Search

The innate immune system is the first line of host defense, which responds rapidly to viral infection. Innate recognition of viruses is mediated by a set of pattern recognition receptors (PRRs) that sense viral genomic nucleic acids and/or replication intermediates. PRRs are mainly localized either to the endosomes, the plasma membrane or the cytoplasm. Recent evidence suggested that several proteins located in the nucleus could also act as viral sensors. In turn, these important elements are becoming the target for most viruses to evade host immune surveillance. In this review, we focus on the recent progress in the study of viral recognition and evasion.

IFN regulatory factor 3 (IRF3) is critical for the transcription of type I IFNs in defensing virus and promoting inflammatory responses. Although several kinds of posttranslational modifications have been identified to modulate the activity of IRF3, whether atypical ubiquitination participates in the function regulation, especially the DNA binding capacity of IRF3, is unknown. In this study, we found that the ovarian tumor domain containing deubiquitinase OTUD1 deubiquitinated IRF3 and attenuated its function. An atypical ubiquitination, K6-linked ubiquitination, was essential for the DNA binding capacity of IRF3 and subsequent induction of target genes. Mechanistically, OTUD1 cleaves the viral infection–induced K6-linked ubiquitination of IRF3, resulting in the disassociation of IRF3 from the promoter region of target genes, without affecting the protein stability, dimerization, and nuclear translocation of IRF3 after a viral infection. Otud1−/− cells as well as Otud1−/− mice produced more type I IFNs and proinflammatory cytokines after viral infection. Otud1−/− mice were more resistant to lethal HSV-1 and VSV infection. Consistent with the former investigations that IRF3 promoted inflammatory responses in LPS-induced sepsis, Otud1−/− mice were more susceptible to LPS stimulation. Taken together, our findings revealed that the DNA binding capacity of IRF3 in the innate immune signaling pathway was modulated by atypical K6-linked ubiquitination and deubiquitination process, which was regulated by the deubiquitinase OTUD1.

Platelet factor 4 (PF4) is an anti-Plasmodium component of platelets. It is expressed in megakaryocytes and released from platelets following infection with Plasmodium. Innate immunity is crucial for the host anti-Plasmodium response, in which type I interferon plays an important role. Whether there is cross-talk between innate immune signaling and the production of anti-Plasmodium defense peptides is unknown. Here we demonstrate that E74, like ETS transcription factor 4 (ELF4), a type I interferon activator, can help protect the host from Plasmodium yoelii infection. Mechanically, ELF4 binds to the promoter of genes of two C-X-C chemokines, Pf4 and pro-platelet basic protein (Ppbp), initiating the transcription of these two genes, thereby enhancing PF4-mediated killing of parasites from infected erythrocytes. Elf4−/− mice are much more susceptible to Plasmodium infection than WT littermates. The expression level of Pf4 and Ppbp in megakaryocytes from Elf4−/− mice is much lower than in those from control animals, resulting in increased parasitemia. In conclusion, our study uncovered a distinct role of ELF4, an innate immune molecule, in host defense against malaria.

Toxoplasma gondii is an important neurotropic pathogen that establishes latent infections in humans that can cause toxoplasmosis in immunocompromised individuals. It replicates inside host cells and has developed several strategies to manipulate host immune responses. However, the cytoplasmic pathogen-sensing pathway that detects T. gondii is not well-characterized. Here, we found that cyclic GMP-AMP synthase (cGAS), a sensor of foreign dsDNA, is required for activation of anti-T. gondii immune signaling in a mouse model. We also found that mice deficient in STING (Sting(gt/gt) mice) are much more susceptible to T. gondii infection than WT mice. Of note, the induction of inflammatory cytokines, type I IFNs, and interferon-stimulated genes in the spleen from Sting(gt/gt) mice was significantly impaired. Sting(gt/gt) mice exhibited more severe symptoms than cGAS-deficient mice after T. gondii infection. Interestingly, we found that the dense granule protein GRA15 from T. gondii is secreted into the host cell cytoplasm and then localizes to the endoplasmic reticulum, mediated by the second transmembrane motif in GRA15, which is essential for activating STING and innate immune responses. Mechanistically, GRA15 promoted STING polyubiquitination at Lys-337 and STING oligomerization in a TRAF protein-dependent manner. Accordingly, GRA15-deficient T. gondii failed to elicit robust innate immune responses compared with WT T. gondii. Consequently, GRA15(−/−) T. gondii was more virulent and caused higher mortality of WT mice but not Sting(gt/gt) mice upon infection. Together, T. gondii infection triggers cGAS/STING signaling, which is enhanced by GRA15 in a STING- and TRAF-dependent manner.

Avian coccidiosis makes a great threat and economic loss to the poultry industry, and fully understanding the innate immune response of chicken against E. tenella infection will play a significant role in avian coccidiosis prevention and treatment. Extracellular traps have been reported as a novel defense mechanism of host against pathogens infection. However, the interaction between chicken heterophil extracellular traps and E. tenella has remained not well known. Thus, this study aims to investigate the effects of E. tenella on chicken heterophil extracellular traps (ETs), and try to clarify the regulatory mechanisms in this process. E. tenella-triggered chicken heterophil ETs structures were analyzed by using scanning electron microscopy (SEM) and scanning confocal microscope. Inhibitors and Pico Green® were used to quantify E. tenella - triggered chicken heterophil ETs release. The results showed that E. tenella sporozoites significantly induced chicken heterophil ETs-like structures release, and histone and elastin co-existed with DNA in these structures of chicken heterophil ETs. Furthermore, it was also demonstrated that NADPH, p38 or Rac1 signaling pathways participated in E. tenella sporozoites-induced chicken heterophil ETs release, but more key molecules or signaling pathways involved in this process still needed to be further investigated. Taken together, this study reports that E. tenella sporozoites could induce chicken heterophil ETs formation via NADPH, p38 and Rac1 signaling pathways, which further suggests the critical role of heterophil ETs in the process of chicken against E. tenella infection.

Pathogen pattern recognition receptors (PRRs) trigger innate immune responses to invading pathogens. All known PRRs for viral RNA have extranuclear localization. However, for many viruses, replication generates dsRNA in the nucleus. Here, we show that the nuclear matrix protein SAFA (also known as HnRNPU) functions as a nuclear viral dsRNA sensor for both DNA and RNA viruses. Upon recognition of viral dsRNA, SAFA oligomerizes and activates the enhancers of antiviral genes, including IFNB1. Moreover, SAFA is required for the activation of super-enhancers, which direct vigorous immune gene transcription to establish the antiviral state. Myeloid-specific SAFA-deficient mice were more susceptible to lethal HSV-1 and VSV infection, with decreased type I IFNs. Thus, SAFA functions as a nuclear viral RNA sensor and trans-activator to bridge innate sensing with chromatin remodeling and potentiate robust antiviral responses.