Type II Toxoplasma gondii Induction of CD40 on Infected Macrophages Enhances Interleukin-12 Responses

Morgado, Pedro; Sudarshana, Dattanand M.; Gov, Lanny; Harker, Katherine S.; Lam, Tonika; Casali, Paolo; Boyle, Jon P.; Lodoen, Melissa B.

doi:10.1128/iai.01615-14

Cited by 30 publications

(29 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To determine whether NLRP3 regulates co-stimulatory pathways, a variety of co-stimulatory ligands and the PD-L1 inhibitory receptor were measured on infected BMDMs. As previously demonstrated for B7 family members CD80, CD86 [ 120 ], PD-L1 [ 100 ], and as demonstrated here, ICOSL, are readily induced on the surface of infected BMDMs ( Fig 9C ). Receptors and ligands of the TNF superfamily are also expressed transcriptionally following infection in BMDMs including CD70, CD40, OX40L and 41BBL [ 100 ], of which surface expression of OX40L appears most sensitive to induction by T .…”

Section: Resultssupporting

confidence: 87%

Naïve CD8 T cell IFNγ responses to a vacuolar antigen are regulated by an inflammasome-independent NLRP3 pathway and Toxoplasma gondii ROP5

et al. 2020

View full text Add to dashboard Cite

Host resistance to Toxoplasma gondii relies on CD8 T cell IFNγ responses, which if modulated by the host or parasite could influence chronic infection and parasite transmission between hosts. Since host-parasite interactions that govern this response are not fully elucidated, we investigated requirements for eliciting naïve CD8 T cell IFNγ responses to a vacuolar resident antigen of T . gondii , TGD057. Naïve TGD057 antigen-specific CD8 T cells (T57) were isolated from transnuclear mice and responded to parasite-infected bone marrow-derived macrophages (BMDMs) in an antigen-dependent manner, first by producing IL-2 and then IFNγ. T57 IFNγ responses to TGD057 were independent of the parasite’s protein export machinery ASP5 and MYR1. Instead, host immunity pathways downstream of the regulatory Immunity-Related GTPases (IRG), including partial dependence on Guanylate-Binding Proteins, are required. Multiple T . gondii ROP5 isoforms and allele types, including ‘avirulent’ ROP5A from clade A and D parasite strains, were able to suppress CD8 T cell IFNγ responses to parasite-infected BMDMs. Phenotypic variance between clades B, C, D, F, and A strains suggest T57 IFNγ differentiation occurs independently of parasite virulence or any known IRG-ROP5 interaction. Consistent with this, removal of ROP5 is not enough to elicit maximal CD8 T cell IFNγ production to parasite-infected cells. Instead, macrophage expression of the pathogen sensors, NLRP3 and to a large extent NLRP1, were absolute requirements. Other members of the conventional inflammasome cascade are only partially required, as revealed by decreased but not abrogated T57 IFNγ responses to parasite-infected ASC, caspase-1/11, and gasdermin D deficient cells. Moreover, IFNγ production was only partially reduced in the absence of IL-12, IL-18 or IL-1R signaling. In summary, T . gondii effectors and host machinery that modulate parasitophorous vacuolar membranes, as well as NLR-dependent but inflammasome-independent pathways, determine the full commitment of CD8 T cells IFNγ responses to a vacuolar antigen.

show abstract

Section: Resultssupporting

confidence: 87%

Naïve CD8 T cell IFNγ responses to a vacuolar antigen are regulated by an inflammasome-independent NLRP3 pathway and Toxoplasma gondii ROP5

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Previously published primers for IL-1β , NLRP3 , and GAPDH ( 26 ) were used. Quantitative real-time PCR (Q-PCR) was performed as previously described ( 77 ), and data were analyzed using the threshold cycle (ΔΔ C T ) method ( 78 ). The values obtained for IL-1β and NLRP3 were normalized to those of GAPDH, and the data were expressed as a ratio of mRNA levels.…”

Section: Methodsmentioning

confidence: 99%

Evasion of Human Neutrophil-Mediated Host Defense duringToxoplasma gondiiInfection

Lima

Gov

Lodoen

2018

mBio

Self Cite

View full text Add to dashboard Cite

Neutrophils are a major player in host immunity to infection; however, the mechanisms by which human neutrophils respond to the intracellular protozoan parasite Toxoplasma gondii are still poorly understood. In the current study, we found that, whereas primary human monocytes produced interleukin-1beta (IL-1β) in response to T. gondii infection, human neutrophils from the same blood donors did not. Moreover, T. gondii inhibited lipopolysaccharide (LPS)-induced IL-1β synthesis in human peripheral blood neutrophils. IL-1β suppression required active parasite invasion, since heat-killed or mycalolide B-treated parasites did not inhibit IL-1β release. By investigating the mechanisms involved in this process, we found that T. gondii infection of neutrophils treated with LPS resulted in reduced transcript levels of IL-1β and NLRP3 and reduced protein levels of pro-IL-1β, mature IL-1β, and the inflammasome sensor NLRP3. In T. gondii-infected neutrophils stimulated with LPS, the levels of MyD88, TRAF6, IKKα, IKKβ, and phosphorylated IKKα/β were not affected. However, LPS-induced IκBα degradation and p65 phosphorylation were reduced in T. gondii-infected neutrophils, and degradation of IκBα was reversed by treatment with the proteasome inhibitor MG-132. Finally, we observed that T. gondii inhibited the cleavage and activity of caspase-1 in human neutrophils. These results indicate that T. gondii suppression of IL-1β involves a two-pronged strategy whereby T. gondii inhibits both NF-κB signaling and activation of the NLRP3 inflammasome. These findings represent a novel mechanism of T. gondii evasion of human neutrophil-mediated host defense by targeting the production of IL-1β.

show abstract

“…As most studies use RH as the prototype for type I strains, one should be careful when extrapolating results to other type I strains (Khan et al, 2009;Yang et al, 2013). Similarly, these intra-clonal group variations are also observed within type II strains; for example the ME49 and Pru strains differ in the induction of CD40 on macrophages due to different GRA15 expression levels likely caused by polymorphisms in its promoter region (Morgado et al, 2014) (see Table 2 for other strain-specific effectors).…”

Section: Toxoplasma Effectorsmentioning

confidence: 99%

Influence of the Host and Parasite Strain on the Immune Response During Toxoplasma Infection

Mukhopadhyay

Arranz-Solís

Saeij

2020

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Toxoplasma gondii is an exceptionally successful parasite that infects a very broad host range, including humans, across the globe. The outcome of infection differs remarkably between hosts, ranging from acute death to sterile infection. These differential disease patterns are strongly influenced by both host-and parasite-specific genetic factors. In this review, we discuss how the clinical outcome of toxoplasmosis varies between hosts and the role of different immune genes and parasite virulence factors, with a special emphasis on Toxoplasma-induced ileitis and encephalitis.

show abstract

Type II Toxoplasma gondii Induction of CD40 on Infected Macrophages Enhances Interleukin-12 Responses

Cited by 30 publications

References 58 publications

Naïve CD8 T cell IFNγ responses to a vacuolar antigen are regulated by an inflammasome-independent NLRP3 pathway and Toxoplasma gondii ROP5

Naïve CD8 T cell IFNγ responses to a vacuolar antigen are regulated by an inflammasome-independent NLRP3 pathway and Toxoplasma gondii ROP5

Evasion of Human Neutrophil-Mediated Host Defense duringToxoplasma gondiiInfection

Influence of the Host and Parasite Strain on the Immune Response During Toxoplasma Infection

Contact Info

Product

Resources

About