Mediation of immunity to intracellular infection (Toxoplasma and Besnoitia) within somatic cells

Chinchílla, Mísael; Frenkel, J. K.

doi:10.1128/iai.19.3.999-1012.1978

Cited by 57 publications

(38 citation statements)

References 43 publications

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“…Nevertheless, it remains unclear whether or not the direct activation of nonhemopoietic cells by IFN-␥ and TNF-␣ is sufficient to completely restrict parasite growth within these cells. Although in vitro experiments have clearly doc- umented that nonhemopoietic cells can do so in the absence of macrophages (11), our in vivo results do not exclude potential synergism between trans-acting diffusible metabolites such as NO derived from hemopoietic cells and the cis-acting IFN-␥/TNF-␣-dependent mechanism in limiting tachyzoite replication within nonhemopoietic cells.…”

Section: Ifn-␥r Expression On Both Hemopoietic and Somatic Cells Is Acontrasting

confidence: 67%

Effector Cells of Both Nonhemopoietic and Hemopoietic Origin Are Required for Interferon (IFN)-γ– and Tumor Necrosis Factor (TNF)-α–dependent Host Resistance to the Intracellular Pathogen, Toxoplasma gondii

Yap

Sher

1999

The Journal of Experimental Medicine

221

196

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Although interferon (IFN)-γ–activated, mononuclear phagocytes are considered to be the major effectors of resistance to intracellular pathogens, it is unclear how they control the growth of microorganisms that reside in nonhemopoietic cells. Pathogens within such cells may be killed by metabolites secreted by activated macrophages or, alternatively, directly controlled by cytokine-induced microbicidal mechanisms triggered within infected nonphagocytic cells. To distinguish between these two basic mechanisms of cell-mediated immunity, reciprocal bone marrow chimeras were constructed between wild-type and IFN-γ receptor–deficient mice and their survival assessed following infection with Toxoplasma gondii, a protozoan parasite that invades both hemopoietic and nonhemopoietic cell lineages. Resistance to acute and persistent infection was displayed only by animals in which IFN-γ receptors were expressed in both cellular compartments. Parallel chimera experiments performed with tumor necrosis factor (TNF) receptor–deficient mice also indicated a codependence on hemopoietic and nonhemopoietic lineages for optimal control of the parasite. In contrast, in mice chimeric for inducible nitric oxide synthase (iNOS), an enzyme associated with IFN-γ–induced macrophage microbicidal activity, expression by cells of hemopoietic origin was sufficient for host resistance. Together, these findings suggest that, in concert with bone marrow–derived effectors, nonhemopoietic cells can directly mediate, in the absence of endogenous iNOS, IFN-γ– and TNF-α–dependent host resistance to intracellular infection.

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Section: Ifn-␥r Expression On Both Hemopoietic and Somatic Cells Is Acontrasting

confidence: 67%

Effector Cells of Both Nonhemopoietic and Hemopoietic Origin Are Required for Interferon (IFN)-γ– and Tumor Necrosis Factor (TNF)-α–dependent Host Resistance to the Intracellular Pathogen, Toxoplasma gondii

Yap

Sher

1999

The Journal of Experimental Medicine

221

196

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“…However, their monolayers probably contained a mixture of cell types, for they included tissue from ground lung, and the proportion of cells that were macrophages was not defined. The presence of nonphagocytic cells in a macrophage monolayer could alter the results, since most nonphagocytes permit intracellular replication of intraceilular Toxoplasma (52). In our experiments, >95% of the cells in the monolayers were macrophages.…”

Section: T Gondii Rarely Causes Serious Illness In Healthy Adult Hummentioning

confidence: 67%

Oxygen-independent killing by alveolar macrophages.

Catterall¹,

Sharma²,

Remington³

1986

The Journal of Experimental Medicine

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Alveolar macrophages play a key role in defense of the host against pulmonary infection (1-6). Their clinical importance is emphasized by the high incidence of life-threatening pneumonia (7,8) in patients with abnormal macrophage function (6) or impaired ceU-mediated immunity (6-9). However, the mechanisms by which alveolar macrophages kill microorganisms are poorly understood.We recently examined the mechanism by which human alveolar macrophages kill the intracellular parasite, Toxoplasma gondii (10). We chose this organism because it causes pneumonia in immunosuppressed patients (11-14) but not in healthy individuals (11), and because macrophages play an important part in the host's resistance to this organism (5,(15)(16)(17). Our studies showed that killing of T. gondii by human alveolar macrophages occurred without involvement of toxic metabolites of oxygen (Catterall, J. R., and J. S. Remington, manuscript in preparation). This suggested that previous studies of intracellular killing by normal macrophages might have limitations as models for the human alveolar macrophage, since most of them (18-20, and reviewed in 21), including all those that employed T. gondii (18-23), have emphasized the overriding importance of oxidative killing mechanisms. Nonoxidative antimicrobial activity has been shown in subcellular macrophage fragments (21, 24) and in oxidatively deficient cells (19,(21)(22)(23)25), but in none of the previously described models using normal intact macrophages has the killing of intracellular parasites been reported as nonoxidative.To facilitate the study of nonoxidative killing by alveolar macrophages, we have sought a laboratory animal model relevant to the human alveolar macrophage. Since rats more closely resemble human subjects in their resistance to T. gondii than many other animals (26, 27), we have examined the interaction between T. gondii and rat alveolar macrophages in vitro. The studies reported here indicate that rat alveolar macrophages, like those from human subjects, also kill T. gondii, and by nonoxidative mechanisms. They suggest that nonoxidative antimicrobial mechanisms may be important in alveolar macrophages, and they provide a convenient model for the study of such mechanisms.

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“…Rats are much more resistant to challenge with T. gondii than are mice, hamsters, and guinea pigs (1,2,6,22). The resistance of rats has been attributed to macrophage function (2).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of killing of Toxoplasma gondii by rat peritoneal macrophages

McCabe¹,

Remington²

1986

Infect Immun

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Rats are resistant to Toxoplasma infection, and macrophages are thought to mediate this resistance. We performed a series of experiments to investigate the mechanism of the anti-Toxoplasma activity of resident rat peritoneal macrophages. Resident rat peritoneal macrophages killed more than 90% of ingested Toxoplasma gondii in vitro.This capacity was reduced progressively with the prolongation of culturing of macrophages in vitro before challenge with T. gondii. Exhaustion of the respiratory burst of macrophages with phorbol myristate acetate impaired their ability to kill and limit the replication of T. gondii. Histidine and diazabicyclooctane, presumed scavengers of singlet oxygen, were the only members of a battery of scavengers of metabolites of the respiratory burst that impaired the anti-Toxoplasma activity of macrophages. Ingestion of heat-killed Candida albicans by macrophages reduced large amounts of intracellular Nitro Blue Tetrazolium dye, whereas little dye was reduced by the ingestion of T. gondii. Challenge of macrophages with T. gondii released no detectable superoxide anion, as measured by the reduction of ferricytochrome c, whereas stimulation of macrophages with phorbol myristate acetate or ingestion of heat-killed Candida by macrophages released abundant superoxide anion. These data are consistent with the contributions of oxygen-dependent and oxygen-independent mechanisms to the anti-Toxoplasma activity of rat peritoneal macrophages. In addition, neonatal rats are known to be susceptible to Toxoplasma infection in vivo. However, resident neonatal rat peritoneal macrophages ingested and killed T. gondii to the same extent as did adult macrophages. Thus, the susceptibility of neonatal rats to Toxoplasma infection probably resides in other aspects of macrophage function or the immune response.

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Mediation of immunity to intracellular infection (Toxoplasma and Besnoitia) within somatic cells

Cited by 57 publications

References 43 publications

Effector Cells of Both Nonhemopoietic and Hemopoietic Origin Are Required for Interferon (IFN)-γ– and Tumor Necrosis Factor (TNF)-α–dependent Host Resistance to the Intracellular Pathogen, Toxoplasma gondii

Effector Cells of Both Nonhemopoietic and Hemopoietic Origin Are Required for Interferon (IFN)-γ– and Tumor Necrosis Factor (TNF)-α–dependent Host Resistance to the Intracellular Pathogen, Toxoplasma gondii

Oxygen-independent killing by alveolar macrophages.

Mechanisms of killing of Toxoplasma gondii by rat peritoneal macrophages

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