Senescence in Monocytes Facilitates Dengue Virus Infection by Increasing Infectivity (original) (raw)
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Senescence Affects Endothelial Cells Susceptibility to Dengue Virus Infection
International Journal of Medical Sciences, 2000
Alteration in the endothelium leading to increased vascular permeability contributes to plasma leakage seen in dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). An earlier study showed that senescent endothelial cells (ECs) altered the ECs permeability. Here we investigated the susceptibility of senescing human umbilical vein endothelial cells (HUVECs) to dengue virus infection and determined if dengue virus infection induces HUVECs senescence. Our results suggest that DENV type-2 (DENV-2) foci forming unit (FFU) and extracellular virus RNA copy number were reduced by at least 35% and 85% in infection of the intermediate young and early senescent HUVECs, respectively, in comparison to infection of young HUVECs. No to low infectivity was recovered from infection of late senescent HUVECs. DENV infection also increases the percentage of HUVECs expressing senescence-associated (SA)-β-gal, cells arrested at the G2/M phase or 4N DNA content stage and cells with enlarged morphology, indicative of senescing cells. Alteration of HUVECs morphology was recorded using impedance-based real-time cell analysis system following DENV-2 infection. These results suggest that senescing HUVECs do not support DENV infection and DENV infection induces HUVECs senescence. The finding highlights the possible role of induction of senescence in DENV infection of the endothelial cells.
European Journal of Inflammation , 2013
We previously demonstrated in young mice that in comparison with animals raised in an impoverished environment (IE), animals from an enriched environment (EE) show more severe dengue disease, associated with an increased expansion of memory T target cells. Because active older adults show less functional decline in T-cell adaptive immunity, we hypothesized that aged mice from EE would show higher mortality and T-lymphocyte expansion than mice from IE. To test this hypothesis, we administered serial i.p. injections of anti-DENV2 hyperimmune serum, followed 24 h later by DENV3 (genotype III)-infected brain homogenate. Control mice received equal volumes of serum but received uninfected brain homogenate. The presence of virus or viral antigens was indirectly detected by real-time quantitative RT-PCR and immunohistochemistry. Compared to infected IE animals, EE mice, independent of age, showed higher mortality and more intense clinical signs. Compared to young mice, the higher mortality of aged mice was associated with a higher degree of T lymphocytic hyperplasia in the spleen and infiltration in kidneys, liver, and lungs, but less viral antigen immunolabeling. We propose that a higher expansion of T cells and serotype cross-reactive antibodies are associated with disease severity in aged mice.
PLoS ONE, 2013
Changes in immune response during lifespan of man are well known. These changes involve decreased neonatal and elderly immune response. In addition, it has been shown a relationship between immune and oxidative mechanisms, suggesting that altered immune response could be associated to altered oxidative response. Increased expression of nitric oxide (NO) has been documented in dengue and in monocyte cultures infected with different types of dengue virus. However, there is no information about the age-dependent NO oxidative response in humans infected by dengue virus. In this study, monocyte cultures from neonatal, elderly and adult individuals (n = 10 each group) were infected with different dengue virus types (DENV-1 to 4) and oxidative/antioxidative responses and apoptosis were measured at days 1 and 3 of culture. Increased production of NO, lipid peroxidation and enzymatic and nonenzymatic anti-oxidative responses in dengue infected monocyte cultures were observed. However, neonatal and elderly monocytes had lower values of studied parameters when compared to those in adult-derived cultures. Apoptosis was present in infected monocytes with higher values at day 3 of culture. This reduced oxidant/antioxidant response of neonatal and elderly monocytes could be relevant in the pathogenesis of dengue disease.
Potential Role of Cellular Senescence on Coronavirus Infections
2020
The disproportionate incidences of COVID-19-related hospitalization and mortality for different age groups and various underlying health conditions is a result of a complex social predisposition to the exposure, resistance, and tolerance for the infection. Based on the observed data as well as the molecular mechanisms for viral entry and replication, cellular senescence related to aging, obesity, hypertension, and diabetes appears to be strongly correlated with the SARS-CoV-2 infections resulting in higher COVID-19 related complications and mortality. Establishing such a correlation may allow us to better explain the pathobiology as well as the differential nature of the SARS-CoV-2 infections and consider targeted control and therapeutic strategies to combat the disease.
Antiviral Research, 2019
Objective: We sought to investigate the differences in monocyte immune responses to the dengue virus (DENV) in those who previously had either severe disease (past SD) or non-severe dengue (past NSD) following a secondary dengue infection. Method: Monocytes from healthy individuals who had either past SD (n=6) or past NSD (n=6) were infected at MOI one with all four DENV serotypes following incubation with autologous serum. 36-hours post infection, levels of inflammatory cytokines and viral loads were measured in the supernatant and expression of genes involved in viral sensing and interferon signaling was determined. Results: Monocytes of individuals with past SD produced significantly higher viral loads (p= 0.0426 and cytokines (IL-10 p=0.008, IL-1β p=0.008 and IL-6 p=0.0411) when infected with DENV serotypes they were not immune to, compared to those who has past NSD. Monocytes of individuals with past SD also produced significantly higher viral loads (p=0.022) and cytokines (IL-10 p<0.0001, IL-1β <0.0001 and IL-6 p<0.0001) when infected with DENV serotypes they were previously exposed to, despite the monocytes being infected in the presence of autologous serum. A significant upregulation of NLRP3 (p=0.005), RIG-I (0.0004) and IFNB-1 (0.01) genes were observed in those who had past SD compared to past NSD when infected with non-immune DENV serotypes. Conclusion: Monocytes from those with past SD appear to show marked differences in viral loads, viral sensing and production of inflammatory mediators in response to the DENV, when compared to those who experienced past NSD, suggesting that initial innate immune responses may influence the disease outcome.
Journal of Infectious Diseases, 2011
West Nile virus (WNV), a mosquito-borne, single-stranded RNA flavivirus, causes significant human morbidity and mortality in the older population; thus, we investigated the effects of aging on infection with WNV in dendritic cells (DCs). We infected DCs with WNV in vitro and quantified cytokines and chemokines (type I IFN and CXCL10), pathogen recognition receptors RIG-I, and Toll-like receptors 3 and 7. The production of type I IFN was significantly lower in DCs from older donors, compared with younger donors. Although we observed no significant age-related difference in expression or nuclear translocation of signaling molecules in initial antiviral responses, DCs from older donors have diminished induction of late-phase responses (eg, STAT1, IRF7, and IRF1), suggesting defective regulation of type I IFN. Our results identify deficits in critical regulatory pathways in the antiviral response that may contribute to the enhanced susceptibility to viral infections observed in aging.
Cellular senescence and COVID-19
Coronaviruses
Older adults are at a higher risk of developing serious illness and mortality from COVID-19. Among a multitude of factors, cellular senescence associated with ageing, obesity, cardiovascular diseases, and diabetes seems to be statistically correlated with severe SARS-CoV-2 infections and mortality. Surface proteins such as vimentin and CD26 that are differentially expressed on senescent cells seem important for SARS-CoV-2 attachment and internalization. Potential therapeutic agents against this novel virus also exhibit senolytic and anti-inflammatory actions, implicating that their beneficial effects could, in part, be attributed to their senescent cell removal and the associated inflammatory phenotype neutralizing properties. Elucidating the underlying molecular mechanisms that connect cellular senescence and severity of SARS-CoV-2 infection might help direct towards development of effective therapeutics for elderly patients of COVID-19.
Journal of General Virology, 2007
The immunopathogenesis of dengue haemorrhagic fever and dengue shock syndrome is thought to be mediated by a variety of host factors. Enhancing antibodies are one of the key regulating molecules. These antibodies, via antibody-dependent enhancement (ADE) of infection, are able to facilitate dengue virus (DENV) growth in Fc-bearing host cells. The mechanism of ADE-enhanced DENV production is believed to be mediated through increasing the infected-cell mass. In the present work, the effect of ADE infection was explored further, focusing on the post-entry events of ADE infection. It was hypothesized that the higher virus production in ADE infection compared with DENV infection may be due to the ability of this infection pathway to suppress key antiviral molecules. Therefore, the influence of ADE infection on pro- and anti-inflammatory cytokines, including interleukin-12 (IL-12), gamma interferon (IFN-γ), tumour necrosis factor alpha (TNF-α), IL-6 and IL-10, was investigated and it was ...
Mechanisms of monocyte cell death triggered by dengue virus infection
Apoptosis : an international journal on programmed cell death, 2018
Arthropod-borne viral diseases caused by dengue virus (DENV) are major re-emerging public health problem worldwide. In spite of intense research, DENV pathogenesis is not fully understood and remains enigmatic; however, current evidence suggests that dengue progression is associated with an inflammatory response, mainly in patients suffering from a second DENV infection. Monocytes are one of the main target cells of DENV infection and play an important role in pathogenesis since they are known to produce several inflammatory cytokines that can lead to endothelial dysfunction and therefore vascular leak. In addition, monocytes play an important role in antibody dependent enhancement, infection with consequences in viral load and immune response. Despite the physiological functions of monocytes in immune response, their life span in the bloodstream is very short, and activation of monocytes by DENV infection can trigger different types of cell death. For example, DENV can induce apopt...
Viral Immunology, 2014
Immunosuppressive status against infections in monocytes from neonates and elderly subjects has been reported. The interaction between dengue virus and monocytes/macrophages plays an important role during dengue disease. The aim of this study was to determine the cytokine response of monocytes from individuals with different ages after infection with dengue virus. Monocyte/macrophage cultures from neonatal, adult, and elderly subjects (n = 10 each group) were incubated with all four dengue virus types (DENV-1 to -4). After 1 and 3 days of culture, cytokine concentrations (TNF-a, IL-6, and IL-1b) were determined in culture supernatants by enzyme-linked immunosorbant assay. Increased production of all studied cytokines was induced by the different viral types in monocyte/macrophage cultures regardless of their source. However, lower cytokine concentrations were found in neonatal and elderly monocytes. The relative monocyte/macrophage immunosuppressive status observed in neonates and the elderly could be relevant during dengue infection in those age groups and important in innate and adaptive immunity responses against this virus.