat bog in New York State