Yuk Ying Tung

Lymphocyte and antibody responses reduce enterovirus 71 lethality in mice by decreasing tissue viral loads

ABSTRACT Enterovirus 71 (EV71) infects the central nervous system and causes death and long-term neurological sequelae in hundreds of thousands of young children, but its pathogenesis remains elusive. Immunopathological mechanisms have been suspected to contribute to the pathogenesis of neurological symptoms, so anti-inflammatory agents have been used to treat patients with neurological symptoms. The present study was therefore designed to investigate the functions of lymphocyte and antibody responses in EV71 infection using a mouse model. Immunohistochemical staining analysis revealed virus and three types of lymphocytes, B cells, CD4 T cells, and CD8 T cells, in the spinal cord of an EV71-infected patient who died. A study of mice showed that the levels of virus and lymphocytes in brains and antibody titers in sera were elevated during the time when the mice succumbed to death in a phenomenon analogous to that observed in patients. Further studies demonstrated that after infection, the disease severity, mortality, and tissue viral loads of mice deficient in B, CD4 T, or CD8 T cells were significantly higher than those of wild-type mice. In addition, treatment with a virus-specific antibody, but not a control antibody, before or after infection significantly reduced the disease severity, mortality, and tissue viral loads of mice deficient in B cells. Our results show that both lymphocyte and antibody responses protect mice from EV71 infection. Our study suggests the use of vaccines and virus-specific antibodies to control fatal outbreaks and raises caution over the use of corticosteroids to treat EV71-infected patients with neurological symptoms.

Enterovirus 71 infection of human dendritic cells.

Enterovirus 71 (EV71) causes death and long-term neurologic sequelae in hundreds of thousands of young children, but its pathogenesis remains elusive. Dendritic cells (DCs) play a crucial role in antiviral immunity by functioning as professional antigen-presenting cells to prime T cells and by secreting cytokines to modulate immune responses. Here, we show that EV71 productively infected human immature DCs and expressed viral antigen in DCs. EV71 entry into DCs was partially mediated by DC-SIGN. Further analyses revealed that EV71 increased the viability, activation, release of cytokines, interleukin-6, interleukin-12, and tumor necrosis factor-α in DCs. Moreover, EV71 enabled DCs to stimulate T-cell proliferation. Collectively, these findings suggest that EV71 infection of human DCs in vivo is very likely to elicit protective immunity, because in infected mice, both T cells and IL-6 function to reduce mortality.

Factors affecting herpes simplex virus reactivation from the explanted mouse brain

The majority of encephalitis induced by herpes simplex virus type I (HSV-1) is due to viral reactivation from latency, but few studies have investigated the factors influencing viral reactivation in the brain due to the lack of a sensitive assay. We have established an ex vivo explant assay, which induced efficient viral reactivation in the dissociated mouse brain. Applying this assay, we investigated the infection of four HSV-1 strains with varying degrees of neurovirulence in three mouse strains with different levels of susceptibility to HSV-1 infection. We found that virulent HSV-1 strains and susceptible mouse strains exhibited prolonged viral growth during acute infection, increased latent viral genomes, and efficient explant reactivation in the brain stem. Collectively, both viral neurovirulence and host susceptibility positively correlate with HSV-1 reactivation from the explanted mouse brain.

In Vivo Reactivation of Latent Herpes Simplex Virus 1 in Mice Can Occur in the Brain before Occurring in the Trigeminal Ganglion

ABSTRACT Herpes simplex virus 1 (HSV-1) establishes latency in neurons of the brains and sensory ganglia of humans and experimentally infected mice. The latent virus can reactivate to cause recurrent infection. Both primary and recurrent infections can induce diseases, such as encephalitis. In humans, the majority of encephalitis cases occur as a recurrent infection. However, in the past, numerous mouse studies documented that viral reactivation occurs efficiently in the ganglion, but extremely rarely in the brain, when assessed ex vivo by cultivating minced tissue explants. Here, we compare the brains and the trigeminal ganglia of mice latently infected with HSV-1 (strain 294.1 or McKrae) for levels of viral genomes and in vivo reactivation. The numbers of copies of 294.1 and McKrae genomes in the brain stem were significantly greater than those in the trigeminal ganglion. Most importantly, 294.1 and McKrae reactivation was detected in the brain stems earlier than in the trigeminal ganglia of mice treated with hyperthermia to reactivate latent virus in vivo. In addition, the brain stem yielded reactivated virus at a high frequency compared with the trigeminal ganglion, especially in mice latently infected with 294.1 after hyperthermia treatment. These results provide evidence that recurrent brain infection can be induced by the reactivation of latent virus in the brain in situ. IMPORTANCE Herpes simplex virus 1 (HSV-1) establishes latency in neurons of the brains and sensory ganglia of humans and experimentally infected mice. The latent virus can reactivate to cause recurrent infection. In the past, studies of viral reactivation focused on the ganglion, because efficient viral reactivation was detected in the ganglion but not in the brain when assessed ex vivo by cultivating mouse tissue explants. In this study, we report that the brain contains more viral genomes than the trigeminal ganglion in latently infected mice. Notably, the brain yields reactivated virus early and efficiently compared with the trigeminal ganglion after mice are stimulated to reactivate latent virus. Our findings raise the potential importance of HSV-1 latent infection and reactivation in the brain.

Absence of CXCL10 Aggravates Herpes Stromal Keratitis with Reduced Primary Neutrophil Influx in Mice

ABSTRACT Herpes simplex virus 1 (HSV-1) replication initiates inflammation and angiogenesis responses in the cornea to result in herpetic stromal keratitis (HSK), which is a leading cause of infection-induced vision impairment. Chemokines are secreted to modulate HSK by recruiting leukocytes, which affect virus growth, and by influencing angiogenesis. The present study used a murine infection model to investigate the significance of the chemokine CXC chemokine ligand 10 (CXCL10; gamma interferon-inducible protein 10 [IP-10]) in HSK. Here, we show that HSV-1 infection of the cornea induced CXCL10 protein expression in epithelial cells. The corneas of mice with a targeted disruption of the gene encoding CXCL10 displayed decreases in levels of neutrophil-attracting cytokine (interleukin-6), primary neutrophil influx, and viral clearance 2 or 3 days postinfection. Subsequently, absence of CXCL10 aggravated HSK with elevated levels of interleukin-6, chemokines for CD4+ T cells and/or neutrophils (macrophage inflammatory protein-1α and macrophage inflammatory protein-2), angiogenic factor (vascular endothelial growth factor A), and secondary neutrophil influx, as well as infiltration of CD4+ T cells to exacerbate opacity and angiogenesis in the cornea at 14 and up to 28 days postinfection. Our results collectively show that endogenous CXCL10 contributes to recruit the primary neutrophil influx and to affect the expression of cytokines, chemokines, and angiogenic factors as well as to reduce the viral titer and HSK severity.

Adolescents' avoidance of secondhand smoke exposure: Model testing

More than half of young adolescents, 13 to 15 years old, suffer exposure to secondhand smoke (SHS) at home and in public places. Despite threats to adolescent health and well-being, little research has been done to identify factors that enable adolescents to avoid SHS. The objective of this study was to develop a model to predict SHS avoidance behavior among young adolescents. The impact of gender differences on predictor variances was investigated. Model testing was conducted using structural equation modeling on data from 1,291 nonsmoking Taiwanese middle school students. Attitude toward SHS is an important factor influencing the avoidance behavior of adolescents. The explanatory model of SHS avoidance behaviors provides useful information for program development aimed at decreasing adolescent exposure to SHS. Interventions focused on influencing adolescent attitudes toward SHS and supporting avoidance self-efficacy are needed.

Enterovirus 71 infection increases expression of interferon-gamma-inducible protein 10 which protects mice by reducing viral burden in multiple tissues.

Enterovirus 71 (EV71) infection has induced fatal encephalitis in thousands of young children in the Asia-Pacific region over the last decade. EV71 infection continues to cause serious problems in areas with outbreaks, because vaccines and antiviral therapies are not available. Lymphocytes are present in the brains of infected patients and mice, and they protect mice from infection by decreasing the viral burden. The chemokines responsible for recruiting lymphocytes to infected organs are yet to be identified. Among the lymphocyte chemokines detected, high levels of interferon-gamma-inducible protein-10 (IP-10) are found in the plasma and cerebral spinal fluid of patients with brainstem encephalitis as compared with the levels of a monokine induced by gamma interferon (Mig). Using a murine model to investigate the induction of IP-10 by EV71 infection, we observed that EV71 infection significantly enhanced IP-10 protein expression in the serum and brain, with kinetics similar to viral titres in the blood and brain. Brain neurons of infected mice expressed IP-10. Using wild-type mice and IP-10 gene knockout mice to investigate the role of IP-10 in EV71 infection, we found that IP-10 deficiency significantly reduced levels of Mig in serum, and levels of gamma interferon and the number of CD8 T cells in the mouse brain. Absence of IP-10 significantly increased the mortality of infected mice by 45%, with slow virus clearance in several vital tissues. Our observations are consistent with a model where EV71 infection boosts IP-10 expression to increase gamma interferon and Mig levels, infiltration of CD8 T cells, virus clearance in tissues and the survival of mice.

Delay in seeking medical evaluations and predictors of self-efficacy among women with newly diagnosed breast cancer: A longitudinal study

BACKGROUND Delaying a diagnosis of breast cancer directly and positively impacts survival. Self-efficacy has been shown to be a causal mechanism in a wide range of health behaviors, a measurable trait that predicts behavior across domains, which is strong associated with psychological variables. However, factors predicting self-efficacy of women with suspected breast cancer who delayed or did not delay seeking a breast cancer diagnosis over time have not been identified. OBJECTIVES To examine the differences between women who delay and women who did not delay seeking a cancer diagnosis, and key factors predicting self-efficacy over time among women with newly-diagnosed breast cancer. DESIGN Descriptive, longitudinal design over 2 months following breast cancer diagnostic evaluation. SETTING A medical center is located in southern Taiwan. PARTICIPANTS Eighty women with suspected breast cancer were approached and 67 subjects with a positive diagnosis of breast cancer were recruited. METHODS Subjects were categorized into women who delayed their diagnosis and women who did not delay their diagnosis. A battery of 5 standardized questionnaires including self-efficacy, anxiety and depression, personality, spiritual support and hope was completed at the first three clinic visits. RESULTS Stage of cancer, trait extroversion/neuroticism and spiritual support were significantly different between groups (p<0.05). Subjects who did not delay (β=-1.613, p<0.05), and time that histology results were provided (β=-2.4333, p<0.001) had a significantly predicted negative change in self-efficacy compared to the group that delayed. Hope at the first clinic visit contributed to the change in self-efficacy over time (β=0.391, p<0.001). CONCLUSIONS Personal factors affecting a womans delay in obtaining medical assessment of breast cancer confirmation. Hope impacts self-efficacy of women with suspected breast cancer and interventions to enhance hope during the early stages of breast cancer evaluation require further study.

Internet use expectancy for tension reduction and disinhibition mediates the relationship between borderline personality disorder features and Internet addiction among college students - One-year follow-up

Borderline personality disorder (BPD) features with affective instability and impulsivity have been shown to correlate with Internet addiction (IA) in cross-sectional studies. Moreover, Internet use expectancies were found to be positively associated with IA. Thus, this follow-up study was aimed to examine whether BPD features would increase the risk for IA severity, mediated through the Internet use expectation as a coping method for tension reduction and disinhibition.1826 Taiwan college students were sampled through a stratified and random clustering in time 1 (T1), and 623 students were followed up one year later (T2). A comprehensive survey was administered.Structure equation modeling results showed that IA severity (T2) was significantly predicted by BPD features (T1), fully mediated through Internet use expectancy for tension reduction and disinhibition (T2). The model yielded an adequate fit, and was able to explain 43.0% of the variance.The mediating role of the Internet use expectation for tension reduction and disinhibition in the relationship between BPD features and IA severity were discussed. BPD features (T1) was significantly correlated with IA severity (T2).BPD features (T1) was significantly correlated with IUETRD (T2).Internet use expectancy fully mediated the relationship between BPD (T1) and IA (T2).

Effect of previous diagnoses of depression, menopause status, vasomotor symptoms, and neuroticism on depressive symptoms among climacteric women: A 30-month follow-up

OBJECTIVES The research was designed to examine the impact of the previous diagnoses of depression, menopause status, vasomotor symptoms, and neuroticism on depressive symptoms among menopausal women in Taiwan over a 30-month follow-up. MATERIALS AND METHODS A community-based sample of 190 middle-aged women was enrolled. The Menopausal Symptoms Scale, Neuroticism Extraversion Openness Five Factor Inventory-Chinese version, and Kos Depression Inventory were applied, and results were assessed. In addition, each woman underwent a semistructured diagnostic interview with the Chinese version of the Modified Schedule of Affective Disorders and Schizophrenia-Lifetime to obtain her lifetime psychiatric history. After 30 months, 111 participants completed follow-up questionnaires. RESULTS Results of the hierarchical multiple regression analyses showed that depressive symptoms during the menopause transition predicted depressive symptoms over 30 months. After controlling for depressive symptoms during the menopause transition, the previous diagnoses of depression, menopause status, and vasomotor symptoms could not predict depressive symptoms over 30 months, whereas neuroticism still predicted depressive symptoms over 30 months. CONCLUSION The research suggested that neuroticism plays an important role in the persistence of depression among climacteric women after 30 months.