scholarly journals A Multi-Phenotype System to Discover Therapies for Age-Related Dysregulation of the Immune Response to Viral Infections

2020 ◽  
Author(s):  
Brandon White ◽  
Ben Komalo ◽  
Lauren Nicolaisen ◽  
Matt Donne ◽  
Charlie Marsh ◽  
...  
Keyword(s):  
Older Adults ◽  
Immune Response ◽  
Viral Infection ◽  
Immune Cells ◽  
Viral Infections ◽  
Cell Interaction ◽  
Rapid Identification ◽  
Beneficial Effects ◽  
Susceptibility To Infection ◽  
Age Related

ABSTRACTAge-related immune dysregulation contributes to increased susceptibility to infection and disease in older adults. We combined high-throughput laboratory automation with machine learning to build a multi-phenotype aging profile that models the dysfunctional immune response to viral infection in older adults. From a single well, our multi-phenotype aging profile can capture changes in cell composition, physical cell-to-cell interaction, organelle structure, cytokines, and other hidden complexities contributing to age-related dysfunction. This system allows for rapid identification of new potential compounds to rejuvenate older adults’ immune response. We used our technology to screen thousands of compounds for their ability to make old immune cells respond to viral infection like young immune cells. We observed beneficial effects of multiple compounds, of which two of the most promising were disulfiram and triptonide. Our findings indicate that disulfiram could be considered as a treatment for severe coronavirus disease 2019 and other inflammatory infections.

Vaccines against viral infections

2017 ◽  
pp. 675-680
Author(s):  
Janet E. McElhaney
Keyword(s):  
Older Adults ◽  
Cytomegalovirus Infection ◽  
Viral Infections ◽  
Functional Dependence ◽  
Psychosocial Health ◽  
Health Issues ◽  
The Public ◽  
Susceptibility To Infection ◽  
Age Related ◽  
Health Need

A decline in immune function and increased susceptibility to infection is a hallmark of ageing. Influenza is foremost among these infections with 90% of deaths occurring in older adults despite widespread vaccination programmes. Common medical conditions and mental and psychosocial health issues, as well as degree of frailty and functional dependence may all contribute to the loss of immune responsiveness to infections and vaccination. The interactions of immune senescence, persistent cytomegalovirus infection, inflammaging (chronic elevation of inflammatory cytokines), and dysregulated cytokine production pose major challenges to the development of new or more effective vaccines. This chapter describes viral infections that have the greatest impact in older adults, age-related changes in the immune system that contribute to loss of vaccine responsiveness, available vaccines against influenza and herpes zoster and the need for vaccines against other viruses, and strategies for improving vaccine effectiveness to address the public health need for ‘vaccine preventable disability’.

scholarly journals Comparing the Protective Value of Human and Pet Social Support on Well-Being of Older Adults During COVID-19

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 936-936
Author(s):  
Juliet Sobering ◽  
Lisa Brown
Keyword(s):  
Social Support ◽  
Older Adults ◽  
Positive Emotions ◽  
Protective Factor ◽  
Behavioral Activation ◽  
Well Being ◽  
Psychological Benefits ◽  
Beneficial Effects ◽  
Age Related ◽  
Media Reports

Abstract Older adults are vulnerable to particular risk factors that contribute to lower well-being and poorer functioning. With the COVID-19 pandemic, the importance of social support has been highlighted in media reports because of its well-known beneficial effects on overall well-being. However, as adults age, social networks, contacts, and activities naturally decrease. These age-related losses are often difficult, if not impossible, to replace. Pets have recently been recognized as a valuable source of social support for many older adults, providing both physical and psychological benefits through mutual connection and behavioral activation. Previous studies have examined how human social support or pet social support enhance older adults’ well-being (i.e., positive emotions, engagement, relationships, accomplishment, and meaning). However, there is a gap in our scientific knowledge as previous research has not evaluated if pet social support can serve as a protective factor in the absence of adequate human social support. Current analyses, with 141 older adult participants, suggests that pet owners with a positive attachment to their pet experience higher well-being as pets serve as a coping resource that protects against common life stressors. Similar to human social support, pet social support appears to be a protective factor that also promotes and fosters a sense of well-being in older adults. Support in late life is especially important for families and agencies to be attuned to, especially during a global pandemic.

scholarly journals CD69 Targeting Enhances Anti-vaccinia Virus Immunity

2019 ◽  
Vol 93 (19) ◽  
Author(s):  
Laura Notario ◽  
Jennifer Redondo-Antón ◽  
Elisenda Alari-Pahissa ◽  
Almudena Albentosa ◽  
Magdalena Leiva ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Infection ◽  
Vaccinia Virus ◽  
Immune Cells ◽  
Nk Cell ◽  
Mtor Signaling ◽  
Cell Reactivity ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha

ABSTRACT CD69 is highly expressed on the leukocyte surface upon viral infection, and its regulatory role in the vaccinia virus (VACV) immune response has been recently demonstrated using CD69−/− mice. Here, we show augmented control of VACV infection using the anti-human CD69 monoclonal antibody (MAb) 2.8 as both preventive and therapeutic treatment for mice expressing human CD69. This control was related to increased natural killer (NK) cell reactivity and increased numbers of cytokine-producing T and NK cells in the periphery. Moreover, similarly increased immunity and protection against VACV were reproduced over both long and short periods in anti-mouse CD69 MAb 2.2-treated immunocompetent wild-type (WT) mice and immunodeficient Rag2−/− CD69+/+ mice. This result was not due to synergy between infection and anti-CD69 treatment since, in the absence of infection, anti-human CD69 targeting induced immune activation, which was characterized by mobilization, proliferation, and enhanced survival of immune cells as well as marked production of several innate proinflammatory cytokines by immune cells. Additionally, we showed that the rapid leukocyte effect induced by anti-CD69 MAb treatment was dependent on mTOR signaling. These properties suggest the potential of CD69-targeted therapy as an antiviral adjuvant to prevent derived infections. IMPORTANCE In this study, we demonstrate the influence of human and mouse anti-CD69 therapies on the immune response to VACV infection. We report that targeting CD69 increases the leukocyte numbers in the secondary lymphoid organs during infection and improves the capacity to clear the viral infection. Targeting CD69 increases the numbers of gamma interferon (IFN-γ)- and tumor necrosis factor alpha (TNF-α)-producing NK and T cells. In mice expressing human CD69, treatment with an anti-CD69 MAb produces increases in cytokine production, survival, and proliferation mediated in part by mTOR signaling. These results, together with the fact that we have mainly worked with a human-CD69 transgenic model, reveal CD69 as a treatment target to enhance vaccine protectiveness.

scholarly journals A Multiscale Multicellular Spatiotemporal Model of Local Influenza Infection and Immune Response

2021 ◽  
Author(s):  
T.J. Sego ◽  
Ericka D. Mochan ◽  
G. Bard Ermentrout ◽  
James A. Glazier
Keyword(s):  
Immune Response ◽  
Viral Infection ◽  
Viral Infections ◽  
Influenza Infection ◽  
Ode Model ◽  
Spatiotemporal Model ◽  
Spatially Resolved ◽  
Ode Models ◽  
Respiratory Viral Infections ◽  
Spatial Cell

AbstractRespiratory viral infections pose a serious public health concern, from mild seasonal influenza to pandemics like those of SARS-CoV-2. Spatiotemporal dynamics of viral infection impact nearly all aspects of the progression of a viral infection, like the dependence of viral replication rates on the type of cell and pathogen, the strength of the immune response and localization of infection. Mathematical modeling is often used to describe respiratory viral infections and the immune response to them using ordinary differential equation (ODE) models. However, ODE models neglect spatially-resolved biophysical mechanisms like lesion shape and the details of viral transport, and so cannot model spatial effects of a viral infection and immune response. In this work, we develop a multiscale, multicellular spatiotemporal model of influenza infection and immune response by combining non-spatial ODE modeling and spatial, cell-based modeling. We employ cellularization, a recently developed method for generating spatial, cell-based, stochastic models from non-spatial ODE models, to generate much of our model from a calibrated ODE model that describes infection, death and recovery of susceptible cells and innate and adaptive responses during influenza infection, and develop models of cell migration and other mechanisms not explicitly described by the ODE model. We determine new model parameters to generate agreement between the spatial and original ODE models under certain conditions, where simulation replicas using our model serve as microconfigurations of the ODE model, and compare results between the models to investigate the nature of viral exposure and impact of heterogeneous infection on the time-evolution of the viral infection. We found that using spatially homogeneous initial exposure conditions consistently with those employed during calibration of the ODE model generates far less severe infection, and that local exposure to virus must be multiple orders of magnitude greater than a uniformly applied exposure to all available susceptible cells. This strongly suggests a prominent role of localization of exposure in influenza A infection. We propose that the particularities of the microenvironment to which a virus is introduced plays a dominant role in disease onset and progression, and that spatially resolved models like ours may be important to better understand and more reliably predict future health states based on susceptibility of potential lesion sites using spatially resolved patient data of the state of an infection. We can readily integrate the immune response components of our model into other modeling and simulation frameworks of viral infection dynamics that do detailed modeling of other mechanisms like viral internalization and intracellular viral replication dynamics, which are not explicitly represented in the ODE model. We can also combine our model with available experimental data and modeling of exposure scenarios and spatiotemporal aspects of mechanisms like mucociliary clearance that are only implicitly described by the ODE model, which would significantly improve the ability of our model to present spatially resolved predictions about the progression of influenza infection and immune response.

scholarly journals The Trans-zoonotic Virome interface: Measures to balance, control and treat epidemics

2020 ◽  
Vol 4 (1) ◽  
pp. 020-027
Author(s):  
Nikhra Vinod
Keyword(s):  
Immune Response ◽  
Viral Load ◽  
Immune System ◽  
Viral Infection ◽  
Antiviral Therapy ◽  
Viral Infections ◽  
Habitat Destruction ◽  
Interferon Response ◽  
Viral Diseases ◽  
Intracellular Parasites

The global virome: The viruses have a global distribution, phylogenetic diversity and host specificity. They are obligate intracellular parasites with single- or double-stranded DNA or RNA genomes, and afflict bacteria, plants, animals and human population. The viral infection begins when surface proteins bind to receptor proteins on the host cell surface, followed by internalisation, replication and lysis. Further, trans-species interactions of viruses with bacteria, small eukaryotes and host are associated with various zoonotic viral diseases and disease progression. Virome interface and transmission: The cross-species transmission from their natural reservoir, usually mammalian or avian, hosts to infect human-being is a rare probability, but occurs leading to the zoonotic human viral infection. The factors like increased human settlements and encroachments, expanded travel and trade networks, altered wildlife and livestock practices, modernised and mass-farming practices, compromised ecosystems and habitat destruction, and global climate change have impact on the interactions between virome and its hosts and other species and act as drivers of trans-species viral spill-over and human transmission. Zoonotic viral diseases and epidemics: The zoonotic viruses have caused various deadly pandemics in human history. They can be further characterized as either newly emerging or re-emerging infectious diseases, caused by pathogens that historically have infected the same host species, but continue to appear in new locations or in drug-resistant forms, or reappear after apparent control or elimination. The prevalence of zoonoses underlines importance of the animal–human–ecosystem interface in disease transmission. The present COVID-19 infection has certain distinct features which suppress the host immune response and promote the disease potential. Treatment for epidemics like covid-19: It appears that certain nutraceuticals may provide relief in clinical symptoms to patients infected with encapsulated RNA viruses such as influenza and coronavirus. These nutraceuticals appear to reduce the inflammation in the lungs and help to boost type 1 interferon response to these viral infections. The human intestinal microbiota acting in tandem with the host’s defence and immune system, is vital for homeostasis and preservation of health. The integrity and balanced activity of the gut microbes is responsible for the protection from disease states including viral infections. Certain probiotics may help in improving the sensitivity and effectivity of immune system against viral infections. Currently, antiviral therapy is available only for a limited number of zoonotic viral infections. Because viruses are intracellular parasites, antiviral drugs are not able to deactivate or destroy the virus but can reduce the viral load by inhibiting replication and facilitating the host’s innate immune mechanisms to neutralize the virus. Conclusion: Lessons from recent viral epidemics - Considering that certain nutraceuticals have demonstrated antiviral effects in both clinical and animal studies, further studies are required to establish their therapeutic efficacy. The components of nutraceuticals such as luteolin, apigenin, quercetin and chlorogenic acid may be useful for developing a combo-therapy. The use of probiotics to enhance immunity and immune response against viral infections is a novel possibility. The available antiviral therapy is inefficient in deactivating or destroying the infecting viruses, may help in reducing the viral load by inhibiting replication. The novel efficient antiviral agents are being explored.

scholarly journals Superior Effects of Modified Chen-Style Tai Chi versus 24-Style Tai Chi on Cognitive Function, Fitness, and Balance Performance in Adults over 55

2019 ◽  
Vol 9 (5) ◽  
pp. 102 ◽  
Author(s):  
Liye Zou ◽  
Paul D. Loprinzi ◽  
Jane Jie Yu ◽  
Lin Yang ◽  
Chunxiao Li ◽  
...  
Keyword(s):  
Older Adults ◽  
Cognitive Function ◽  
Tai Chi ◽  
Dynamic Balance ◽  
Aging Population ◽  
Balance Performance ◽  
Timed Up And Go ◽  
Beneficial Effects ◽  
Global Cognitive Function ◽  
Age Related

Background: Cognitive decline and balance impairment are prevalent in the aging population. Previous studies investigated the beneficial effects of 24-style Tai Chi (TC-24) on either cognitive function or balance performance of older adults. It still remains largely unknown whether modified Chen-style TC (MTC) that includes 18 complex movements is more beneficial for these age-related health outcomes, as compared to TC-24. Objective: We investigated if MTC would show greater effects than TC-24 on global cognitive function and balance-related outcomes among older adults. Methods: We conducted a randomized trial where 80 eligible adults aged over 55 were allocated into two different styles of Tai Chi (TC) arms (sixty-minute session × three times per week, 12 weeks). Outcome assessments were performed at three time periods (baseline, Week 6, and Week 12) and included the Chinese Version of the Montreal Cognitive Assessment (MoCA) for overall cognitive function, One-leg Standing Test (LST) for static balance, Timed Up and Go Test (TUGT) for dynamic balance, chair Stand Test (CST) for leg power, and the six-meter Walk Test (6MWT) for aerobic exercise capacity. Results: Compared to TC-24 arm, MTC arm demonstrated significantly greater improvements in MoCA, LST, TUGT, CST, and 6MWT (all p < 0.05). Conclusions: Both forms of TC were effective in enhancing global cognitive function, balance, and fitness. Furthermore, MTC was more effective than TC-24 in enhancing these health-related parameters in an aging population.

The War Against SARS-CoV-2: The Immune Giant Collapsing Under Its Own Rampaging Cytokine Storm

2021 ◽  
Author(s):  
Xanya Sofra
Keyword(s):  
Skeletal Muscle ◽  
Immune Response ◽  
Immune Cells ◽  
Preventive Intervention ◽  
Inflammatory Marker ◽  
The Body ◽  
Alternative Methods ◽  
Cytokine Storm ◽  
Protective Function ◽  
Age Related

We examined SARS-CoV-2 (Covid-19) available treatments and prophylactic methods that included interventions associated with inhibiting the ‘type II transmembrane serine protease’ (TMPRSS2) to limit the fusion between the Covid-19 Spike proteins and ACE2 receptors, or newly developed therapeutics like Remdesivir that interferes with the viral RNA replication. We explored the dilemma of ACE2 receptors that have a protective function against high blood pressure associated disorders, yet, they serve as the viral points of entry, elevating the probability of infection. Human tissues’ analysis reveals a higher ACE2 expression in adipose tissue, placing obesity-related conditions in the eye of the pandemic storm. It primarily exposes males due to the surge of ACE2 receptors in the testes along with other tissues. Males manifest a relatively higher positive ACE2 correlation with certain immune cells in the lungs, thyroid, adrenals, liver and colon, while females evidence higher ACE2 correlations with immune cells in the heart. The remaining tissues’ ACE2/immunity expressions are equivalent in both sexes, indicating that despite its preference for males, the threat of Covid-19 can easily target females. Recent reports indicate that Covid-19 is empowered by hindering the critical process of viral recognition during the adaptive immune response leading to the “cytokine storm,” the aggravated immune response that indiscriminately perseveres, rampaging the host’s vital organs. Sedentary lifestyle, age-related hormonal imbalance, and adiposity induced inflammation predispose the body to the immune collapse following Covid-19 invasion, spotlighting the detrimental aftermath of metabolic dysfunction, and excess food consumption, provoked by elevated cortisol and dysregulated appetite hormones. ACE2 expression is suppressed in the skeletal muscle, rendering fitness and weight management an effective Covid-19 preventive intervention, along with social distancing, hygiene, and facial coverings. Physical activity, or exercise alternative methods have recently demonstrated statistically significant reductions of the inflammatory marker C-Reactive Protein (CRP), triglycerides, visceral fat, cortisol and the orexigenic hormone ghrelin, juxtaposed by optimal increases of IGF-1, skeletal muscle mass, Free T3, HDL, and the anorexic hormone leptin.

JP-8 jet fuel exposure suppresses the immune response to viral infections

2008 ◽  
Vol 24 (4) ◽  
pp. 209-216 ◽  
Author(s):  
DT Harris ◽  
D Sakiestewa ◽  
D Titone ◽  
X He ◽  
J Hyde ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Viral Infection ◽  
Viral Infections ◽  
Immune Cell ◽  
Immunosuppressive Agents ◽  
Interleukin 10 ◽  
Jet Fuel ◽  
Us Air Force ◽  
Influenza Viral Infection

The US Air Force has implemented the widespread use of JP-8 jet fuel in its operations, although a thorough understanding of its potential effects upon exposed personnel is unclear. Previous work has reported that JP-8 exposure is immunosuppressive. Exposure of mice to JP-8 for 1 h/day resulted in immediate secretion of two immunosuppressive agents, namely, interleukin-10 and prostaglandin E2. Thus, it was of interest to determine if jet fuel exposure might alter the immune response to infectious agents. The Hong Kong influenza model was used for these studies. Mice were exposed to 1000 mg/m3 JP-8 (1 h/day) for 7 days before influenza viral infection. Animals were infected intra-nasally with virus and followed in terms of overall survival as well as immune responses. All surviving animals were killed 14 days after viral infection. In the present study, JP-8 exposure increased the severity of the viral infection by suppressing the anti-viral immune responses. That is, exposure of mice to JP-8 for 1 h/day for 7 days before infection resulted in decreased immune cell viability after exposure and infection, a greater than fourfold decrease in immune proliferative responses to mitogens, as well as an overall loss of CD3+, CD4+, and CD8+ T cells from the lymph nodes, but not the spleens, of infected animals. These changes resulted in decreased survival of the exposed and infected mice, with only 33% of animals surviving as compared with 50% of mice infected but not jet fuel–exposed (and 100% of mice exposed only to JP-8). Thus, short-term, low-concentration JP-8 jet fuel exposures have significant suppressive effects on the immune system which can result in increased severity of viral infections.

scholarly journals The Cellular Immunity Agent Based Model (CIABM): Replicating the cellular immune response to viral respiratory infection

2019 ◽  
Author(s):  
Andrew Becker ◽  
Gary An ◽  
Chase Cockrell
Keyword(s):  
Immune Response ◽  
Viral Infection ◽  
Respiratory Infection ◽  
Viral Infections ◽  
Immune Memory ◽  
Agent Based Model ◽  
Agent Based ◽  
Viral Respiratory Infection ◽  
Cellular Immune ◽  
Viral Respiratory

AbstractViral respiratory infections, such as influenza, result in over 1 million deaths worldwide each year. To date, there are few therapeutic interventions able to affect the course of the disease once acquired, a deficit with stark consequences that were readily evident in the current COVID-19 pandemic. We present the Cellular Immune Agent Based Model (CIABM) as a flexible framework for modeling acute viral infection and cellular immune memory development. The mechanism/rule-based nature of the CIABM allows for interrogation of the complex dynamics of the human immune system during various types of viral infections. The CIABM is an extension of a prior agent-based model of the innate immune response, incorporating additional cellular types and mediators involved in the response to viral infection. The CIABM simulates the dynamics of viral respiratory infection in terms of epithelial invasion, immune cellular population changes and cytokine measurements. Validation of the CIABM involved effectively replicating in vivo measurements of circulating mediator levels from a clinical cohort of influenza patients. The general purpose nature of the CIABM allows for both the representation of various types of known viral infections and facilitates the exploration of hypothetical, novel viral pathogens.

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