The intracellular protozoan Toxoplasma gondii is a widespread opportunistic parasite of humans and animals. Normally, T. gondii establishes itself within brain and skeletal muscle tissues, persisting for the life of the host. Initiating and sustaining strong T-cell-mediated immunity is crucial in preventing the emergence of T. gondii as a serious pathogen. The parasite induces high levels of gamma interferon (IFN-γ) during initial infection as a result of early T-cell as well as natural killer (NK) cell activation. Induction of interleukin-12 by macrophages is a major mechanism driving early IFN-γ synthesis. The latter cytokine, in addition to promoting the differentiation of Th1 effectors, is important in macrophage activation and acquisition of microbicidal functions, such as nitric oxide release. During chronic infection, parasite-specific T lymphocytes release high levels of IFN-γ, which is required to prevent cyst reactivation. T-cell-mediated cytolytic activity against infected cells, while easily demonstrable, plays a secondary role to inflammatory cytokine production. While part of the clinical manifestations of toxoplasmosis results from direct tissue destruction by the parasite, inflammatory cytokine-mediated immunopathologic changes may also contribute to disease progression.

https://cmr.asm.org/content/cmr/11/4/569.full.pdf

Regulation and Function of T-Cell-Mediated Immunity during Toxoplasma gondii Infection

The roles of γδ T, NK and NKT cells in an early stage of protective immunity against infection with Leishmania major were investigated. Further, the contribution of these innate cells to the expression of 65 kDa heat shock protein (HSP65) in host macrophages was examined, since we found previously that this expression prevents apoptotic death of infected macrophages and is a crucial step in the acquisition of protective immunity against infection with various obligate intracellular protozoa including L. major. C57BL/6 and DBA/2 mice were found to be resistant against the infection on the basis of the parasite burden in their regional lymph nodes, and to strongly express HSP65 in their macrophages, whereas BALB/c mice were susceptible and barely expressed the HSP65. In those resistant mice, CD4 NKT cells prominently increased in their regional lymph node and were the main effector cells at least for an early stage of the protective immunity and for the HSP65 expression, whereas this subset did not increase in susceptible BALB/c mice. Further, neither γδ T nor NK cells in resistant mice contributed to those protective immune responses. The NKT cell subset bore CD3, CD4, TCR αβ, IL-2Rβ and NK1.1 but scarcely asialo-GM1. Moreover, this effector subset was confirmed to be Vα14 NKT cells by using Jα281 ‐/‐ mice.

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CD4+ Vα14 NKT cells play a crucial role in an early stage of protective immunity against infection with Leishmania major.

Immune compromise can modify the severity and manifestation of some parasitic infections. More widespread use of newer immnosuppressive therapies, the growing population of individuals with immunocompromised states as well as the prolonged survival of these patients have altered the pattern of parasitic infection. This review article discusses the burden and immunology of parasitic infections in patients who are immunocompromised secondary to congenital immunodeficiency, malnutrition, malignancy, and immunosuppressive medications. This review does not address the literature on parasitic infections in the setting of HIV-1 infection.

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The immunology of parasite infections in immunocompromised hosts

Immunity to Toxoplasma gondii

With the advent of the acquired immunodeficiency syndrome (AIDS) epidemic the importance of toxoplasmosis as an opportunistic infection has markedly increased. This parasite has long been recognized as an important cause of disease in other patients with deficiencies in T cell functions including those with Hodgkin’s and non-Hodgkin’s lymphoma, those with acute lymphocytic leukemia, and those patients undergoing bone marrow transplantation (Israelski and Remington 1992, 1993). The fact that life-threatening toxoplasmosis occurs in these patients, in contrast to immunologically normal individuals, indicates the importance of T cells in resistance to this infection. However, other aspects of the immune system are also involved in resistance or susceptibility to this disease. In this review we will present data from recent studies from our laboratory on the role of a major histocompatibility complex (MHC) class I gene in resistance to toxoplasmic encephalitis (TE) in murine models, the role of interleukin (IL)-6 and tumor necrosis factor (TNF)-α in the pathogenesis of TE, the response of human γδ T cells to T. gondii, and the role of cytokines in the regulation of T cell-independent resistance to the parasite.

Cells and Cytokines in Resistance to Toxoplasma gondii

Heat shock proteins (HSPs) are evolutionarily highly conserved polypeptides that appear to be produced by many cells to preserve cellular functions under a variety of conditions of stress, including infections. We report that a 65-kDa HSP is present in mouse peritoneal cells that have been infected with a low-virulence (Beverley) strain of Toxoplasma gondii, as determined by electroblot assay using a monoclonal antibody specific for microbial HSP65. This HSP is, however, not expressed when infection occurs with the high-virulence RH strain of T. gondii. Furthermore, HSP was demonstrable in mice that acquired resistance against infection with a lethal dose of bradyzoites of the Beverley strain or even of an inoculum of a highly virulent strain of T. gondii (RH). From these results, it can be suggested that HSPs play an important role in developing effective defenses that include effective immune responses against infection with Toxoplasma parasites in vivo.

Chai Jian-Guo

Papers

Induction of heat shock protein closely correlates with protection against Toxoplasma gondii infection.