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Mucosal immune responses to microbes in genital tract
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
HSV infection is sensed by multiple PRRs. In pDCs, HSV is recognized by TLR9 in the endosome, while in infected cell types, HSV genome is recognized by DNA sensors, cGAS and IFI16. In addition, in some infected cells, HSV-derived RNA is recognized in the cytosol by a RIG-I-dependent pathway following transcription of HSV by DNA-dependent RNA polymerase III (see Figure 21.3b). In the cytosol, viral DNA is sensed by the DNA sensor cGAS and IFI16, and in the nucleus IFI16 can bind to nucleosome-free incoming genomic DNA to induce type I IFNs (see Figure 21.3b). Certain strains of HSV also trigger TLR2 on DCs and macrophages. In addition to these pathways, mutations in TLR3 and downstream signaling molecules are highly associated with uncontrolled HSV infection. TLR3 presumably detects higher-order viral RNA in infected cells within the endosomes (see Figure 21.2). In humans, a rare TLR3 P554S homozygous mutation and an L412F mutation, both resulting in impaired activity of TLR3, were found in patients with HSV-1 encephalitis and HSV-2-associated Mollaret meningitis, respectively.
IFN-γ activates the tumor cell-intrinsic STING pathway through the induction of DNA damage and cytosolic dsDNA formation
Published in OncoImmunology, 2022
Hui Xiong, Yu Xi, Zhiwei Yuan, Boyu Wang, Shaojie Hu, Can Fang, Yixin Cai, Xiangning Fu, Lequn Li
To further understand how IFI16 is involved in the IFN-γ-mediated activation of STING signaling, we first examined the cellular localization of IFI16 at a steady state and in response to IFN-γ stimulation in A549 and HCC827 cells. Immunoblotting of cytoplasmic and nuclear fractions was carried out to determine the level and distribution of the IFI16 protein. A549 and HCC827 cells exhibited high levels of IFI16 in the nuclear fraction and very low to almost undetectable levels of IFI16 in the cytoplasmic fraction. IFN-γ stimulation increased the expression level of IFI16 in the nuclear fraction, and interestingly, cytoplasmic IFI16 was also enhanced (Figure 6f). Subsequently, to determine whether the cytoplasmic translocation of IFI16 in response to IFN-γ stimulation is a critical step in activating the STING pathway, we used leptomycin B (LMB) to inhibit CRM1-mediated nuclear export49 and examined cytosolic IFI16 expression. As shown in Figure 6g, LMB prevented the translocation of IFI16 from the nucleus to the cytoplasm in response to IFN-γ. Moreover, LMB significantly inhibited IFN-γ-induced IFN-β expression (Figure 6h).
The crosstalk between DNA damage response components and DNA-sensing innate immune signaling pathways
Published in International Reviews of Immunology, 2022
Feng Lin, Yan-Dong Tang, Chunfu Zheng
IFI16, a member of the PYHIN protein family that contains a pyrin domain and two DNA binding HIN domains, is shown to involve in recognition of synthetic dsDNA and ssDNA and UV-induced damaged DNA [31]. IFI16 is also identified as a DNA sensor recognizing the viral genomic DNA to mediate IFN-β induction [15]. BRCA1 is involved in a series of important cellular functions as a DNA damage repair sensor and transcription regulator. BRCA1 is a constituent of the triggered IFI16-inflammasome and is translocated into the cytoplasm after genome recognition along with the IFI16-inflammasome. BRCA1 plays as a cofactor with IFI16 in the nucleus to detect herpesviral DNA and subsequently promotes inflammasome activation and the production of IFN-β induced by the IFI16-STING- TBK1-IRF3 signaling pathway [32].
Immunology of HPV-mediated cervical cancer: current understanding
Published in International Reviews of Immunology, 2021
Babban Jee, Renu Yadav, Sangeeta Pankaj, Shivendra Kumar Shahi
As discussed above, several other cell surface receptors including AIM2 [39], IFI16 [40] and cGAS[41] also take part in the recognition of HPV DNA in the host system, in addition to TLRs. IFI16 and AIM2 are the members of the interferon-inducible HIN-200 family [120]. Reinholz and his colleagues by conducting a mechanistic study showed that AIM2 is able to sense HPV DNA by its oligonucleotide/oligosaccharide-binding domain. They further observed that binding of AIM2 to the viral DNA leads to the activation of caspase-1 which in turn induces the production of IL1β [121]. IFI16 which is thought to be the first viral DNA sensor works within the nucleus, after recognizing the cytoplasmic HPV DNA, binds to viral DNA in order to activate the immune signaling cascades for producing the IFN [122,123]. In addition, IFI16 restricts the replication of HPV 18 DNA [124]. The recognition of cytosolic HPV DNA by cGAS which is an important component of cGAS - STING pathway, results in the activation of type I interferons (IFNs) and other inflammatory cytokines through up-regulation of interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB) to keep the host in anti-viral state [125–127].