African Swine Fever Virus E184L Protein Interacts with Innate Immune Adaptor STING to Block IFN Production for Viral Replication and Pathogenesis.

African swine fever is one of the most serious viral diseases that affects domestic and wild pigs. The causative agent, African swine fever virus (ASFV), has evolved sophisticated immune evasion mechanisms that target both innate and adaptive immune responses. However, the underlying molecular mechanisms have not been fully understood. Here, we report that ASFV E184L protein inhibits host innate immune response via targeting the stimulator of IFN genes (STING)-mediated signaling pathway in both human embryonic kidney HEK-293T cells and porcine pulmonary alveolar macrophages. E184L interacts with STING, impairing dimerization and oligomerization of STING but not affecting its puncta formation at the perinuclear region. Furthermore, E184L disrupts STING-TBK1-IRF3 complex formation, leading to inhibition of STING phosphorylation, and IRF3 dimerization and nuclear translocation. The 1-20 aa region in E184L is essential for E184L-STING interaction and blocking IL-1ß and type I IFN production. Deletion of E184L in ASFV considerably impairs antagonistic function of the virus in suppression of the STING-mediated antiviral response, an effect that is reversible by introduction of E184L. Importantly, the virulence of mutant ASFV lacking E184L is reduced in pigs compared with its parental virus due to induction of higher IFN production in vivo. Our findings indicate that ASFV E184L is an important antagonist of IFN signaling to evade host innate immune antiviral responses, which improves our understanding of immune evasion mechanisms of ASFV.

Porcine Epidemic Diarrhea Virus Membrane Protein Interacted with IRF7 to Inhibit Type I IFN Production during Viral Infection.

Porcine epidemic diarrhea virus (PEDV) is a highly pathogenic porcine enteropathogenic coronavirus causing severe enteritis and lethal watery diarrhea in piglets. PEDV infection suppresses the synthesis of type I IFN, and multiple viral proteins of PEDV have been shown to target the adaptors of innate immune pathways to inhibit type I IFN production. In this study, we identified PEDV membrane (M) protein as a new antagonist of type I IFN production in both human embryonic kidney HEK293T cells and porcine kidney PK-15 cells and determined the antagonistic mechanism used by M protein to target IFN regulatory factor 7 (IRF7), an important regulator of type I IFN production. IRF7 is phosphorylated and activated by TBK1 and IKKε in response to viral infection. We found that PEDV M protein interacted with the inhibitory domain of IRF7 and significantly suppressed TBK1/IKKε-induced IRF7 phosphorylation and dimerization of IRF7, leading to the decreased expression of type I IFN, although it did not affect the interaction between TBK1/IKKε and IRF7. As expected, overexpression of M protein significantly increased PEDV replication in porcine cells. The M proteins of both epidemic PEDV strains and vaccine strain showed similar antagonistic effect on type I IFN production, and the 1-55 region of M protein was essential for disruption of IRF7 function by interacting with IRF7. Taken together, our data identified a new, to our knowledge, IFN antagonist of PEDV, as well as a novel, to our knowledge, antagonistic mechanism evolved by PEDV to inhibit type I IFN production.

Sex differences in residual somatic symptoms in patients with first-episode depression after acute-phase treatment.

BACKGROUND: Residual somatic symptoms (RSS) are common in depressed patients, predicting treatment effectiveness. However, sex differences in RSS have received little systematic study. This study was conducted to compare sex differences of RSS in patients with first-episode depression (FED). METHODS: Nine hundred eighty-two patients with FED were selected and treated for 8 to 12 weeks. We evaluated the subjects' socio-demographic characteristics and residual depressive symptoms. Using the Patient Health Questionnaire-15 (PHQ-15) scale to assess residual somatic symptoms, the Sheehan Disability Scale (SDS) for the assessment of patients' function, the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) for quality of life. RESULTS: The incidence of RSS with FED was 46.4%. For patients with residual symptoms, the age and age of onset in females were higher than males, but males had more years of education than females. The degree of "stomach pain" in females was more severe than in males, while "trouble sleeping" in males was more severe than that in females. Multiple regression analysis showed that the total Q-LES-Q-SF score was an independent influencing factor of RSS in both males and females, while the total SDS score only affected female RSS. CONCLUSIONS: The prevalence of RSS in FED after acute-phase treatment is high. The symptom of "stomachache" is more pronounced in females, while "trouble sleeping" is more severe in males. Quality of life plays an essential role in RSS in both genders. Thus, sex needs to be considered when assessing the relationship between RSS and therapeutic effect in depression.

TREM2 regulates BV2 microglia activation and influences corticosterone-induced neuroinflammation in depressive disorders.

Depressive disorders is a serious mental illness, and its underlying pathological mechanisms remain unclear. The overactivation of microglia and neuroinflammation are thought to play an essential role in the occurrence and development of depressive disorders. TREM2, an immune protein mainly expressed in microglia, is an important part of nerve cells involved in inflammatory response. Corticosterone (CORT) is often referred to as a stress hormone and plays a role in the immune system and stress response. Therefore, this study investigated the role of TREM2 in CORT-induced BV2 cell damage and preliminarily analyzed the effects of TREM2 on JAK2/STAT3 signaling pathway and microglia polarization. The cell model of CORT-induced depression in vitro was established, and the effect of CORT on the activity of BV2 microglia was detected by CCK8. Plasmid transfection was used to overexpress and interfere with TREM2 in BV2 cells cultured by CORT. Western blotting, PCR, and ELISA analyzed the expression of related proteins and inflammatory factors. The results showed that CORT could affect BV2 cell proliferation and TREM2 levels. In the presence of CORT, overexpression of TREM2 decreased the levels of TNF-α, IL-1ß, and IL-6 and increased the levels of IL-10. Interference with TREM2 increased the levels of TNF-α, IL-1ß, and IL-6 and decreased the levels of IL-10. TREM2 can affect the release of inflammatory factors through the JAK2/STAT3 signaling pathway and regulate the M1/M2 phenotypic transformation of microglia. TREM2 plays a role in regulating CORT-induced inflammatory responses, revealing the influence of TREM2 on the neuroinflammatory pathogenesis of depressive disorders and suggesting that TREM2 may be a new target for the prevention and treatment of depressive disorders.

FoxJ1 inhibits African swine fever virus replication and viral S273R protein decreases the expression of FoxJ1 to impair its antiviral effect.

African swine fever (ASF) is a highly pathogenic swine infectious disease that affects domestic pigs and wild boar, which is caused by the African swine fever virus (ASFV). ASF has caused huge economic losses to the pig industry and seriously threatens global food security and livestock health. To date, there is no safe and effective commercial vaccine against ASF. Unveiling the underlying mechanisms of ASFV-host interplay is critical for developing effective vaccines and drugs against ASFV. In the present study, RNA-sequencing, RT-qPCR and Western blotting analysis revealed that the transcriptional and protein levels of the host factor FoxJ1 were significantly down-regulated in primary porcine alveolar macrophages (PAMs) infected by ASFV. RT-qPCR analysis showed that overexpression of FoxJ1 upregulated the transcription of type I interferon and interferon stimulating genes (ISGs) induced by poly(dA:dT). FoxJ1 revealed a function to positively regulate innate immune response, therefore, suppressing the replication of ASFV. In addition, Western blotting analysis indicated that FoxJ1 degraded ASFV MGF505-2R and E165R proteins through autophagy pathway. Meanwhile, RT-qPCR and Western blotting analysis showed that ASFV S273R inhibited the expression of FoxJ1. Altogether, we determined that FoxJ1 plays an antiviral role against ASFV replication, and ASFV protein impairs FoxJ1-mediated antiviral effect by degradation of FoxJ1. Our findings provide new insights into the antiviral function of FoxJ1, which might help design antiviral drugs or vaccines against ASFV infection.

Porcine epidemic diarrhea virus nsp14 inhibits NF-κB pathway activation by targeting the IKK complex and p65.

Coronaviruses (CoVs) are a group of related enveloped RNA viruses that have severe consequences in a wide variety of animals by causing respiratory, enteric or systemic diseases. Porcine epidemic diarrhea virus (PEDV) is an economically important CoV distributed worldwide that causes diarrhea in pigs. nsp14 is a nonstructural protein of PEDV that is involved in regulation of innate immunity and viral replication. However, the function and mechanism by which nsp14 modulates and manipulates host immune responses remain largely unknown. Here, we report that PEDV nsp14 is an NF-κB pathway antagonist. Overexpression PEDV nsp14 protein remarkably decreases SeV-, poly (I:C)- and TNF-α-induced NF-κB activation. Meanwhile, expression of proinflammatory cytokines is suppressed by nsp14. nsp14 inhibits the phosphorylation of IKKs by interacting with IKKs and p65. Furthermore, nsp14 suppresses TNF-α-induced phosphorylation and nuclear import of p65. Overexpression nsp14 considerably increases PEDV replication. These results suggest a novel mechanism employed by PEDV to suppress the host antiviral response, providing insights that can guide the development of antivirals against CoVs.