Both Lymphotoxin-α and TNF Are Crucial for Control ofToxoplasma gondiiin the Central Nervous System

Abstract

Immunity to Toxoplasma gondii critically depends on TNFR type I-mediated immune reactions, but the precise role of the individual ligands of TNFR1, TNF and lymphotoxin-α (LTα), is still unknown. Upon oral infection with T. gondii, TNF−/−, LTα−/−, and TNF/LTα−/− mice failed to control intracerebral T. gondii and succumbed to an acute necrotizing Toxoplasma encephalitis, whereas wild-type (WT) mice survived. Intracerebral inducible NO synthase expression and–early after infection–splenic NO levels were reduced. Additionally, peritoneal macrophages produced reduced levels of NO upon infection with T. gondii and had significantly reduced toxoplasmastatic activity in TNF−/−, LTα−/−, and TNF/LTα−/− mice as compared with WT animals. Frequencies of parasite-specific IFN-γ-producing T cells, intracerebral and splenic IFN-γ production, and T. gondii-specific IgM and IgG titers in LTα−/− and TNF/LTα−/− mice were reduced only early after infection. In contrast, intracerebral IL-10 and IL-12p40 mRNA expression and splenic IL-2, IL-4, and IL-12 production were identical in all genotypes. In addition, TNF−/−, LTα−/−, and TNF/LTα−/−, but not WT, mice succumbed to infection with the highly attenuated ts-4 strain of T. gondii or to a subsequent challenge infection with virulent RH toxoplasms, although they had identical frequencies of IFN-γ-producing T cells as compared with WT mice. Generation and infection of bone marrow reconstitution chimeras demonstrated an exclusive role of hematogeneously produced TNF and LTα for survival of toxoplasmosis. These findings demonstrate the crucial role of both LTα and TNF for control of intracerebral toxoplasms.

Ly6Chigh Monocytes Control Cerebral Toxoplasmosis

“…In the murine models of chronic infection, the characteristics of T cell subsets (24,(63)(64)(65), specific mononuclear cells, for example, resident microglia and APCs, have been extensively studied. In contrast, the role of the newly described myeloid cell subsets is controversial and thus requires further investigation (19)(20)(21). Microglia cells have been shown to eliminate parasites in an IFN-g-dependent manner, in addition to their efficient phagocytic capacity and cytokine production (19,20,66,67).…”

“…In contrast, the role of the newly described myeloid cell subsets is controversial and thus requires further investigation (19)(20)(21). Microglia cells have been shown to eliminate parasites in an IFN-g-dependent manner, in addition to their efficient phagocytic capacity and cytokine production (19,20,66,67). Some early studies suggest that brain DCs differentiate from local resident cells, whereas others have proposed a peripheral hematopoietic cell origin upon cerebral toxoplasmosis (27,39,68).…”

“…Upon immunosuppression, the latent infection can reactivate and develop into life-threatening encephalomyelitis (1,6,7,(16)(17)(18). Within the inflamed brain, resident immune cells, such as microglia and astrocytes, become activated, displaying significant antiparasitic properties (19)(20)(21). Despite limited access, the CNS is inundated by immune cells from the periphery during the chronic stage of T. gondii infection.…”

Astrocyte gp130 Expression Is Critical for the Control of Toxoplasma Encephalitis

“…T. gondii is critically dependent on the local IFN-␥-production of CD4 and CD8 T cells and, to a lesser extent, on B cells (2)(3)(4). IFN-␥ is important for the induction of other protective cytokines, including TNF, and induces protective effector mechanisms in infected cells (5,6). In vitro studies revealed that IFN-␥-activated astrocytes control T. gondii via the small inducibly expressed GTPase IGTP (7); IGTP Ϫ/Ϫ mice are unable to control T. gondii and succumb to a necrotizing TE (8).…”

ProtectiveToxoplasma gondii-Specific T-Cell Responses Require T-Cell-Specific Expression of Protein Kinase C-Theta

“…Since IFN-␥-producing CD4 and CD8 T cells are absolutely required for the control of T. gondii (10), the diminished T-cell response of PKC-Ϫ/Ϫ mice consequently resulted in a lethal necrotizing TE. The protective function of IFN-␥ is partially mediated by the induction of other protective cytokines, including TNF, as well as the induction of antiparasitic effector molecules, including iNOS and IGTP (11,38,39,41,49). This explains (i) why the strong reduction of intracerebral and splenic IFN-␥ mRNA levels was accompanied by the massive reduction of TNF, iNOS, and IGTP levels in infected PKC-Ϫ/Ϫ mice compared to the levels in WT mice and (ii) why PKC-Ϫ/Ϫ mice were unable to restrict T. gondii proliferation in the brain.…”