Aging and the Immune System: the Impact of Immunosenescence on Viral Infection, Immunity and Vaccine Immunogenicity

Immunosenescence is characterized by a progressive deterioration of the immune system associated with aging. Multiple components of both innate and adaptive immune systems experience aging-related changes, such as alterations in the number of circulating monocytic and dendritic cells, reduced phagocytic activities of neutrophils, limited diversity in B/T cell repertoire, T cell exhaustion or inflation, and chronic production of inflammatory cytokines known as inflammaging. The elderly are less likely to benefit from vaccinations as preventative measures against infectious diseases due to the inability of the immune system to mount a successful defense. Therefore, aging is thought to decrease the efficacy and effectiveness of vaccines, suggesting aging-associated decline in the immunogenicity induced by vaccination. In this review, we discuss aging-associated changes in the innate and adaptive immunity and the impact of immunosenescence on viral infection and immunity. We further explore recent advances in strategies to enhance the immunogenicity of vaccines in the elderly. Better understanding of the molecular mechanisms underlying immunosenescence-related immune dysfunction will provide a crucial insight into the development of effective elderly-targeted vaccines and immunotherapies.

Zika Virus Impairs Host NLRP3-mediated Inflammasome Activation in an NS3-dependent Manner

Zika virus (ZIKV) is a mosquito-borne flavivirus associated with severe neurological disorders including Guillain-Barré syndrome and microcephaly. The host innate immune responses against ZIKV infection are essential for protection; however, ZIKV has evolved strategies to evade and antagonize antiviral responses via its nonstructural (NS) proteins. Here, we demonstrated that ZIKV infection unexpectedly inhibits NLRP3-dependent inflammasome activation in bone marrow-derived macrophages and mixed glial cells from mouse brain. ZIKV infection led to increased transcript levels of proinflammatory cytokines such as IL-1β and IL-6 via activating NF-κB signaling. However, ZIKV infection failed to trigger the secretion of active caspase-1 and IL-1β from macrophages and glial cells even in the presence of LPS priming or ATP costimulation. Intriguingly, ZIKV infection significantly attenuated NLRP3-dependent, but not absent in melanoma 2-dependent caspase-1 activation and IL-1β secretion from both cells. ZIKV infection further blocked apoptosis-associated speck-like protein containing a caspase recruitment domain oligomerization in LPS/ATP-stimulated macrophages. Interestingly, expression of ZIKV NS3 protein reduced NLRP3-mediated caspase-1 activation and IL-1β secretion in macrophages, whereas NS1 and NS5 proteins showed no effects. Furthermore, NLRP3 was found to be degraded by the overexpression of ZIKV NS3 in 293T cells. Collectively, these results indicate that ZIKV evades host NLRP3 inflammasome-mediated innate immune responses in macrophages and glial cells; this may facilitate ZIKV's ability to enhance the replication and dissemination in these cells.

Systems Biology-Based Platforms to Accelerate Research of Emerging Infectious Diseases

Emerging infectious diseases (EIDs) pose a major threat to public health and security. Given the dynamic nature and significant impact of EIDs, the most effective way to prevent and protect against them is to develop vaccines in advance. Systems biology approaches provide an integrative way to understand the complex immune response to pathogens. They can lead to a greater understanding of EID pathogenesis and facilitate the evaluation of newly developed vaccine-induced immunity in a timely manner. In recent years, advances in high throughput technologies have enabled researchers to successfully apply systems biology methods to analyze immune responses to a variety of pathogens and vaccines. Despite recent advances, computational and biological challenges impede wider application of systems biology approaches. This review highlights recent advances in the fields of systems immunology and vaccinology, and presents ways that systems biology-based platforms can be applied to accelerate a deeper understanding of the molecular mechanisms of immunity against EIDs.

Understanding the Pathogenesis of Zika Virus Infection Using Animal Models

Zika virus (ZIKV) is a member of Flaviviridae family that has emerged as a pathogen of significant public health importance. The rapid expansion of ZIKV in the South and Central America has recently gained medical attention emphasizing the capacity of ZIKV to spread to non-endemic regions. ZIKV infection during pregnancy has been demonstrated to cause microcephaly and other fetal developmental abnormalities. An increased incidence of Guillain-Barre syndrome, an immune mediated neuropathy of the peripheral nervous system, has also been reported in ZIKV-infected patients in French Polynesia and Brazil. No effective therapies currently exist for treating patients infected with ZIKV. Despite the relatively short time interval, an intensive effort by the global scientific community has resulted in development of animal models to study multiple aspects of ZIKV biology. Several animal models have been established to investigate pathogenesis of ZIKV in adults, pregnant mothers, and developing fetuses. Here we review the remarkable progress of newly developed small and large animal models for understanding ZIKV pathogenesis.

Humoral and Cellular Immunogenicity Induced by Avian Influenza A (H7N9) DNA Vaccine in Mice

BACKGROUND: In March 2013, human infection with avian influenza A (H7N9) virus emerged in China, causing serious public health concerns and raising the possibility of avian-source pandemic influenza. Thus, the development of an effective vaccine for preventing and rapidly controlling avian influenza A (H7N9) virus is needed. In this study, we evaluated the immunogenicity of a synthetic DNA vaccine against H7 HA antigens in mice. MATERIALS AND METHODS: The synthetic consensus H7 HA DNA vaccine (25 or 50 µg) was administered to BALB/c mice at 0, 14, and 28 days by intramuscular injection followed by electroporation. Humoral and cellular immune responses were analyzed in a hemagglutination inhibition test and interferon-gamma enzyme-linked immunospot (ELISpot) assay, respectively. RESULTS: H7 HA-vaccinated mice showed 100% seroprotection and seroconversion rate against H7N9 reassortant influenza virus after both second and third immunizations. The geometric mean titer by the hemagglutination inhibition test increased with an increasing number of immunizations. However, there was no significant difference in geometric titer between the two groups injected with 25 and 50 µg of H7 HA DNA vaccine after two (79.98 vs. 107.65, P = 0.39) and three (159.96 vs. 215.28, P = 0.18) doses. In addition, the ELISpot assay revealed that administration of H7 HA DNA vaccine induced potent interferon-gamma production from mouse splenocytes. CONCLUSIONS: This study demonstrated the humoral and cellular immunogenicity of synthetic consensus H7 HA DNA vaccine in mice. This work demonstrates the potential of the H7 HA DNA vaccine as an efficient tool for the rapid control of emerging influenza A (H7N9) virus.

Invasive fungal infection (IFI) in pediatric leukemia: better outcome with ACT

No abstract available.

Enhanced Viral Replication by Cellular Replicative Senescence

Cellular replicative senescence is a major contributing factor to aging and to the development and progression of aging-associated diseases. In this study, we sought to determine viral replication efficiency of influenza virus (IFV) and Varicella Zoster Virus (VZV) infection in senescent cells. Primary human bronchial epithelial cells (HBE) or human dermal fibroblasts (HDF) were allowed to undergo numbers of passages to induce replicative senescence. Induction of replicative senescence in cells was validated by positive senescence-associated β-galactosidase staining. Increased susceptibility to both IFV and VZV infection was observed in senescent HBE and HDF cells, respectively, resulting in higher numbers of plaque formation, along with the upregulation of major viral antigen expression than that in the non-senescent cells. Interestingly, mRNA fold induction level of virus-induced type I interferon (IFN) was attenuated by senescence, whereas IFN-mediated antiviral effect remained robust and potent in virus-infected senescent cells. Additionally, we show that a longevity-promoting gene, sirtuin 1 (SIRT1), has antiviral role against influenza virus infection. In conclusion, our data indicate that enhanced viral replication by cellular senescence could be due to senescence-mediated reduction of virus-induced type I IFN expression.

Oligonol promotes anti-aging pathways via modulation of SIRT1-AMPK-Autophagy Pathway

BACKGROUND/OBJECTIVES: Oligonol, mainly found in lychee fruit, is an antioxidant polyphenolic compound which has been shown to have anti-inflammatory and anti-cancer properties. The detailed mechanisms by which oligonol may act as an anti-aging molecule have not been determined. MATERIALS/METHODS: In this study, we evaluated the ability of oligonol to modulate sirtuin (SIRT) expression in human lung epithelial (A549) cells. Oligonol was added to A549 cells and reactive oxygen species production, mitochondrial superoxide formation, and p21 protein levels were measured. Signaling pathways activated upon oligonol treatment were also determined by western blotting. Furthermore, the anti-aging effect of oligonol was evaluated ex vivo in mouse splenocytes and in vivo in Caenorhabditis elegans. RESULTS: Oligonol specifically induced the expression of SIRT1, whose activity is linked to gene expression, metabolic control, and healthy aging. In response to influenza virus infection of A549 cells, oligonol treatment significantly up-regulated SIRT1 expression and down-regulated viral hemagglutinin expression. Oligonol treatment also resulted in the activation of autophagy pathways and the phosphorylation of AMP-activated protein kinase (AMPK). Furthermore, oligonol-treated spleen lymphocytes from old mice showed increased cell proliferation, and mRNA levels of SIRT1 in the lungs of old mice were significantly lower than those in the lungs of young mice. Additionally, in vivo lethality assay revealed that oligonol extended the lifespan of C. elegans infected with lethal Vibrio cholerae. CONCLUSIONS: These data demonstrated that oligonol may act as an anti-aging molecule by modulating SIRT1/autophagy/AMPK pathways.

Insight into the Pathogenesis of Lyme Disease

Lyme disease is the most common vector-borne disease in the United States and Europe, caused by a tick-borne spirochete, Borrelia burgdorferi. Life cycle alternation between arthropod and mammals enhanced B. burgdorferi to adapt to two diverse niches. Although B. burgdorferi infection in these reservoir hosts appears asymptomatic, infection in human can typically cause inflammation in the skin, nervous system, musculoskeletal system and heart. In this review, we discuss the basic molecular characteristics and cell biology of B. burgdorferi and provide an overview of spirochete-induced activation of innate and adaptive immunity, resulting in particular immunopathology. Advancing understanding of the immune evasion mechanisms of B. burgdorferi provides important implications for ongoing research and clinical practice of Lyme disease.