Mitochondrial translocation of oxidized cofilin induces caspase-independent necrotic-like programmed cell death of T cells

Oxidative stress leads to T-cell hyporesponsiveness or death. The actin-binding protein cofilin is oxidized during oxidative stress, which provokes a stiff actin cytoskeleton and T-cell hyporesponsiveness. Here, we show that long-term oxidative stress leads to translocation of cofilin into the mitochondria and necrotic-like programmed cell death (PCD) in human T cells. Notably, cofilin mutants that functionally mimic oxidation by a single mutation at oxidation-sensitive cysteins (Cys-39 or Cys-80) predominately localize within the mitochondria. The expression of these mutants alone ultimately leads to necrotic-like PCD in T cells. Accordingly, cofilin knockdown partially protects T cells from the fatal effects of long-term oxidative stress. Thus, we introduce the oxidation and mitochondrial localization of cofilin as the checkpoint for necrotic-like PCD upon oxidative stress as it occurs, for example, in tumor environments

High Pro-Inflammatory Cytokine Secretion and Loss of High Avidity Cross-Reactive Cytotoxic T-Cells during the Course of Secondary Dengue Virus Infection

BACKGROUND: Dengue is one of the most important human diseases transmitted by an arthropod vector and the incidence of dengue virus infection has been increasing - over half the world's population now live in areas at risk of infection. Most infections are asymptomatic, but a subset of patients experience a potentially fatal shock syndrome characterised by plasma leakage. Severe forms of dengue are epidemiologically associated with repeated infection by more than one of the four dengue virus serotypes. Generally attributed to the phenomenon of antibody-dependent enhancement, recent observations indicate that T-cells may also influence disease phenotype. METHODS AND FINDINGS: Virus-specific cytotoxic T lymphocytes (CTL) showing high level cross reactivity between dengue serotypes could be expanded from blood samples taken during the acute phase of secondary dengue infection. These could not be detected in convalescence when only CTL populations demonstrating significant serotype specificity were identified. Dengue cross-reactive CTL clones derived from these patients were of higher avidity than serotype-specific clones and produced much higher levels of both type 1 and certain type 2 cytokines, many previously implicated in dengue pathogenesis. CONCLUSION: Dengue serotype cross-reactive CTL clones showing high avidity for antigen produce higher levels of inflammatory cytokines than serotype-specific clones. That such cells cannot be expanded from convalescent samples suggests that they may be depleted, perhaps as a consequence of activation-induced cell death. Such high avidity cross-reactive memory CTL may produce inflammatory cytokines during the course of secondary infection, contributing to the pathogenesis of vascular leak. These cells appear to be subsequently deleted leaving a more serotype-specific memory CTL pool. Further studies are needed to relate these cellular observations to disease phenotype in a large group of patients. If confirmed they have significant implications for understanding the role of virus-specific CTL in pathogenesis of dengue disease

Expeditious responses to COVID-19 crisis: From governmental management to laboratory approach

[[abstract]]On the basis of recently published literatures about COVID-19 in Biomedical Journal, we are bringing together this collection of News, Short Communication, Reviews and Original Articles and highlighting the prompt, direct responses of the Taiwanese government in managing this crisis and several thorough reviews and fundamental research on COVID-19. Taiwan is so close to Mainland China and was expected to have a very high incidence and number of COVID-19 cases in 2020. However, given a painful experience and lesion learnt from SARS 17 years ago, the Taiwanese government has been on constant alert and ready to promptly respond to this pandemic arising from China. At the beginning of the COVID-19 outbreak, the National Health Command Center (NHCC) of Taiwan, unifying a central command system that is composed of the Central Epidemic Command Center (CECC), the Biological Pathogen Disaster Command Center, the Central Medical Emergency Operations Center and the Counter-Bioterrorism Command Center, rapidly established several critical and timely actions including border control from the air and sea in early January, big data- and technology-based identification of cases, systematic quarantine of suspected cases, proactive case finding, resource allocation, daily press conference and extensive public education, negotiation with other countries and regions, formulation of policies for schools, childcare and nursing homes, and relief to businesses [1]. Apparently, the CECC effectively coordinated different efforts by various ministries, including the ministries of transportation, economics, labor, education, and environmental protection to comprehensively counteract the emerging public health crisis, allowing Taiwan to manage the outbreak exceptionally well. In addition to these strategies mentioned above, the commander of CECC requested National Health Research Institutes (NHRI), the only mission-oriented medical and health research center in Taiwan, to take the responsibility in coordinating clinical resources and provide a national technology platform for COVID-19 research. In order to develop rapid diagnostic reagents or new drugs, high quality human samples with comprehensive clinical data for testing and verification prior to real clinical application are extremely critical. Those bio-specimens are also essential for the basic research and epidemiological analyses. Within two weeks, the NHRI Biobank completed all the ethical and regulatory processes, and the National Biobank Consortium of Taiwan (NBCT), also operated by NHRI, started to recruit patients and collect their blood samples [2]. Meanwhile, the Taiwanese government made several endeavors to improve the current practice of epidemiological investigation by introducing new technologies in digital platform and knowledge graphs [3]. Contact tracing is an important control measure to contain the spread, especially in the early stage of an infectious disease outbreak. In this issue, a swift development of an e-Outbreak Platform that provides a semi-structured, multifaceted and computer-aided questionnaire to reinforce disease control and contact tracing was described by Chen and his colleagues. Furthermore, Dr. Seak presented very proactive strategies implemented by Lin-Kou Chang Gung Memorial Hospital (LCGMH) to effectively prevent spread of COVID-19 among healthcare workers of emergency department (ED) during outbreak [4]. LCGMH is one of the largest hospitals in the world and the nearest tertiary hospital to Taiwan Taoyuan International Airport, the largest and busiest airport in Taiwan. Its ED, with approximately 15,000 visits per month, is also one of the largest and busiest EDs in the world. During the COVID-19 outbreak, they have successfully managed to maintain a “zero-infection” rate among their ED healthcare workers through various, systematic approaches including a clear flowchart with route planning, strict infection control policies and regulation of medical equipment, and team-based segregation in the workplace. The meticulous implementation of these strategies in LCGMH is certainly the key to contribute the successful management against COVID-19

The Bcl-2 family pro-apoptotic molecule, BNIP3 regulates activation-induced cell death of effector cytotoxic T lymphocytes

BNIP3 is a recently described pro-apoptotic member of the Bcl-2 family and in BNIP3 cDNA-transfected cell lines, cell death occurs via a caspase-independent pathway with opening of the mitochondrial permeability transition (PT) pore and rapid loss of mitochondrial transmembrane potential (Δψ(m)). However, its expression or function in physiologic cell types is not known. Our results using the T-cell receptor transgenic mice P14, specific for lymphocyte choreomeningitis virus (LCMV) glycoprotein, show that in contrast to the other Bcl-2 family pro-apoptotic molecules, BNIP3 is transcriptionally highly up-regulated in effector cytotoxic T lymphocytes (CTL). Because CTL have a propensity to undergo activation-induced cell death (AICD) upon restimulation, we tested for other features associated with BNIP3-induced cell death. AICD of CTL was caspase-independent as determined by measuring caspase activation during target cell killing as well as by lack of inhibition with caspase inhibitors. Moreover, similar to BNIP3-induced cell death, CTL apoptosis was associated with increased production of reactive oxygen species and decreased Δψ(m). Finally, retroviral transduction of BNIP3 antisense RNA diminished AICD in effector CTL. These results suggest that BNIP3 may play an important role in T-cell homeostasis by regulating effector CTL numbers