Depressive symptoms and neuroticism mediate the association between traumatic events and suicidality - A latent class mediation analysis of UK Biobank Database.

BACKGROUND: Mental disorders that follow traumatic experience may increase risk of suicidality, but a comprehensive approach to understand how these mental disorders mediate the association between psychological traumatic experience and suicidality should be elucidated. In this study, we attempted to provide comprehensive evidence on how depressive symptoms and neuroticism can mediate the association between psychological traumatic experiences and suicidal behaviours including suicidal ideation, suicidal planning, and suicide attempts. METHODS: We analyzed 111,931 participants from UK Biobank who had completed mental health web-based questionnaire from 2016 to 2017. "Self-harm and suicidal behaviour and ideation (SSBI) score" was calculated by the response from suicidal behaviours and self-harm questionnaires. Conducting multivariate linear regression, depressive symptoms, anxiety symptoms, and neuroticism were selected as potential mediators. We constructed a latent class mediation model estimated direct effect of psychological traumatic events on suicidality and indirect effect of psychological traumatic events mediated by depressive symptoms and neuroticism. RESULTS: Psychological traumatic events were positively associated with suicidal behaviours. Depressive symptoms and neuroticism significantly mediated the effect of psychological traumatic events on suicidality. Anxiety symptoms did not mediate the association between psychological traumatic events and suicidality. CONCLUSION: Psychological traumatic events, irrespective of life stage of occurrence, are associated with suicidality. The association between psychological traumatic events and suicidality can be partially explained by depressive symptoms and neuroticism of those who were exposed to psychological trauma.

COVID-19 Pandemic-Related Job Loss Impacts on Mental Health in South Korea.

OBJECTIVE: The economic hardship brought by the coronavirus disease-2019 (COVID-2019) pandemic has caused mental health problems among people of different socioeconomic status (SES). As social support helps to buffer these problems, we investigated the association between job loss related to COVID-19 and depression, anxiety, and suicidal thoughts; the differences in the effects according to SES; and the mediating effects of social support. METHODS: The effects of COVID-19-related job loss on depression, anxiety, and suicidal thoughts among 1,364 people were investigated through semi-structured and self-administered questionnaires: Patient Health Questionnaire-9, General Anxiety Disorder-7, and the Functional Social Support Questionnaire. Logistic regression and subgroup analyses were performed to assess the association between job loss and mental health status, and the moderating effects of income and educational levels. Moreover, the mediating effects of perceived social support on the association between job loss and depression, anxiety, and suicidal thoughts were analyzed. RESULTS: COVID-19-related job loss increased the risk of depression and suicidal thoughts. Adults with lower income and education level were at higher risk of depression, anxiety, and suicidal thoughts; perceived social support level had significant mediating effects on the association between job loss and depression/anxiety; and income level had significant moderating effects on this mediating pathway. CONCLUSION: COVID-19-related job loss were likely to be significantly associated with negative mental health outcomes, especially among individuals with low income and education levels. As social support had buffering effects on such outcomes, related government policies in cooperation with the governance of communities and stakeholders must be prepared.

Time-Series Trends of Depressive Levels of Korean Adults During the 2020 COVID-19 Pandemic in South Korea.

OBJECTIVE: This study aimed to observe the changes in people's depressive levels over 9 months since the coronavirus disease of 2019 (COVID-19) outbreak as well as to identify the predictors of people's depressive levels including COVID-19 infection fear in the context of South Korea in 2020. METHODS: For these purposes, four cross-sectional surveys were periodically implemented from March to December 2020. We randomly recruited 6,142 Korean adults (aged 19 to 70) by using a quota survey. Along with descriptive analysis, which included a one-way analysis of variance and correlations, multiple regression models were built to identify the predictors of people's depressive levels during the pandemic. RESULTS: Overall, people's depressive levels and fear of COVID-19 infection gradually increased since the COVID-19 outbreak. In addition to demographic variables (i.e., being a female, young age, unemployed, and living alone) and the duration of the pandemic, people's COVID-19 infection fear was associated with their depressive levels. CONCLUSION: To ameliorate these rising mental health issues, access to mental health services should be secured and expanded, particularly for individuals who present greater vulnerabilities due to socioeconomic characteristics that may affect their mental health.

Downregulation of SOCS1 increases interferon-induced ISGylation during differentiation of induced-pluripotent stem cells to hepatocytes.

Background & Aims: Increased expression of IFN-stimulated gene 15 (ISG15) and subsequently increased ISGylation are key factors in the host response to viral infection. In this study, we sought to characterize the expression of ISG15, ISGylation, and associated enzymes at each stage of differentiation from induced pluripotent stem cells (iPSCs) to hepatocytes. Methods: To study the regulation of ISGylation, we utilized patient samples and in vitro cell culture models including iPSCs, hepatocytes-like cells, immortalized cell lines, and primary human hepatocytes. Protein/mRNA expression were measured following treatment with poly(I:C), IFNα and HCV infection. Results: When compared to HLCs, we observed several novel aspects of the ISGylation pathway in iPSCs. These include a lower baseline expression of the ISGylation-activating enzyme, UBE1L, a lack of IFN-induced expression of the ISGylation-conjugation enzyme UBE2L6, an attenuated activation of the transcription factor STAT1 and constitutive expression of SOCS1. ISGylation was observed in iPSCs following downregulation of SOCS1, which facilitated STAT1 activation and subsequently increased expression of UBE2L6. Intriguingly, HCV permissive transformed hepatoma cell lines demonstrated higher intrinsic expression of SOCS1 and weaker ISGylation following IFN treatment. SOCS1 downregulation in HCV-infected Huh 7.5.1 cells led to increased ISGylation. Conclusions: Herein, we show that high basal levels of SOCS1 inhibit STAT1 activation and subsequently IFN-induced UBE2L6 and ISGylation in iPSCs. Furthermore, as iPSCs differentiate into hepatocytes, epigenetic mechanisms regulate ISGylation by modifying UBE1L and SOCS1 expression levels. Overall, this study demonstrates that the development of cell-intrinsic innate immunity during the differentiation of iPSCs to hepatocytes provides insight into cell type-specific regulation of host defense responses and related oncogenic processes. Impact and implications: To elucidate the mechanism underlying regulation of ISGylation, a key process in the innate immune response, we studied changes in ISGylation-associated genes at the different stages of differentiation from iPSCs to hepatocytes. We found that high basal levels of SOCS1 inhibit STAT1 activation and subsequently IFN-induced UBE2L6 and ISGylation in iPSCs. Importantly, epigenetic regulation of SOCS1 and subsequently ISGylation may be important factors in the development of cell type-specific host defense responses in hepatocytes that should be considered when studying chronic infections and oncogenic processes in the liver.

Factors Related to Anxiety and Depression Among Adolescents During COVID-19: A Web-Based Cross-Sectional Survey.

BACKGROUND: The coronavirus disease 2019 (COVID-19) outbreak and subsequent disease-containment measures (such as school closures) significantly affected the lives of adolescents. We evaluated the mental-health status and factors associated with anxiety and depression among South Korean adolescents. METHODS: A nationwide online survey was conducted to evaluate the mental-health status of South Korean adolescents during the COVID-19 pandemic. In total, 570 adolescents aged 13-18 years were surveyed between May 27 and June 11, 2021. The participants completed the Generalized Anxiety Disorder Scale (GAD-7) and Patient Health Questionnaire (PHQ-9) to determine anxiety and depression symptoms, respectively. Stepwise logistic regression models were constructed to determine factors related to anxiety and depression. RESULTS: Among the study participants, 11.2% and 14.2% had anxiety and depression, respectively. The results suggested that several factors, such as the experience of COVID-19 infection and quarantine of oneself, a family member or an acquaintance, physical and mental health problems, and fear of one's local community being discriminated against as a COVID-19 area were related to anxiety and depression. CONCLUSION: The present study identified COVID-19-related factors associated with anxiety and depression among adolescents, and provides insights regarding potential interventions to improve the mental health of adolescents. To promote the mental health of adolescents during the COVID-19 pandemic, special attention should be paid to individuals with physical or mental-health problems, and efforts should be made to reduce the negative social and emotional impacts of infection-control measures.

Structural Model Analysis of Discriminatory Behavior Toward People With Severe Mental Illness.

OBJECTIVE: This study aimed to determine how prejudice and attitude toward people with severe mental illness, formed through exposure to the mass media, affect discriminatory behavior toward them. METHODS: Between September and November 2019, demographic data were collected using an online survey of 622 adults residing in South Korea. The scales used in this study were taken from the 2008 survey by the National Human Rights Commission of Korea. Structural equation modeling was performed for a comparative analysis of the direct and indirect effects. RESULTS: Virtual experience through mass media exposure had a statistically significant effect on prejudice against people with severe mental illness. Direct experience had a positive influence on reducing prejudice and discriminatory behavior. The direct effects of prejudice on discriminatory behavior were significant. In terms of indirect effects, the full mediating effect of prejudice was significant for the virtual experience through the mass media-prejudice-discriminatory behavior path, and the partial mediating effect of prejudice was significant on the direct experience-prejudice-discrimination behavior path. CONCLUSION: This study recommends more careful reporting of mental illness in the media, promoting anti-stigmatization programs that provide opportunities for direct contact between the public and people with severe mental illness.

Effects of COVID-19-related stress and fear on depression in schizophrenia patients and the general population.

This study compared the coronavirus disease 2019 (COVID-19)-related stress, fear of infection, loneliness, and depression between patients with schizophrenia and the general population. A face-to-face survey was administered to 1340 patients with a schizophrenia spectrum disorder and online survey of the general population (n = 2000) was conducted. The information gathered included the level of COVID-19-related stress, fear of infection, the Patient Health Questionnaire-9 score, and the three-item UCLA Loneliness Scale score. Structural equation modeling revealed a significant effect of fear of COVID-19 infection on depression among the general population and on loneliness among patients with schizophrenia. Loneliness experienced during COVID-19 exacerbated depression in both groups. In the COVID-19-related stress-loneliness-depression pathway, the partial mediating effect of loneliness was significant in both groups. Conversely, in the COVID-19-related fear-loneliness-depression pathway, the full mediating effect of loneliness was only significant in patients with schizophrenia. In conclusion, the loneliness associated with COVID-19-related stress and fear of infection was an important factor influencing depression, and the impact was greater in patients with schizophrenia compared with the general population. Thus, different mental health intervention plans are needed for patients with schizophrenia during the COVID-19 pandemic. During the long-lasting COVID-19 pandemic, social support and provision of mental health services to prevent loneliness and consequent depression are required in patients with schizophrenia.

COVID-19 and Risk Factors of Anxiety and Depression in South Korea.

OBJECTIVE: The aims of this study were to explore the prevalence of and identify predictors of anxiety and depression related to coronavirus disease of 2019 (COVID-19) in South Korea. METHODS: The analysis is based on a quota survey design and a sampling frame that permitted recruitment of a national sample of 1,014 individuals between March 17-31, 2020. Several standardized measurements were used, including GAD-7, PHQ-9, COVID-19 related fear, restrictions in deaily life, as well as sociodemographic information and physical and psychosocial needs during the pandemic. Multiple logistic regression was conducted to analyze the influence of sociodemographic factors, fear, and physical/psychosocial needs on anxiety and depression. RESULTS: Significant numbers of the respondents were identifiable anxiety (19.0%) and depression group (17.5%), respectively. This indicates that the depression and anxiety prevalence rate after the COVID-19 is substantially high compared to the depression rate of 2.6% in 2020 and 2.8% in 2018 both reported in the Korea Community Health Survey and the anxiety rate of 5.7% reported in 2016 Survey of Mental Disorders in Korea. Multiple logistic regression results showed age, COVID-19 related fear, and the level of restrictions in daily as significant factors in understanding and predicting the anxiety group. Likfewise, the COVID-19 related fear, restrictions in daily life, and need for economic support were important predictors in predicting the depression group. CONCLUSION: Findings on predictors for greater vulnerability to anxiety and depression has important implications for public mental health in the context of the COVID-19 pandemic.

Psychosocial Support during the COVID-19 Outbreak in Korea: Activities of Multidisciplinary Mental Health Professionals.

As of April 18, 2020, there have been a total of 10,653 confirmed cases and 232 deaths due to coronavirus disease 2019 (COVID-19) in Korea. The pathogen spread quickly, and the outbreak caused nationwide anxiety and shock. This study presented the anecdotal records that provided a detailed process of the multidisciplinary teamwork in mental health during the COVID-19 outbreak in the country. Psychosocial support is no less important than infection control during an epidemic, and collaboration and networking are at the core of disaster management. Thus, a multidisciplinary team of mental health professionals was immediately established and has collaborated effectively with its internal and external stakeholders for psychosocial support during the COVID-19 outbreak.

HIV and HCV augments inflammatory responses through increased TREM-1 expression and signaling in Kupffer and Myeloid cells.

Chronic infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) affects an estimated 35 million and 75 million individuals worldwide, respectively. These viruses induce persistent inflammation which often drives the development or progression of organ-specific diseases and even cancer including Hepatocellular Carcinoma (HCC). In this study, we sought to examine inflammatory responses following HIV or HCV stimulation of macrophages or Kupffer cells (KCs), that may contribute to virus mediated inflammation and subsequent liver disease. KCs are liver-resident macrophages and reports have provided evidence that HIV can stimulate and infect them. In order to characterize HIV-intrinsic innate immune responses that may occur in the liver, we performed microarray analyses on KCs following HIV stimulation. Our data demonstrate that KCs upregulate several innate immune signaling pathways involved in inflammation, myeloid cell maturation, stellate cell activation, and Triggering Receptor Expressed on Myeloid cells 1 (TREM1) signaling. TREM1 is a member of the immunoglobulin superfamily of receptors and it is reported to be involved in systemic inflammatory responses due to its ability to amplify activation of host defense signaling pathways. Our data demonstrate that stimulation of KCs with HIV or HCV induces the upregulation of TREM1. Additionally, HIV viral proteins can upregulate expression of TREM1 mRNA through NF-кB signaling. Furthermore, activation of the TREM1 signaling pathway, with a targeted agonist, increased HIV or HCV-mediated inflammatory responses in macrophages due to enhanced activation of the ERK1/2 signaling cascade. Silencing TREM1 dampened inflammatory immune responses elicited by HIV or HCV stimulation. Finally, HIV and HCV infected patients exhibit higher expression and frequency of TREM1 and CD68 positive cells. Taken together, TREM1 induction by HIV contributes to chronic inflammation in the liver and targeting TREM1 signaling may be a therapeutic option to minimize HIV induced chronic inflammation.

TIR-Domain-Containing Adapter-Inducing Interferon-ß (TRIF) Regulates CXCR5+ T helper Cells in the Intestine.

OBJECTIVE: Establishing an effective humoral immunity is an important host defense mechanism in intestinal mucosa. T follicular helper (Tfh) cells are a spectrum of CXCR5 expressing T helper cells that induce antigen-specific B cell differentiation. Because the differentiation of T helper cells is largely regulated by innate immunity, we addressed whether TRIF signaling regulates Tfh cell differentiation and its ability to trigger humoral immune responses in the intestine. METHOD: CD4+CXCR5+ T cells, B cells, and plasma cells in the Peyer's patches (PPs) of WT and TRIF-deficient (TrifLPS2) mice were analyzed by flow cytometry at the baseline, 9 days post primary infection, and 7 days post-secondary infection with Y. enterocolitica. Y. enterocolitica-specific CD4+CXCR5+ T cells were generated in vitro by co-culturing peritoneal macrophages with splenic naïve T cells in the presence of Y. enterocolitica lysate. WT and TrifLPS2 mice received CD4+CXCR5+ T cells isolated either from Y. enterocolitica-primed WT mice or generated in vitro. These mice were infected with Y. enterocolitica and followed up to 4 weeks. Y. enterocolitica-specific IgA and IgG were measured in stool and serum samples, respectively. RESULTS: At baseline, CD4+CXCR5+ T cell proportion was higher but the proportion of B cells and plasma cells was lower in the PPs of TrifLPS2 mice compared to WT mice. After infection, the proportion of plasma cells also became higher in the PPs of TrifLPS2 mice compared to WT mice. Corresponding increase of Y. enterocolitica-specific stool IgA but not serum IgG was found in TrifLPS2 mice compared to WT mice. Both in vivo isolated and in vitro generated CD4+CXCR5+ T cells induced protective immunity against Y. enterocolitica infection. CONCLUSION: Our results reveal a novel role of TRIF in the regulation of humoral immunity in the intestine that can be utilized as a basis for a unique vaccine strategy.

Hepatitis B Virus and DNA Stimulation Trigger a Rapid Innate Immune Response through NF-κB.

Cell-intrinsic innate immunity provides a rapid first line of defense to thwart invading viral pathogens through the production of antiviral and inflammatory genes. However, the presence of many of these signaling pathways in the liver and their role in hepatitis B virus (HBV) pathogenesis is unknown. Recent identification of intracellular DNA-sensing pathways and involvement in numerous diverse disease processes including viral pathogenesis and carcinogenesis suggest a role for these processes in HBV infection. To characterize HBV-intrinsic innate immune responses and the role of DNA- and RNA-sensing pathways in the liver, we used in vivo and in vitro models including analysis of gene expression in liver biopsies from HBV-infected patients. In addition, mRNA and protein expression were measured in HBV-stimulated and DNA-treated hepatoma cell lines and primary human hepatocytes. In this article, we report that HBV and foreign DNA stimulation results in innate immune responses characterized by the production of inflammatory chemokines in hepatocytes. Analysis of liver biopsies from HBV-infected patients supported a correlation among hepatic expression of specific chemokines. In addition, HBV elicits a much broader range of gene expression alterations. The induction of chemokines, including CXCL10, is mediated by melanoma differentiation-associated gene 5 and NF-κB-dependent pathways after HBV stimulation. In conclusion, HBV-stimulated pathways predominantly activate an inflammatory response that would promote the development of hepatitis. Understanding the mechanism underlying these virus-host interactions may provide new strategies to trigger noncytopathic clearance of covalently closed circular DNA to ultimately cure patients with HBV infection.

Oncogenic human T-cell lymphotropic virus type 1 tax suppression of primary innate immune signaling pathways.

UNLABELLED: Human T-cell lymphotropic virus type I (HTLV-1) is an oncogenic retrovirus considered to be the etiological agent of adult T-cell leukemia (ATL). The viral transactivator Tax is regarded as the oncoprotein responsible for contributing toward the transformation process. Here, we demonstrate that Tax potently inhibits the activity of DEx(D/H) box helicases RIG-I and MDA5 as well as Toll-dependent TIR-domain-containing adapter-inducing interferon-ß (TRIF), which function as cellular sensors or mediators of viral RNA and facilitate innate immune responses, including the production of type I IFN. Tax manifested this function by binding to the RIP homotypic interaction motif (RHIM) domains of TRIF and RIP1 to disrupt interferon regulatory factor 7 (IRF7) activity, a critical type I IFN transcription factor. These data provide further mechanistic insight into HTLV-1-mediated subversion of cellular host defense responses, which may help explain HTLV-1-related pathogenesis and oncogenesis. IMPORTANCE: It is predicted that up to 15% of all human cancers may involve virus infection. For example, human T-cell lymphotropic virus type 1 (HTLV-1) has been reported to infect up to 25 million people worldwide and is the causative agent of adult T-cell leukemia (ATL). We show here that HTLV-1 may be able to successfully infect the T cells and remain latent due to the virally encoded product Tax inhibiting a key host defense pathway. Understanding the mechanisms by which Tax subverts the immune system may lead to the development of a therapeutic treatment for HTLV-1-mediated disease.

Human intestinal epithelial cells express interleukin-10 through Toll-like receptor 4-mediated epithelial-macrophage crosstalk.

In the intestine, interaction between epithelial cells and macrophages (MΦs) create a unique immunoregulatory microenvironment necessary to maintain local immune and tissue homeostasis. Human intestinal epithelial cells (IECs) have been shown to express interleukin (IL)-10, which keeps epithelial integrity. We have demonstrated that bacterial signaling through Toll-like receptor (TLR) 4 induces 15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2) synthesis in intestinal MΦs by cyclooxygenase (Cox)-2 expression. Here, we show that TLR4 signaling generates crosstalk between IECs and MΦs that enhances IL-10 expression in IECs. Direct stimulation of TLR4 leads to the expression of IL-10 in IECs, while the presence of MΦs in a Transwell system induces another peak in IL-10 expression in IECs at a later time point. The second peak of the IL-10 expression is two times greater than the first peak. This late induction of IL-10 depends on the nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ that is accumulated in IECs by TLR4-mediated inhibition of the ubiquitin-proteasomal pathway. TLR4 signaling in MΦs in turn synthesizes 15d-PGJ2 through p38 and ERK activation and Cox-2 induction, which activates PPARγ in IECs. These results suggest that TLR4 signaling maintains IL-10 production in IECs by generating epithelial-MΦs crosstalk, which is an important mechanism in the maintenance of intestinal homeostasis mediated through host-bacterial interactions.

A unique host defense pathway: TRIF mediates both antiviral and antibacterial immune responses.

Both anti-viral and anti-bacterial host defense mechanisms involve TRIF signaling. TRIF provides early clearance of pathogens and coordination of a local inflammatory ensemble through an interferon cascade, while it may trigger organ damage. The multipotentiality of TRIF-mediated immune machinery may direct the fate of our continuous battle with microbes.

TRIF mobilizes unique primary defense against Gram-negative bacteria in intestinal interface.

The gastrointestinal tract is the largest mucosal surface in our body. It houses diverse microorganisms that collectively form the commensal microbial community. The security of this community is kept by host-microbial interactions and is violated by foreign pathogens that induce local as well as systemic pathology. In most cases, gastrointestinal infections are caused by Gram-negative enteropathogens, which trigger host immune responses through the TLR4 signaling pathways. Although TRIF is one of the major pathways downstream of TLR4, very little is known about how the TRIF pathway contributes to intestinal defense against pathogenic infection. Recently, we reported a unique role of TRIF signaling in host response to an enterophathogen Yersinia enterocolitica, which consisted of IFN-ß induction from regional macrophages followed by activation of NK cells in the mesenteric lymph nodes. In this addendum, we show distinct roles for TRIF-dependent host response in intestinal vs. systemic infection with Gram-negative enterophathogens.