Abstract
Clearance of infection with intracellular pathogens in mice involves interferon-regulated GTPases of the IRG protein family. Experiments with mice genetically deficient in members of this family such as Irgm1(LRG-47), Irgm3(IGTP), and Irgd(IRG-47) has revealed a critical role in microbial clearance, especially for Toxoplasma gondii. The in vivo role of another member of this family, Irga6 (IIGP, IIGP1) has been studied in less detail. We investigated the susceptibility of two independently generated mouse strains deficient in Irga6 to in vivo infection with T. gondii, Mycobacterium tuberculosis, Leishmania mexicana, L. major, Listeria monocytogenes, Anaplasma phagocytophilum and Plasmodium berghei. Compared with wild-type mice, mice deficient in Irga6 showed increased susceptibility to oral and intraperitoneal infection with T. gondii but not to infection with the other organisms. Surprisingly, infection of Irga6-deficient mice with the related apicomplexan parasite, P. berghei, did not result in increased replication in the liver stage and no Irga6 (or any other IRG protein) was detected at the parasitophorous vacuole membrane in IFN-γ-induced wild-type cells infected with P. berghei in vitro. Susceptibility to infection with T. gondii was associated with increased mortality and reduced time to death, increased numbers of inflammatory foci in the brains and elevated parasite loads in brains of infected Irga6-deficient mice. In vitro, Irga6-deficient macrophages and fibroblasts stimulated with IFN-γ were defective in controlling parasite replication. Taken together, our results implicate Irga6 in the control of infection with T. gondii and further highlight the importance of the IRG system for resistance to this pathogen.
Highlights
Infection with the obligate intracellular pathogen Toxoplasma gondii causes disease in humans and animals [1,2]
Groups of B-Irga62/2 mice on a C57BL/6-background and wild-type littermates were infected with L. mexicana and L. major promastigotes into the hind footpad and infection-induced footpad swelling was recorded as a measure of disease severity
These results indicate that Irga6 is probably not significantly involved in resistance against L. major and L. mexicana, L. monocytogenes, M. tuberculosis and A. phagocytophilum
Summary
Infection with the obligate intracellular pathogen Toxoplasma gondii causes disease in humans and animals [1,2]. Active invasion of host cells in the small intestine results in formation of parasitophorous vacuoles (PV) that resist lysosome fusion and thereby allow intracellular survival [3]. Whereas acute infection only rarely causes symptoms in man, severe immunosuppression (i.e., AIDS and transplantation) may result in reactivation of latent infection presenting as toxoplasmic encephalitis [1]. Limitation of parasite replication and cyst formation relies on the development of a type 1 T helper (Th1) response involving secretion of IL-12 by dendritic cells [4] and interferon-gamma (IFN-c) and tumor necrosis factor (TNF) by T cells and natural killer (NK) cells [5]. Mice on the C57BL/6 background (H-2b haplotype) develop a fatal chronic progressive infection; pathologic changes include parasite-associated follicular infiltrations in the brain parenchyma and meninges similar to toxoplasmic encephalitis in AIDS patients [12,13]. Mice on the BALB/c (H-2d) background and outbred strains of mice are resistant to the infection and do not develop symptoms of encephalitis [12]
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