Modulation of Mitochondria During Viral Infections

Mitochondria are organelles critical for cell survival because they produce ATP and modulate programmed cell death (PCD) pathways. PCD pathways are important in many clinical disorders, such as ischemia/reperfusion injuries, trauma, and toxic/metabolic syndromes, as well as in chronic neurodegenerative conditions, such as amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Moreover, many viruses and other pathogens target the mitochondria. Viruses induce the production of various proteins in their hosts that have proapoptotic and anti-apoptotic activities, depending on the cellular environment. More specifically, many viruses that target mitochondria regulate the balance between the anti- and proapoptotic Bcl-2 family proteins and thereby increase their own survival within the host cell. Recent studies indicated that mitochondria centralize several critical innate immune responses based on the presence of several important signaling proteins within the mitochondria: mitochondrial antiviral signaling (MAVS), stimulation of interferon genes (STING), and NLR family member X1. Therefore, mitochondria are not only vital because they regulate cell survival and death but also they have broad roles in the control of cell functions following pathogen invasion. This chapter highlights the tight interplay between viral infection and mitochondria

Betanodavirus non-structural protein B1: A novel anti-necrotic death factor that modulates cell death in early replication cycle in fish cells

AbstractThe functions of the Betanodavirus non-structural protein B1 is still unknown. We examined B1 expression patterns and investigated novel cell death regulatory functions for this viral protein following RGNNV infection in fish cells. The B1 gene (336 nt) was cloned from the redspotted grouper nervous necrosis virus (RGNNV) genome. B1 mRNA was rapidly expressed in the fish cells from viral RNA3 at 12 h post-infection (p.i.). At the protein level, expression was low at 12 h p.i., and then increased rapidly between 24 h and 72 h p.i. In RGNNV-infected, B1-containing fish cells, over expression of RGNNV B1 reduced Annexin-V positive cells by 50% and 65% at 48 h and 72 h p.i., respectively, and decreased loss of mitochondrial membrane potential (MMP) by 20% and 70% at 48 h and 72 h p.i., respectively. Finally, B1 knockdown during RGNNV infection using anti-sense RNA increased necrotic cell death and reduced cell viability during the early replication cycle (24 h p.i.). Our results suggest that B1 is an early expression protein that has an anti-necrotic cell death function which reduces the MMP loss and enhances viral host cell viability. This finding provides new insights into RNA viral pathogenesis and disease control

The Role of PSR in Zebrafish (Danio rerio) at Early Embryonic Development

During development, the role of the phosphatidylserine receptor (PSR) in the professional removal of apoptotic cells that have died is few understood. Programmed cell death (PCD) began during the shield stage (5.4 hpf), with dead cells being engulfed by a neighboring cell that showed a normal-looking nucleus and the nuclear condensation multi-micronuclei of an apoptotic cell. Recently, in the zebrafish model system, PS receptor played a new role on corpse cellular cleaning for further normal development during early embryonic development, which also correlated with tissues’ or organs’ complete development and organogenesis. In the present, we summary new story that a transcriptional factor, YY1a, in the upstream of PSR is how to regulate PS receptor expression that linked to function of PSR-phagocyte mediated apoptotic cell engulfment during development, especially the development of organs such as the brain and heart. YY1a/PSR-mediated engulfing system may involve in diseases and therapy. This engulfing system may provide new insight into phosphatidylserine receptor how to dynamitic interaction with apoptotic cell during priming programmed cell death

Betanodavirus Induces Oxidative Stress-Mediated Cell Death That Prevented by Anti-Oxidants and Zfcatalase in Fish Cells

The role of oxidative stress in the pathogenesis of RNA nervous necrosis virus infection is still unknown. Red-spotted grouper nervous necrosis virus (RGNNV) induced free radical species (ROS) production at 12–24 h post-infection (pi; early replication stage) in fish GF-1 cells, and then at middle replication stage (24–48 h pi), this ROS signal may upregulate some expressions of the anti-oxidant enzymes Cu/Zn SOD and catalase, and eventually expression of the transcription factor Nrf2. Furthermore, both antioxidants diphenyliodonium and N-acetylcysteine or overexpression of zebrafish catalase in GF-1 cells also reduced ROS production and protected cells for enhancing host survival rate due to RGNNV infection

Stage-Specific Expression of TNFα Regulates Bad/Bid-Mediated Apoptosis and RIP1/ROS-Mediated Secondary Necrosis in Birnavirus-Infected Fish Cells

Infectious pancreatic necrosis virus (IPNV) can induce Bad-mediated apoptosis followed by secondary necrosis in fish cells, but it is not known how these two types of cell death are regulated by IPNV. We found that IPNV infection can regulate Bad/Bid-mediated apoptotic and Rip1/ROS-mediated necrotic death pathways via the up-regulation of TNFα in zebrafish ZF4 cells. Using a DNA microarray and quantitative RT-PCR analyses, two major subsets of differentially expressed genes were characterized, including the innate immune response gene TNFα and the pro-apoptotic genes Bad and Bid. In the early replication stage (0–6 h post-infection, or p.i.), we observed that the pro-inflammatory cytokine TNFα underwent a rapid six-fold induction. Then, during the early-middle replication stages (6–12 h p.i.), TNFα level was eight-fold induction and the pro-apoptotic Bcl-2 family members Bad and Bid were up-regulated. Furthermore, specific inhibitors of TNFα expression (AG-126 or TNFα-specific siRNA) were used to block apoptotic and necrotic death signaling during the early or early-middle stages of IPNV infection. Inhibition of TNFα expression dramatically reduced the Bad/Bid-mediated apoptotic and Rip1/ROS-mediated necrotic cell death pathways and rescued host cell viability. Moreover, we used Rip1-specific inhibitors (Nec-1 and Rip1-specific siRNA) to block Rip1 expression. The Rip1/ROS-mediated secondary necrotic pathway appeared to be reduced in IPNV-infected fish cells during the middle-late stage of infection (12–18 h p.i.). Taken together, our results indicate that IPNV triggers two death pathways via up-stream induction of the pro-inflammatory cytokine TNFα, and these results may provide new insights into the pathogenesis of RNA viruses

Association Between Acid-Sensing Ion Channel 3 Gene Variants and Balance Impairment in People With Mild Traumatic Brain Injury

Introduction: Dizziness and balance impairment are common symptoms of mild traumatic brain injury (mTBI). Acid-sensing ion channel 3 (ASIC3) is expressed in the vestibular and proprioceptive systems and associated with balance functions. However, whether the genetic variants of ASIC3 are associated with people who suffer dizziness and balance impairment after mTBI remained unknown.Materials and methods: A total of 200 people with mTBI and 109 non-mTBI controls were recruited. Dizziness, balance functions, and the ability to perform daily activities were assessed by Dizziness Handicap Inventory (DHI), and objective balance functions were investigated by the postural stability test. Three diseases-related genetic variants of ASIC3 were determined through polymerase chain reaction and followed by restriction fragment length polymorphism. The Student's t-test and Mann-Whitney U-test were used for normal and abnormal distributed data, respectively. The regression was applied to adjust gender and age. The normality of continuous data was evaluated by Shapiro-Wilk test.Results: In the mTBI people, the rs2288645-A allele carriers exhibited a significantly worse physical domain DHI score (A-allele carriers: 11.39 ± 8.42, non-A carriers: 8.76 ± 7.87, p = 0.03). The rs4148855-GTC deletion carriers an exhibited significantly worse overall postural stability (GTC deletion carriers: 0.53 ± 0.33, non-carriers: 0.46 ± 0.20, p = 0.03). In the controls, rs2288646-A allele carriers were significant worse in the medial-to-lateral postural stability (A-allele carriers: 0.31 ± 0.17, non-A carriers: 0.21 ± 0.10, p = 0.01).Conclusion: The present study demonstrated that ASIC3 genetic variants were associated with certain aspects of balance functions and dizziness questionnaires in people of mTBI and non-mTBI. It provides a possible evidence that ASIC3 could be a new target for the management of the balancing disorders. However, further investigations are warranted to elucidate the underlying mechanisms and clinical significance

Aquatic Birnavirus-Induced ER Stress-Mediated Death Signaling Contribute to Downregulation of Bcl-2 Family Proteins in Salmon Embryo Cells

Aquatic birnavirus induces mitochondria-mediated cell death, but whether connects to endoplasmic reticulum (ER) stress is still unknown. In this present, we characterized that IPNV infection triggers ER stress-mediated cell death via PKR/eIF2α phosphorylation signaling for regulating the Bcl-2 family protein expression in fish cells. The IPNV infection can induce ER stress as follows: (1) ER stress sensor ATF6 cleavaged; (2) ER stress marker GRP78 upregulation, and (3) PERK/eIF2αphosphorylation. Then, the IPNV-induced ER stress signals can induce the CHOP expression at early (6 h p.i.) and middle replication (12 h p.i.) stages. Moreover, IPNV-induced CHOP upregulation dramatically correlates to apparently downregulate the Bcl-2 family proteins, Bcl-2, Mcl-1 and Bcl-xL at middle replication stage (12 h p.i.) and produces mitochondria membrane potential (MMP) loss and cell death. Furthermore, with GRP78 synthesis inhibitor momitoxin (VT) and PKR inhibitor 2-aminopurine (2-AP) treatment for blocking GRP78 expression and eIF2α phosphorylation, PKR/PERK may involve in eIF2α phosphorylation/CHOP upregulation pathway that enhances the downstream regulators Bcl-2 family proteins expression and increased cell survival. Taken together, our results suggest that IPNV infection activates PKR/PERK/eIF2α ER stress signals for regulating downstream molecules CHOP upregulation and Bcl-2 family downregulation that led to induce mitochondria-mediated cell death in fish cells, which may provide new insight into RNA virus pathogenesis and disease

Complete Genome Sequence of a Giant Sea Perch Iridovirus in Kaohsiung, Taiwan

The south portal, looking up; The several important buildings preserved from the early Ottoman period exemplify the Ottoman pattern of urbanization whereby sultans successively built architectural complexes (kulliye) in unurbanized parts of the city, which then became the nuclei of new quarters. The city was also an international centre for the silk and textile trade. Bayezid i Yildirim (Bayezid the Thunderbolt; reigned 1389-1402) chose a hill to the east of the city for his complex (1390-1395), which comprises a Bursa-type mosque, madrasa, tomb for the founder and bath, along with a kitchen, hospital and palace (destroyed). In the commercial centre he commissioned the congregational mosque (Ulu Cami; 1396-1400), a large (68 x 56 m) rectangular building with 12 piers supporting 20 domed bays. [The complex underwent extensive renovation following the 1855 Bursa earthquake.] Source: Grove Art Online; http://www.groveart.com/ (accessed 1/28/2008