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Identification of the microsporidian Encephalitozoon cuniculi as a new target of the IFNγ-inducible IRG resistance system.

Ferreira-da-Silva Mda F, da Fonseca Ferreira-da-Silva M, Springer-Frauenhoff HM, Bohne W, Howard JC - PLoS Pathog. (2014)

Bottom Line: We hypothesized that unusual features of the entry mechanisms and intracellular replicative niches of these two organisms, neither of which resembles a phagosome, might hint at a common principle.The suppression of E. cuniculi growth by IFNγ is completely reversed in cells lacking regulatory (GMS subfamily) IRG proteins, cells that effectively lack all IRG function.The phylogenetic divergence of the three organisms whose vacuoles are now known to be involved in IRG-mediated immunity and the non-phagosomal character of the vacuoles themselves strongly suggests that the IRG system is triggered not by the presence of specific parasite components but rather by absence of specific host components on the vacuolar membrane.

View Article: PubMed Central - PubMed

Affiliation: Institute for Genetics, University of Cologne, Cologne, Germany.

ABSTRACT
The IRG system of IFNγ-inducible GTPases constitutes a powerful resistance mechanism in mice against Toxoplasma gondii and two Chlamydia strains but not against many other bacteria and protozoa. Why only T. gondii and Chlamydia? We hypothesized that unusual features of the entry mechanisms and intracellular replicative niches of these two organisms, neither of which resembles a phagosome, might hint at a common principle. We examined another unicellular parasitic organism of mammals, member of an early-diverging group of Fungi, that bypasses the phagocytic mechanism when it enters the host cell: the microsporidian Encephalitozoon cuniculi. Consistent with the known susceptibility of IFNγ-deficient mice to E. cuniculi infection, we found that IFNγ treatment suppresses meront development and spore formation in mouse fibroblasts in vitro, and that this effect is mediated by IRG proteins. The process resembles that previously described in T. gondii and Chlamydia resistance. Effector (GKS subfamily) IRG proteins accumulate at the parasitophorous vacuole of E. cuniculi and the meronts are eliminated. The suppression of E. cuniculi growth by IFNγ is completely reversed in cells lacking regulatory (GMS subfamily) IRG proteins, cells that effectively lack all IRG function. In addition IFNγ-induced cells infected with E. cuniculi die by necrosis as previously shown for IFNγ-induced cells resisting T. gondii infection. Thus the IRG resistance system provides cell-autonomous immunity to specific parasites from three kingdoms of life: protozoa, bacteria and fungi. The phylogenetic divergence of the three organisms whose vacuoles are now known to be involved in IRG-mediated immunity and the non-phagosomal character of the vacuoles themselves strongly suggests that the IRG system is triggered not by the presence of specific parasite components but rather by absence of specific host components on the vacuolar membrane.

No MeSH data available.


Related in: MedlinePlus

Scheme of different dynamics of IRG action.Upon E. cuniculi infection, a low but steady number of IRG-positive vacuoles can be detected over the first 24 h post infection accompanied by a continuous loss of viable meronts. Moreover, host cell death is triggered by the combination of E. cuniculi infection and IFNγ induction. Initiation of IRG loading might be a stochastic and asynchronous event that is followed by a rapid elimination of the pathogen. In contrast, IRG loading on PVs of avirulent T. gondii strains starts immediately after parasite invasion. IRG-positive vacuoles seem to accumulate reaching a maximum at about 2 h post infection. When fully loaded, the vacuoles disrupt followed by T. gondii death and host cell death in an invariant order.
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ppat-1004449-g007: Scheme of different dynamics of IRG action.Upon E. cuniculi infection, a low but steady number of IRG-positive vacuoles can be detected over the first 24 h post infection accompanied by a continuous loss of viable meronts. Moreover, host cell death is triggered by the combination of E. cuniculi infection and IFNγ induction. Initiation of IRG loading might be a stochastic and asynchronous event that is followed by a rapid elimination of the pathogen. In contrast, IRG loading on PVs of avirulent T. gondii strains starts immediately after parasite invasion. IRG-positive vacuoles seem to accumulate reaching a maximum at about 2 h post infection. When fully loaded, the vacuoles disrupt followed by T. gondii death and host cell death in an invariant order.

Mentions: The cooperative pattern of loading of the different IRG proteins is also familiar from T. gondii. The frequency of vacuoles loaded at any time is low, but the majority of vacuoles carry more than one IRG protein (Figure 3). This result could of course also arise if only a few vacuoles are receptive to IRG proteins at any time. However, data from T. gondii showed that the loading of Irgb6 was stabilised and enhanced by the loading of Irga6, and thus clearly cooperative [18]. There is also a tendency in the E. cuniculi infection, perhaps not so well marked as in T. gondii infection, for Irgb6 to load more vacuoles than Irga6, and Irgd to load fewer. Also, as in T. gondii[1], [4] and in C. trachomatis infection [8], [10], [23], the IRG regulatory protein, Irgm1, does not load onto any E. cuniculi vacuoles, while Irgm2 can be found on some. In another respect, however, the loading of E. cuniculi vacuoles with IRG proteins appears to be different from the loading of T. gondii vacuoles. With avirulent T. gondii, the number of vacuoles loaded with IRG proteins rises to as much as 90% of all vacuoles within 2 h after infection. With E. cuniculi, the number of vacuoles loaded reaches a plateau between 5 and 15% within 30 minutes of infection, and persists at that level for many hours while the number of live meronts progressively falls (Figure 2). These different loading behaviours can be reconciled with qualitatively similar processes operating on the vacuoles of both organisms, if the initiation of IRG protein loading onto individual E. cuniculi vacuoles takes on average longer than onto T. gondii vacuoles, and if E. cuniculi vacuoles subsequently disintegrate and are cleared with faster kinetics than T. gondii vacuoles. With increasing time after infection more and more parasites are cleared from the cells, accounting for the long, slow loss of detectable meronts (Figure 1) reaching about 90% only 24 h after infection (Figure 7).


Identification of the microsporidian Encephalitozoon cuniculi as a new target of the IFNγ-inducible IRG resistance system.

Ferreira-da-Silva Mda F, da Fonseca Ferreira-da-Silva M, Springer-Frauenhoff HM, Bohne W, Howard JC - PLoS Pathog. (2014)

Scheme of different dynamics of IRG action.Upon E. cuniculi infection, a low but steady number of IRG-positive vacuoles can be detected over the first 24 h post infection accompanied by a continuous loss of viable meronts. Moreover, host cell death is triggered by the combination of E. cuniculi infection and IFNγ induction. Initiation of IRG loading might be a stochastic and asynchronous event that is followed by a rapid elimination of the pathogen. In contrast, IRG loading on PVs of avirulent T. gondii strains starts immediately after parasite invasion. IRG-positive vacuoles seem to accumulate reaching a maximum at about 2 h post infection. When fully loaded, the vacuoles disrupt followed by T. gondii death and host cell death in an invariant order.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214799&req=5

ppat-1004449-g007: Scheme of different dynamics of IRG action.Upon E. cuniculi infection, a low but steady number of IRG-positive vacuoles can be detected over the first 24 h post infection accompanied by a continuous loss of viable meronts. Moreover, host cell death is triggered by the combination of E. cuniculi infection and IFNγ induction. Initiation of IRG loading might be a stochastic and asynchronous event that is followed by a rapid elimination of the pathogen. In contrast, IRG loading on PVs of avirulent T. gondii strains starts immediately after parasite invasion. IRG-positive vacuoles seem to accumulate reaching a maximum at about 2 h post infection. When fully loaded, the vacuoles disrupt followed by T. gondii death and host cell death in an invariant order.
Mentions: The cooperative pattern of loading of the different IRG proteins is also familiar from T. gondii. The frequency of vacuoles loaded at any time is low, but the majority of vacuoles carry more than one IRG protein (Figure 3). This result could of course also arise if only a few vacuoles are receptive to IRG proteins at any time. However, data from T. gondii showed that the loading of Irgb6 was stabilised and enhanced by the loading of Irga6, and thus clearly cooperative [18]. There is also a tendency in the E. cuniculi infection, perhaps not so well marked as in T. gondii infection, for Irgb6 to load more vacuoles than Irga6, and Irgd to load fewer. Also, as in T. gondii[1], [4] and in C. trachomatis infection [8], [10], [23], the IRG regulatory protein, Irgm1, does not load onto any E. cuniculi vacuoles, while Irgm2 can be found on some. In another respect, however, the loading of E. cuniculi vacuoles with IRG proteins appears to be different from the loading of T. gondii vacuoles. With avirulent T. gondii, the number of vacuoles loaded with IRG proteins rises to as much as 90% of all vacuoles within 2 h after infection. With E. cuniculi, the number of vacuoles loaded reaches a plateau between 5 and 15% within 30 minutes of infection, and persists at that level for many hours while the number of live meronts progressively falls (Figure 2). These different loading behaviours can be reconciled with qualitatively similar processes operating on the vacuoles of both organisms, if the initiation of IRG protein loading onto individual E. cuniculi vacuoles takes on average longer than onto T. gondii vacuoles, and if E. cuniculi vacuoles subsequently disintegrate and are cleared with faster kinetics than T. gondii vacuoles. With increasing time after infection more and more parasites are cleared from the cells, accounting for the long, slow loss of detectable meronts (Figure 1) reaching about 90% only 24 h after infection (Figure 7).

Bottom Line: We hypothesized that unusual features of the entry mechanisms and intracellular replicative niches of these two organisms, neither of which resembles a phagosome, might hint at a common principle.The suppression of E. cuniculi growth by IFNγ is completely reversed in cells lacking regulatory (GMS subfamily) IRG proteins, cells that effectively lack all IRG function.The phylogenetic divergence of the three organisms whose vacuoles are now known to be involved in IRG-mediated immunity and the non-phagosomal character of the vacuoles themselves strongly suggests that the IRG system is triggered not by the presence of specific parasite components but rather by absence of specific host components on the vacuolar membrane.

View Article: PubMed Central - PubMed

Affiliation: Institute for Genetics, University of Cologne, Cologne, Germany.

ABSTRACT
The IRG system of IFNγ-inducible GTPases constitutes a powerful resistance mechanism in mice against Toxoplasma gondii and two Chlamydia strains but not against many other bacteria and protozoa. Why only T. gondii and Chlamydia? We hypothesized that unusual features of the entry mechanisms and intracellular replicative niches of these two organisms, neither of which resembles a phagosome, might hint at a common principle. We examined another unicellular parasitic organism of mammals, member of an early-diverging group of Fungi, that bypasses the phagocytic mechanism when it enters the host cell: the microsporidian Encephalitozoon cuniculi. Consistent with the known susceptibility of IFNγ-deficient mice to E. cuniculi infection, we found that IFNγ treatment suppresses meront development and spore formation in mouse fibroblasts in vitro, and that this effect is mediated by IRG proteins. The process resembles that previously described in T. gondii and Chlamydia resistance. Effector (GKS subfamily) IRG proteins accumulate at the parasitophorous vacuole of E. cuniculi and the meronts are eliminated. The suppression of E. cuniculi growth by IFNγ is completely reversed in cells lacking regulatory (GMS subfamily) IRG proteins, cells that effectively lack all IRG function. In addition IFNγ-induced cells infected with E. cuniculi die by necrosis as previously shown for IFNγ-induced cells resisting T. gondii infection. Thus the IRG resistance system provides cell-autonomous immunity to specific parasites from three kingdoms of life: protozoa, bacteria and fungi. The phylogenetic divergence of the three organisms whose vacuoles are now known to be involved in IRG-mediated immunity and the non-phagosomal character of the vacuoles themselves strongly suggests that the IRG system is triggered not by the presence of specific parasite components but rather by absence of specific host components on the vacuolar membrane.

No MeSH data available.


Related in: MedlinePlus