Host- Toxoplasma gondii Coadaptation Leads to Fine Tuning of the Immune Response

Abstract

Toxoplasma gondii has successfully developed strategies to evade host's immune response and reach immune privileged sites, which remains in a controlled environment inside quiescent tissue cysts. In this review, we will approach several known mechanisms used by the parasite to modulate mainly the murine immune system at its favor. In what follows, we review recent findings revealing interference of host's cell autonomous immunity and cell signaling, gene expression, apoptosis, and production of microbicide molecules such as nitric oxide and oxygen reactive species during parasite infection. Modulation of host's metalloproteinases of extracellular matrix is also discussed. These immune evasion strategies are determinant to parasite dissemination throughout the host taking advantage of cells from the immune system to reach brain and retina, crossing crucial hosts' barriers.

Keywords: T cells; Toxoplasma gondii; cell signalling; immunity; immunomodulation.

Figure 1

Mechanisms used by Toxoplasma gondii, type I strain, to modulate mainly immune system at its favor. (A) Interfering with cell-autonomous immunity. In infection with virulent strain (e.g., type I), the polymorphic effector proteins like ROP5, ROP17, and ROP18 cooperate to phosphorylate and inactivate mouse IRG proteins to preserve PVM integrity. In human cells (endothelial, retinal pigment epithelial, and microglia), T. gondii activates EGFR-Akt signaling to prevent targeting of the parasite by LC3 structures and pathogen killing dependent on autophagy proteins and lysosomal protease activity. (B) Cell signaling interference. The Toxoplasma rhoptry 16 kinase (ROP16), ROP18, and 38 can mediate the induction of arginase-1, suppress toll-like receptors (TLRs), IL-12, and nuclear factor-kappa B (NF-κB) through phosphorylation of signal transducer and activator of transcription (STAT) 3 and 6. T. gondii also interferes with STAT1 signaling, resulting in blockage of interferon regulatory factor 1 (Irf1), p65 guanylate-binding proteins (GBPs), inducible nitric oxide synthase (iNOS/Nos2), indoleamine 2,3-dioxygenase 1 (IDO1) and major histocompatibility complex (MHC). Furthermore, the infection upregulation SOCS1, 2 and 3. Together, T. gondii inhibiting pro-inflammatory response in different ways. (C) Silencing microbicide molecules. T. gondii [phosphatidylserine positive (PS+)] infection of murine blood monocyte-derived and peritoneal macrophages activated in vitro with IFN-γ and lipopolysaccharide (LPS) lead to a substantial decrease in NO production. Decreased mechanisms include phosphorylation of STAT6 by ROP16 resulting in arginine degradation and induction of TGFβ1 through Smad 2 and 3 leading to destruction of iNOS, actin filament (F-actin) depolymerization, and lack of NF-κB in the nucleus. (D) Maintaining the host cell alive. T. gondii has several strategies for inhibiting the initiation of the apoptotic cascade triggered by mitochondrial pathway or death receptor pathway in infected cells. The effector proteins like ROP16, ROP18, and ROP38 phosphorylate STAT3 and STAT6 and promotes mechanisms that include blocking of mitochondrial cytochrome c release, alterations of the balance between pro- and anti-apoptotic Bcl-2 proteins, degradation of caspase 8, blocking Fas/CD95-mediated apoptosis, and inactivation of effector caspases (-3, -6, -7) in infected cells.

Figure 2

Using cells as Trojan horses. Host extracellular matrix metalloproteases (MMPs) are involved in infected macrophage dissemination. In vitro infection of murine macrophages induced an increase in membrane type-1 matrix metalloproteinase (MT1-MMP) and disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), while decreased levels of CD44 are observed at cell surface. On the other hand, augmented active MMP-9, MMP-2, and a multiprotein complex containing MMP-9/TIMP1/urokinase-type PA receptor (uPAR) are present at cell supernatant. This mechanism resembling metastasis allows Toxoplasma gondii to disseminate throughout the host, reaching immune-privileged sites, where it remains in low proliferative state, with little damage to the host.