Toxoplasma gondii CDPK3 Controls the Intracellular Proliferation of Parasites in Macrophages

Wu, Minmin; An, Ran; Zhou, Nan; Chen, Ying; Cai, Haijian; Yan, Qi; Wang, Ru; Luo, Qingli; Yu, Li; Chen, Lijian; Du, Jian

doi:10.3389/fimmu.2022.905142

Cited by 4 publications

(1 citation statement)

References 50 publications

(63 reference statements)

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“…The increases in TNF-α in pregnant mice resulted in worse pregnancy outcomes by affecting vertical transmission of T. gondii [ 35 ]. IFN-γ-activated macrophages inhibit the replication of intracellular parasites and disrupt the integrity of vacuolar pathogens [ 36 ]. The role of TNF-α in T. gondii infection is still controversial; however, it has been reported that TNF-α can facilitate the intracerebral spread of T. gondii in mice [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

A novel 2B4 receptor leads to worse pregnancy outcomes by facilitating TNF-α and IFN-γ production in dNK cells during Toxoplasma gondii infection

Zheng

Ren

et al. 2022

Parasites Vectors

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Background Infections are a major threat to human reproductive health because they can induce pregnancy failure, including recurrent abortion, stillbirth, and preterm birth. Toxoplasma gondii (T. gondii) infection can result in adverse pregnancy outcomes by affecting certain immune molecules and cytokines. However, the detailed mechanisms behind T. gondii-induced pregnancy failure are poorly understood. Methods Toxoplasma gondii-infected wild-type (WT) pregnant mice and 2B4 knockout (2B4−/−) pregnant mice were established for in vivo study. Human decidual natural killer (dNK) cells were cultured for in vitro study. Abnormal pregnancy outcomes were observed, and the expression of 2B4, functional molecules (CD69, CD107a, tumor necrosis factor alpha [TNF-α], interferon gamma [IFN-γ]), and signaling molecules (SHP-2, Fyn, p-ERK, p-P38) in dNK cells were detected by flow cytometry, Western blot, reverse transcriptase polymerase chain reaction (RT-PCR), and/or immunofluorescence. The direct interactions (2B4 interacts with SHP-2 and Fyn; SHP-2 interacts with p-P38 and 2B4; Fyn interacts with p-ERK and 2B4) were verified by co-immunoprecipitation (co-IP) in NK-92 cells. Results Here, results showed that 2B4 was significantly downregulated after T. gondii infection. Subsequently, infected 2B4−/− pregnant mice displayed worse pregnancy outcomes compared with infected WT pregnant mice. Also, increased TNF-α and IFN-γ expression and elevated dNK cell cytotoxicity were found in 2B4−/− pregnant mice during T. gondii infection. In contrast, reduced TNF-α and IFN-γ expression and decreased human dNK cell activity were found following 2B4 activation during T. gondii infection. Interestingly, results showed that 2B4 binds to adaptor SHP-2 or Fyn, which then triggers different signaling pathways to regulate TNF-α and IFN-γ expression in dNK cells during T. gondii infection. Further, SHP-2 binds 2B4 and p-P38 directly after 2B4 activation, which generates an inhibitory signal for TNF-α and IFN-γ in NK-92 cells. In addition, Fyn can bind to 2B4 and p-ERK after activation of 2B4, thereby inhibiting TNF-α and IFN-γ expression in NK-92 cells following T. gondii infection. Conclusions These data suggest that 2B4 may be a novel danger-signaling molecule that is implicated in pregnancy failure during T. gondii infection. Unraveling the mechanism by which 2B4 regulates dNK cell activity will provide novel insights to aid our understanding of T. gondii-induced adverse pregnancy outcomes. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

A novel 2B4 receptor leads to worse pregnancy outcomes by facilitating TNF-α and IFN-γ production in dNK cells during Toxoplasma gondii infection

Zheng

Ren

et al. 2022

Parasites Vectors

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Effect of deleting four Toxoplasma gondii calcium-binding EGF domain-containing proteins on parasite replication and virulence

Wang

Elsheikha

et al. 2022

Parasitol Res

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Several calcium-binding proteins including calcium-dependent protein kinases, play important roles in several facets of the intracellular infection cycle of the apicomplexan protozoan parasite Toxoplasma gondii. However, the role of the calcium binding epidermal growth factor (EGF) domain-containing proteins (CBDPs) remains poorly understood. In this study, we examined the functions of four CBDP genes in T. gondii RH strain of Type I by generating knock-out strains using CRISPR-Cas9 system. We investigated the ability of mutant strains deficient in CBDP1, CBDP2, CBDP3 or CBDP4 to form plaques, replicate intracellularly, and egress the host cells. The results showed that no definite differences between any of these four CBDP mutant strains and the wild-type strain in terms of their ability to form plaques, intracellular replication, and egress. Additionally, CBDP mutants did not exhibit any significant attenuated virulence compared to the wild-type strain in mice. The expression profiles of CBDP2-4 genes were conserved among T. gondii strains of different genotypes, life cycle stages, and developmental forms. Whether other CBDP genes play any roles in the pathogenicity of T. gondii strains of different genotypes remains to be elucidated.

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Pathogenesis of Uveitis in Humans

Forrester,

Kuffova,

Dick

2024

Reference Module in Neuroscience and Biobehavioral Psychology

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Toxoplasma gondii CDPK3 Controls the Intracellular Proliferation of Parasites in Macrophages

Cited by 4 publications

References 50 publications

A novel 2B4 receptor leads to worse pregnancy outcomes by facilitating TNF-α and IFN-γ production in dNK cells during Toxoplasma gondii infection

A novel 2B4 receptor leads to worse pregnancy outcomes by facilitating TNF-α and IFN-γ production in dNK cells during Toxoplasma gondii infection

Effect of deleting four Toxoplasma gondii calcium-binding EGF domain-containing proteins on parasite replication and virulence

Pathogenesis of Uveitis in Humans

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