Epigenetic Control of IFN-γ Host Responses During Infection With Toxoplasma gondii

The intracellular parasite Toxoplasma gondii has long provided a tractable experimental system to investigate how the immune system deals with intracellular infections. This review highlights the advances in defining how this organism was first detected and the studies with T. gondii that contribute to our understanding of how the cytokine IFN-γ promotes control of vacuolar pathogens. In addition, the genetic tractability of this eukaryote organism has provided the foundation for studies into the diverse strategies that pathogens use to evade antimicrobial responses and now provides the opportunity to study the basis for latency. Thus, T. gondii remains a clinically relevant organism whose evolving interactions with the host immune system continue to teach lessons broadly relevant to host–pathogen interactions.

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Infection-Induced Intestinal Dysbiosis Is Mediated by Macrophage Activation and Nitrate Production

mBio ◽

10.1128/mbio.00935-19 ◽

2019 ◽

Vol 10 (3) ◽

Cited By ~ 10

Author(s):

Shuai Wang ◽

Ayah El-Fahmawi ◽

David A. Christian ◽

Qun Fang ◽

Enrico Radaelli ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Oral Infection ◽

Nitrate Respiration ◽

Characteristic Change ◽

Intestinal Immunity ◽

Parasite Control ◽

Shotgun Metagenomics ◽

Content Type ◽

Distal Small Intestine ◽

Ifn Γ

ABSTRACT Oral infection of C57BL/6J mice with Toxoplasma gondii results in a marked bacterial dysbiosis and the development of severe pathology in the distal small intestine that is dependent on CD4+ T cells and interferon gamma (IFN-γ). This dysbiosis and bacterial translocation contribute to the development of ileal pathology, but the factors that support the bloom of bacterial pathobionts are unclear. The use of microbial community profiling and shotgun metagenomics revealed that Toxoplasma infection induces a dysbiosis dominated by Enterobacteriaceae and an increased potential for nitrate respiration. In vivo experiments using bacterial metabolic mutants revealed that during this infection, host-derived nitrate supports the expansion of Enterobacteriaceae in the ileum via nitrate respiration. Additional experiments with infected mice indicate that the IFN-γ/STAT1/iNOS axis, while essential for parasite control, also supplies a pool of nitrate that serves as a source for anaerobic respiration and supports overgrowth of Enterobacteriaceae. Together, these data reveal a trade-off in intestinal immunity after oral infection of C57BL/6J mice with T. gondii, in which inducible nitric oxide synthase (iNOS) is required for parasite control, while this host enzyme is responsible for specific modification of the composition of the microbiome that contributes to pathology. IMPORTANCE Toxoplasma gondii is a protozoan parasite and a leading cause of foodborne illness. Infection is initiated when the parasite invades the intestinal epithelium, and in many host species, this leads to intense inflammation and a dramatic disruption of the normal microbial ecosystem that resides in the healthy gut (the so-called microbiome). One characteristic change in the microbiome during infection with Toxoplasma—as well as numerous other pathogens—is the overgrowth of Escherichia coli or similar bacteria and a breakdown of commensal containment leading to seeding of peripheral organs with gut bacteria and subsequent sepsis. Our findings provide one clear explanation for how this process is regulated, thereby improving our understanding of the relationship between parasite infection, inflammation, and disease. Furthermore, our results could serve as the basis for the development of novel therapeutics to reduce the potential for harmful bacteria to bloom in the gut during infection.

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Immediate Interferon Gamma Induction Determines Murine Host Compatibility Differences between Toxoplasma gondii and Neospora caninum

Infection and Immunity ◽

10.1128/iai.00027-20 ◽

2020 ◽

Vol 88 (4) ◽

Cited By ~ 1

Author(s):

Rachel S. Coombs ◽

Matthew L. Blank ◽

Elizabeth D. English ◽

Yaw Adomako-Ankomah ◽

Ifeanyi-Chukwu Samuel Urama ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Immune Responses ◽

Interferon Gamma ◽

Neospora Caninum ◽

Ectopic Expression ◽

Parasite Burden ◽

Interleukin 12 ◽

Content Type ◽

Ifn Γ ◽

And Control

ABSTRACT Rodents are critical for the transmission of Toxoplasma gondii to the definitive feline host via predation, and this relationship has been extensively studied as a model for immune responses to parasites. Neospora caninum is a closely related coccidian parasite of ruminants and canines but is not naturally transmitted by rodents. We compared mouse innate immune responses to N. caninum and T. gondii and found marked differences in cytokine levels and parasite growth kinetics during the first 24 h postinfection (hpi). N. caninum-infected mice produced significantly higher levels of interleukin-12 (IL-12) and interferon gamma (IFN-γ) by as early as 4 hpi, but the level of IFN-γ was significantly lower or undetectable in T. gondii-infected mice during the first 24 hpi. “Immediate” IFN-γ and IL-12p40 production was not detected in MyD88−/− mice. However, unlike IL-12p40−/− and IFN-γ−/− mice, MyD88−/− mice survived N. caninum infections at the dose used in this study. Serial measures of parasite burden showed that MyD88−/− mice were more susceptible to N. caninum infections than wild-type (WT) mice, and control of parasite burdens correlated with a pulse of serum IFN-γ at 3 to 4 days postinfection in the absence of detectable IL-12. Immediate IFN-γ was partially dependent on the T. gondii mouse profilin receptor Toll-like receptor 11 (TLR11), but the ectopic expression of N. caninum profilin in T. gondii had no impact on early IFN-γ production or parasite proliferation. Our data indicate that T. gondii is capable of evading host detection during the first hours after infection, while N. caninum is not, and this is likely due to the early MyD88-dependent recognition of ligands other than profilin.

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Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection

Experimental & Molecular Medicine ◽

10.1038/s12276-019-0353-9 ◽

2019 ◽

Vol 51 (12) ◽

pp. 1-10 ◽

Cited By ~ 7

Author(s):

Miwa Sasai ◽

Masahiro Yamamoto

Keyword(s):

Immune Response ◽

Toxoplasma Gondii ◽

Immune Responses ◽

Parasitophorous Vacuole ◽

Interferon Γ ◽

Protective Role ◽

Ifn Γ ◽

Acquired Immune Responses ◽

Toxoplasma Gondii Infection ◽

Antimicrobial Immunity

AbstractHosts have been fighting pathogens throughout the evolution of all infectious diseases. Toxoplasma gondii is one of the most common infectious agents in humans but causes only opportunistic infection in healthy individuals. Similar to antimicrobial immunity against other organisms, the immune response against T. gondii activates innate immunity and in turn induces acquired immune responses. After activation of acquired immunity, host immune cells robustly produce the proinflammatory cytokine interferon-γ (IFN-γ), which activates a set of IFN-γ-inducible proteins, including GTPases. IFN-inducible GTPases are essential for cell-autonomous immunity and are specialized for effective clearance and growth inhibition of T. gondii by accumulating in parasitophorous vacuole membranes. Recent studies suggest that the cell-autonomous immune response plays a protective role in host defense against not only T. gondii but also various intracellular bacteria. Moreover, the negative regulatory mechanisms of such strong immune responses are also important for host survival after infection. In this review, we will discuss in detail recent advances in the understanding of host defenses against T. gondii and the roles played by cell-autonomous immune responses.

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B Cells Are Essential for Vaccination-Induced Resistance to Virulent Toxoplasma gondii

Infection and Immunity ◽

10.1128/iai.68.3.1026-1033.2000 ◽

2000 ◽

Vol 68 (3) ◽

pp. 1026-1033 ◽

Cited By ~ 131

Author(s):

Peter C. Sayles ◽

George W. Gibson ◽

Lawrence L. Johnson

Keyword(s):

B Cells ◽

Toxoplasma Gondii ◽

B Cell ◽

Induced Resistance ◽

Immune Serum ◽

Challenge Infection ◽

Host Cells ◽

Cell Functions ◽

Ifn Γ ◽

Deficient Mice

ABSTRACT T lymphocytes and gamma interferon (IFN-γ) are known mediators of immune resistance to Toxoplasma gondii infection, but whether B cells also play an important role is not clear. We have investigated this issue using B-cell-deficient (μMT) mice. If vaccinated with attenuated T. gondii tachyzoites, μMT mice are susceptible to a challenge intraperitoneal infection with highly virulent tachyzoites that similarly vaccinated B-cell-sufficient mice resist. Susceptibility is evidenced by increased numbers of parasites at the challenge infection site and by extensive mortality. The susceptibility of B-cell-deficient mice does not appear to be caused by deficient T-cell functions or diminished capacity of vaccinated and challenged B-cell-deficient mice to produce IFN-γ. Administration of Toxoplasma-immune serum, but not nonimmune serum, to vaccinated B-cell-deficient mice significantly prolongs their survival after challenge with virulent tachyzoites. Vaccinated mice lacking Fc receptors or the fifth component of complement resist a challenge infection, suggesting that neither Fc-receptor-dependent phagocytosis of antibody-coated tachyzoites nor antibody-dependent cellular cytotoxicity nor antibody-and-complement-dependent lysis of tachyzoites is a crucial mechanism of resistance. However, Toxoplasma-immune serum effectively inhibits the infection of host cells by tachyzoites in vitro. Together, the results support the hypothesis that B cells are required for vaccination-induced resistance to virulent tachyzoites in order to produce antibodies and that antibodies may function protectively in vivo by blocking infection of host cells by tachyzoites.

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NADPH Oxidase and Guanylate Binding Protein 5 Restrict Survival of Avirulent Type III Strains of Toxoplasma gondii in Naive Macrophages

mBio ◽

10.1128/mbio.01393-18 ◽

2018 ◽

Vol 9 (4) ◽

Cited By ~ 10

Author(s):

Sumit K. Matta ◽

Kelley Patten ◽

Quiling Wang ◽

Bae-Hoon Kim ◽

John D. MacMicking ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Nadph Oxidase ◽

Binding Protein ◽

Parasitic Infections ◽

Type I ◽

Content Type ◽

Innate Defense ◽

Type Iii ◽

Ifn Γ ◽

Guanylate Binding Protein

ABSTRACT Phagocytic cells are the first line of innate defense against intracellular pathogens, and yet Toxoplasma gondii is renowned for its ability to survive in macrophages, although this paradigm is based on virulent type I parasites. Surprisingly, we find that avirulent type III parasites are preferentially cleared in naive macrophages, independent of gamma interferon (IFN-γ) activation. The ability of naive macrophages to clear type III parasites was dependent on enhanced activity of NADPH oxidase (Nox)-generated reactive oxygen species (ROS) and induction of guanylate binding protein 5 (Gbp5). Macrophages infected with type III parasites (CTG strain) showed a time-dependent increase in intracellular ROS generation that was higher than that induced by type I parasites (GT1 strain). The absence of Nox1 or Nox2, gp91 subunit isoforms of the Nox complex, reversed ROS-mediated clearance of CTG parasites. Consistent with this finding, both Nox1−/− and Nox2−/− mice showed higher susceptibility to CTG infection than wild-type mice. Additionally, Gbp5 expression was induced upon infection and the enhanced clearance of CTG strain parasites was reversed in Gbp5−/− macrophages. Expression of a type I ROP18 allele in CTG prevented clearance in naive macrophages, suggesting that it plays a role counteracting Gbp5. Although ROS and Gbp5 have been linked to activation of the NLRP3 inflammasome, clearance of CTG parasites did not rely on induction of pyroptosis. Collectively, these findings reveal that not all strains of T. gondii are adept at avoiding clearance in macrophages and define new roles for ROS and Gbps in controlling this important intracellular pathogen. IMPORTANCE Toxoplasma infections in humans and other mammals are largely controlled by IFN-γ produced by the activated adaptive immune system. However, we still do not completely understand the role of cell-intrinsic functions in controlling Toxoplasma or other apicomplexan infections. The present work identifies intrinsic activities in naive macrophages in counteracting T. gondii infection. Using an avirulent strain of T. gondii, we highlight the importance of Nox complexes in conferring protection against parasite infection both in vitro and in vivo. We also identify Gbp5 as a novel macrophage factor involved in limiting intracellular infection by avirulent strains of T. gondii. The rarity of human infections caused by type III strains suggests that these mechanisms may also be important in controlling human toxoplasmosis. These findings further extend our understanding of host responses and defense mechanisms that act to control parasitic infections at the cellular level.

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GABARAPL2 Is Critical for Growth Restriction of Toxoplasma gondii in HeLa Cells Treated with Gamma Interferon

Infection and Immunity ◽

10.1128/iai.00054-20 ◽

2020 ◽

Vol 88 (5) ◽

Author(s):

Zhaoxia Zhang ◽

Haorong Gu ◽

Qi Li ◽

Jun Zheng ◽

Shinuo Cao ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Hela Cells ◽

Critical Role ◽

Gamma Interferon ◽

Growth Restriction ◽

Membrane Structures ◽

Content Type ◽

Receptor Associated Protein ◽

Ifn Γ ◽

And Function

ABSTRACT Gamma interferon (IFN-γ)-induced innate immune responses play important roles in the inhibition of Toxoplasma gondii infection. It has been reported that IFN-γ stimulates non-acidification-dependent growth restriction of T. gondii in HeLa cells, but the mechanism remains unclear. Here, we found that γ-aminobutyric acid (GABA) receptor-associated protein-like 2 (GABARAPL2) plays a critical role in parasite restriction in IFN-γ-treated HeLa cells. GABARAPL2 is recruited to membrane structures surrounding parasitophorous vacuoles (PV). Autophagy adaptors are required for the proper localization and function of GABARAPL2 in the IFN-γ -induced immune response. These findings provide further understanding of a noncanonical autophagy pathway responsible for IFN-γ-dependent inhibition of T. gondii growth in human HeLa cells and demonstrate the critical role of GABARAPL2 in this response.

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Interleukin-18 (IL-18) Enhances Innate IL-12-Mediated Resistance to Toxoplasma gondii

Infection and Immunity ◽

10.1128/iai.68.12.6932-6938.2000 ◽

2000 ◽

Vol 68 (12) ◽

pp. 6932-6938 ◽

Cited By ~ 83

Author(s):

Guifang Cai ◽

Robert Kastelein ◽

Christopher A. Hunter

Keyword(s):

Toxoplasma Gondii ◽

Nk Cells ◽

Nk Cell ◽

Parasite Burden ◽

Scid Mice ◽

Interleukin 12 ◽

Cell Mediated Immunity ◽

Protective Effects ◽

Innate Resistance ◽

Ifn Γ

ABSTRACT Innate resistance to Toxoplasma gondii is dependent on the ability of interleukin-12 (IL-12) to stimulate natural killer (NK) cell production of gamma interferon (IFN-γ). Since IL-18 is a potent enhancer of IL-12-induced production of IFN-γ by NK cells, SCID mice (which lack an adaptive immune response) were used to assess the role of IL-18 in innate resistance to T. gondii. Administration of anti-IL-18 to SCID mice infected with T. gondii resulted in an early reduction in serum levels of IFN-γ but did not significantly decrease resistance to this infection. In contrast, administration of exogenous IL-18 to infected SCID mice resulted in increased production of IFN-γ, reduced parasite burden, and a delay in time to death. The protective effects of IL-18 treatment correlated with increased NK cell numbers and cytotoxic activity at the local site of administration and with elevated levels of inducible nitrous oxide synthose in the spleens of treated mice. In addition, in vivo depletion studies demonstrated that the ability of exogenous IL-18 to enhance resistance to T. gondii was dependent on IL-12, IFN-γ, and NK cells. Together, these studies demonstrate that although endogenous IL-18 appears to have a limited role in innate resistance to T. gondii, treatment with IL-18 can augment NK cell-mediated immunity to this pathogen.

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Virulence comparison of human and poultry Campylobacter jejuni isolates in a mouse model

Medical Research Archives ◽

10.18103/mra.v5i10.1581 ◽

2017 ◽

Vol 5 (10) ◽

Author(s):

Darinka Vučković ◽

Maja Šikić Pogačar ◽

Peter Raspor ◽

Maja Abram ◽

Sonja Smole Možina ◽

...

Keyword(s):

Campylobacter Jejuni ◽

Mouse Liver ◽

Virulence Genes ◽

Cytokine Production ◽

Host Responses ◽

Human Origin ◽

Tnf Α ◽

Food Isolate ◽

Ifn Γ ◽

Food Model

ABSTRACTObjective: Research into Campylobacter jejuni pathogenesis and host responses to C. jejuni infection is needed in the fight against human campylobacteriosis.Methods: We established intravenous infections of BALB/c mice with either a C. jejuni food isolate or C. jejuni of human origin. Further we include PCR to demonstrate the presence and stability of the putative virulence genes cadF, virbB11, cdtB, cdtC, ceuE in C. jejuni isolates and we examined cytokine production of IL-6, IL-12, TNF-α, IFN-γ, IL-10 in the livers of these infected mice.Results: We confirm here the presence of the cadF, cdtB, cdtC and ceuE genes in a food and a clinical C. jejuni isolate, with no sequence changes after the C. jejuni sub-culturing in a food model and when recovered from mouse liver after infection. Both of these C. jejuni isolates persisted in the mouse livers and activated comparable cytokine patterns for IL-12, TNF-α, IFN-γ and IL-10, with down-regulation of IL-6.Conclusions: These data show the comparability of these C. jejuni food and clinical isolates in terms of the prevalence and stability of their putative virulence genes and the outcome of disease during systemic murine campylobacteriosis.

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The Proinflammatory Response Induced by Wild-Type Yersinia pseudotuberculosis Infection Inhibits Survival of yop Mutants in the Gastrointestinal Tract and Peyer's Patches

Infection and Immunity ◽

10.1128/iai.74.3.1516-1527.2006 ◽

2006 ◽

Vol 74 (3) ◽

pp. 1516-1527 ◽

Cited By ~ 25

Author(s):

Lauren K. Logsdon ◽

Joan Mecsas

Keyword(s):

Yersinia Pseudotuberculosis ◽

Intestinal Inflammation ◽

Peyer's Patches ◽

Host Responses ◽

Infection Model ◽

Peyer’S Patches ◽

Wild Type ◽

Single Strain ◽

Infection Models ◽

Ifn Γ

ABSTRACT Single-strain infections and coinfections are frequently used to assess roles of virulence factors in infected tissues. After oral inoculation of mice, Yersinia pseudotuberculosis yopE and yopH mutants colonize the intestines and Peyer's patches in single-strain infections but fail to persist in competition with wild-type Y. pseudotuberculosis, indicating that these two infection models provide different insights into the roles of Yops. To determine how wild-type Y. pseudotuberculosis hinders yop mutant survival, yop mutant colonization and host responses were investigated in several different infection models that isolated specific features of wild-type Y. pseudotuberculosis infection. Infection with wild-type Y. pseudotuberculosis caused significantly more inflammation than yop mutants. Results from coinfections of gamma interferon (IFN-γ)−/− mice revealed that IFN-γ-regulated defenses target these mutants, suggesting that YopE and YopH protect Y. pseudotuberculosis from these defenses in BALB/c mice. We developed an oral-intraperitoneal infection model to evaluate the effects of spleen and liver colonization by Y. pseudotuberculosis on yop mutants in the intestines. Spleen and liver infection increased inflammation and decreased yop mutant survival in the intestines, indicating that infection of these organs has consequences in intestinal tissues. Finally, competition infections with Y. pseudotuberculosis mutants with various abilities to induce inflammation demonstrated that survival of the yopE, but not the yopH, mutant was consistently decreased in inflamed tissues. In summary, infection with Y. pseudotuberculosis in intestinal and systemic sites induces intestinal inflammation, which decreases yop mutant survival. Thus, competition studies with wild-type yersiniae reveal critical roles of Yops in combating host responses to a normal virulent infection.

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