scholarly journals Short Palate, Lung, and Nasal Epithelial Clone1 (SPLUNC1) level determines steroid-resistant airway inflammation in aging

2021 ◽  
Author(s):  
Anil Kumar Jaiswal ◽  
Jyoti Yadav ◽  
Sangeet Makhija ◽  
Maninder Sandey ◽  
Amol Suryawanshi ◽  
...  
Keyword(s):  
Immune Response ◽  
Airway Inflammation ◽  
Adaptive Immune Response ◽  
The Elderly ◽  
Metabolic Adaptation ◽  
Steroid Resistant ◽  
Aged Mice ◽  
Adult Mice ◽  
Inflammatory Mechanism ◽  
Age Dependent

Asthma and its heterogeneity changes with age. Increased airspace neutrophil numbers contribute to severe steroid-resistant asthma exacerbation in the elderly, which correlates with the changes seen in adult asthmatics. However, whether that resembles the same disease mechanism and pathophysiology in aged and adults is poorly understood. Here, we sought to address the underlying molecular mechanism of steroid-resistant airway inflammation development and response to corticosteroid (Dex) therapy in aged mice. To study the changes in inflammatory mechanism, we employed a clinically relevant treatment model of house-dust mite (HDM)-induced allergic asthma and investigated lung adaptive immune response in adults (20-22 weeks) and aged (80-82 weeks) mice. Our result indicates an age-dependent increase in AHR, mixed granulomatous airway inflammation comprising eosinophils and neutrophils, and Th1/Th17 immune response with progressive decrease in frequencies and numbers of HDM-bearing dendritic cells (DC) accumulation in the draining lymph node (DLn) of aged mice as compared with adult mice. RNAseq experiments of the aged lung revealed SPLUNC1 (Short Palate, Lung, and Nasal Epithelial Clone 1) as one of the steroid-responsive genes, which progressively declined with age and further by HDM-induced inflammation. Moreover, we found increased glycolytic reprogramming, maturation/activation of DCs, the proliferation of OT-II cells, and Th2 cytokine secretion with recombinant SPLUNC1 (rSPLUNC1) treatment. Our results indicate a novel immunomodulatory role of SPLUNC1 regulating metabolic adaptation/maturation of DC. An age-dependent decline in the SPLUNC1 level may be involved in developing steroid-resistant airway inflammation and asthma heterogeneity.

scholarly journals Neonatal hyperoxia enhances age-dependent expression of SARS-CoV-2 receptors in mice

2020 ◽  
Author(s):  
Min Yee ◽  
E. David Cohen ◽  
Jeannie Haak ◽  
Andrew M. Dylag ◽  
Michael A. O’Reilly
Keyword(s):  
Lung Disease ◽  
Influenza A ◽  
The Elderly ◽  
Virus Infections ◽  
Alveolar Epithelial ◽  
Mitochondrial Superoxide ◽  
Adult Mice ◽  
Club Cells ◽  
Age Dependent ◽  
Neonatal Hyperoxia

ABSTRACTThe severity of COVID-19 lung disease is higher in the elderly and people with pre-existing co-morbidities. People who were born preterm may be at greater risk for COVID-19 because their early exposure to oxygen at birth increases their risk of being hospitalized when infected with RSV and other respiratory viruses. Our prior studies in mice showed how high levels of oxygen (hyperoxia) between postnatal days 0-4 increases the severity of influenza A virus infections by reducing the number of alveolar epithelial type 2 (AT2) cells. Because AT2 cells express the SARS-CoV-2 receptors angiotensin converting enzyme (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2), we expected their expression would decline as AT2 cells were depleted by hyperoxia. Instead, we made the surprising discovery that expression of Ace2 and Tmprss2 mRNA increases as mice age and is accelerated by exposing mice to neonatal hyperoxia. ACE2 is primarily expressed at birth by airway Club cells and becomes detectable in AT2 cells by one year of life. Neonatal hyperoxia increases ACE2 expression in Club cells and makes it detectable in 2-month-old AT2 cells. This early and increased expression of SARS-CoV-2 receptors was not seen in adult mice who had been administered the mitochondrial superoxide scavenger mitoTEMPO during hyperoxia. Our finding that early life insults such as hyperoxia enhances the age-dependent expression of SARS-CoV-2 receptors in the respiratory epithelium helps explain why COVID-19 lung disease is greater in the elderly and people with pre-existing co-morbidities.

scholarly journals Immune responses of meningococcal B outer membrane vesicles in middle-aged mice

2020 ◽  
Vol 78 (5) ◽  
Author(s):  
Gabriela Trzewikoswki de Lima ◽  
Thais Sousa Rodrigues ◽  
Amanda Izeli Portilho ◽  
Victor Araujo Correa ◽  
Emanuelle Baldo Gaspar ◽  
...  
Keyword(s):  
Immune Response ◽  
Outer Membrane ◽  
Membrane Vesicles ◽  
The Elderly ◽  
Outer Membrane Vesicles ◽  
Control Group ◽  
Middle Aged ◽  
Aged Mice ◽  
Robust Immune Response

ABSTRACT The elderly are more likely to die when infected with Neisseria meningitidis. Aging is associated with immune system dysfunctions that impair responses to vaccines and infections. Therefore, immunization of middle-aged individuals could be beneficial. This study aims to evaluate the immunogenicity of N. meningitidis B outer membrane vesicles (OMVs) complexed to two different adjuvants. Middle-aged BALB/c and A/Sn mice were immunized and subsequent immune response was assessed by ELISA, immunoblotting and ELISpot. IgG levels were similar between the animals immunized with OMVs complexed to adjuvants. A total of 235 days after the last immunization only A/Sn mice presented higher IgG levels than those observed in the baseline, especially the group immunized with OMVs and aluminum hydroxide. The predominant IgG subclasses were IgG2a and IgG2b. Immunization with the three-dose regimen generated IgG antibodies that recognized a variety of antigens present in the homologous and heterologous meningococcal OMVs evaluated. There was an increase in the frequency of antigen-specific IFN-γ secreting splenocytes, after in vitro stimulation, in mice immunized with OMVs and adjuvants compared to the control group, almost 1 year after the last immunization. Both adjuvants showed similar performance. Immunization of middle-aged mice has generated a robust immune response and it appears to be advantageous.

scholarly journals Age-dependent differences in microglial responses to systemic inflammation are evident as early as middle age

2016 ◽  
Vol 48 (5) ◽  
pp. 336-344 ◽  
Author(s):  
Maria Nikodemova ◽  
Alissa L. Small ◽  
Rebecca S. Kimyon ◽  
Jyoti J. Watters
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Systemic Inflammation ◽  
Middle Age ◽  
Middle Aged ◽  
Aged Mice ◽  
Lps Challenge ◽  
Age Dependent ◽  
Proinflammatory Responses

Whereas age increases microglial inflammatory activities and impairs their ability to effectively regulate their immune response, it is unclear at what age these exaggerated responses begin. We tested the hypotheses that augmented microglial responses to inflammatory challenge are present as early as middle age and that repeated stimulation of primed microglia in vivo would reveal microglial senescence. Microglial gene expression was investigated in a mouse model of repeated systemic inflammation induced by intraperitoneal injection of bacterial lipopolysaccharide (LPS). Following LPS, microglia from middle-aged mice (9–10 mo) displayed larger increases in Tnfα, Il-6, and Il-1β gene expression compared with young adults (2 mo). Similar results were observed in the spleens of middle-aged mice, indicating that exaggeration of both central and peripheral immune responses are already evident at early middle age. Interestingly, despite greater proinflammatory responses to the first LPS challenge in the aged mice, there were no age-dependent differences in either microglia or spleen following a subsequent LPS dose, suggesting that animals at this age retain the ability to effectively control their immune response following repeated challenge. The exacerbated microglial immune response to systemic inflammation at early middle age suggests that the CNS may be vulnerable to age-dependent alterations earlier than previously appreciated.

scholarly journals A booster dose enhances immunogenicity of the COVID-19 vaccine candidate ChAdOx1 nCoV-19 in aged mice

2020 ◽  
Author(s):  
Alyssa Silva-Cayetano ◽  
William S. Foster ◽  
Silvia Innocentin ◽  
Sandra Belij-Rammerstorfer ◽  
Alexandra J. Spencer ◽  
...  
Keyword(s):  
Immune Response ◽  
Human Life ◽  
Significant Risk ◽  
Rational Approach ◽  
Aged Mice ◽  
Robust Immune Response ◽  
Adult Mice ◽  
Global Pandemic ◽  
Cellular And Humoral Immunity ◽  
Vectored Vaccine

AbstractThe spread of SARS-CoV-2 has caused a global pandemic that has affected almost every aspect of human life. The development of an effective COVID-19 vaccine could limit the morbidity and mortality caused by infection, and may enable the relaxation of social distancing measures. Age is one of the most significant risk factors for poor health outcomes after SARS-CoV-2 infection, therefore it is desirable that any new vaccine candidates should elicit a robust immune response in older adults. Here, we test the immunogenicity of the adenoviral vectored vaccine ChAdOx1 nCoV-19 (AZD-1222) in aged mice. We find that a single dose of this vaccine induces cellular and humoral immunity in aged mice, but at a reduced magnitude than in younger adult mice. Furthermore, we report that a second dose enhances the immune response to this vaccine in aged mice, indicating that a primeboost strategy may be a rational approach to enhance immunogenicity in older persons.

COVID-19 vaccine race: analysis of age-dependent immune responses against SARS-CoV-2 indicates that more than just one strategy may be needed.

2020 ◽  
Vol 27 ◽  
Author(s):  
Nuria E. Campillo ◽  
Mercedes Jimenez ◽  
Matilde Canelles
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
The Elderly ◽  
Finish Line ◽  
Individual Level ◽  
Worldwide Distribution ◽  
Age Dependent ◽  
The Individual ◽  
Respiratory Coronavirus ◽  
Race Analysis

: In December 2019, a novel respiratory coronavirus named SARS-CoV-2 appeared in China, causing the disease termed COVID-19 that has caused millions of infections worldwide. In this article we have analyzed existing evidence on the immune response against SARS coronaviruses in order to understand the possible outcome of a vaccine for COVID-19. From our analysis it becomes clear that there is a big difference in the immune response against SARS in children, young adults and the elderly, both at the innate and adaptive levels. Taking this information into account, we have studied the strategies that are being used for development of COVID-19 vaccines. We discuss the perspectives for obtention and worldwide distribution of reliable vaccines using this perspective. The conclusion is that different vaccines may be protective for different age segments within the population, depending on the strategy used for their design. Therefore, it will become necessary for several vaccines to reach the finish line, not only to ensure availability, but also to guarantee an adequate immune response at the individual level.

scholarly journals Neonatal hyperoxia enhances age-dependent expression of SARS-CoV-2 receptors in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Min Yee ◽  
E. David Cohen ◽  
Jeannie Haak ◽  
Andrew M. Dylag ◽  
Michael A. O’Reilly
Keyword(s):  
Lung Disease ◽  
Influenza A ◽  
Viral Infections ◽  
The Elderly ◽  
Virus Infections ◽  
Mitochondrial Superoxide ◽  
Adult Mice ◽  
Club Cells ◽  
Age Dependent ◽  
Neonatal Hyperoxia

AbstractThe severity of COVID-19 lung disease is higher in the elderly and people with pre-existing co-morbidities. People who were born preterm may be at greater risk for COVID-19 because their early exposure to oxygen (hyperoxia) at birth increases the severity of respiratory viral infections. Hyperoxia at birth increases the severity of influenza A virus infections in adult mice by reducing the number of alveolar epithelial type 2 (AT2) cells. Since AT2 cells express the SARS-CoV-2 receptors angiotensin converting enzyme (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2), their expression should decline as AT2 cells are depleted by hyperoxia. Instead, ACE2 was detected in airway Club cells and endothelial cells at birth, and then AT2 cells at one year of age. Neonatal hyperoxia stimulated expression of ACE2 in Club cells and in AT2 cells by 2 months of age. It also stimulated expression of TMPRSS2 in the lung. Increased expression of SARS-CoV-2 receptors was blocked by mitoTEMPO, a mitochondrial superoxide scavenger that reduced oxidative stress and DNA damage seen in oxygen-exposed mice. Our finding that hyperoxia enhances the age-dependent expression of SARS-CoV-2 receptors in mice helps explain why COVID-19 lung disease is greater in the elderly and people with pre-existing co-morbidities.

scholarly journals Age-Related Impairment of Innate and Adaptive Immune Responses Following Intranasal Herpes Simplex Infection

2022 ◽  
Author(s):  
Ruchi Srivastava ◽  
Anshu Agrawal ◽  
Hawa Vahed ◽  
Lbachir BenMohamed
Keyword(s):  
Immune Response ◽  
Herpes Simplex ◽  
Immune Responses ◽  
The Elderly ◽  
Adaptive Immune Responses ◽  
Herpes Infection ◽  
Aged Mice ◽  
Adaptive Immune ◽  
Age Related ◽  
Hsv 1

Immune function declines with age, leading to an increased vulnerability to respiratory viral infections. The mechanisms by which aging negatively impacts the innate and adaptive immune system leading to enhanced susceptibility to infections remain to be fully elucidated. In the present study, we used a mouse model of intranasal infection with herpes simplex virus type 1 (HSV-1), a virus that can enter the lungs through the nasal route causing pneumonia, a serious health concern in the elderly. Following intranasal inoculation of young (6 weeks), adult (36 weeks), and aged (68 weeks) with HSV-1 (KOS strain) we: (i) compared the local and systemic innate and adaptive immune response to infection; and (ii) correlated the level and type of immune response to protection against HSV-1 infection. Compared to young and adult mice, aged mice displayed: (i) increased basal level activation of epithelial cells with a decreased expression of TLR3; (ii) increased activation of dendritic cells with increased expression of MHC-1, MHC-II and CD80/86; and (iii) decreased production of type-I interferons upon stimulation; (iv) a delay in cytokines and chemokines production in the lungs; and (v) an impairment in function (CD107 and IFN-g production) of HSV-specific CD8+ T cells. These impairment in innate and adaptive immune responses in aged mice following intranasal HSV-1 inoculation was associated with symptomatic herpes infection. The findings suggest an age-related impairment of both innate and adaptive immune responses which may exacerbate herpes infection and disease in the elderly.

Metabolic costs of mounting an antigen-stimulated immune response in adult and aged C57BL/6J mice

1997 ◽  
Vol 273 (5) ◽  
pp. R1631-R1637 ◽  
Author(s):  
Gregory E. Demas ◽  
Vladimir Chefer ◽  
Mark I. Talan ◽  
Randy J. Nelson
Keyword(s):  
Immune Response ◽  
Antibody Response ◽  
Keyhole Limpet Hemocyanin ◽  
Energetic Cost ◽  
Aged Mice ◽  
Adult Mice ◽  
Energy Demands ◽  
Physiological Processes ◽  
Trade Offs ◽  
Metabolic Costs

Animals must balance their energy budget despite seasonal changes in both energy availability and physiological expenditures. Immunity, in addition to growth, thermoregulation, and cellular maintenance, requires substantial energy to maintain function, although few studies have directly tested the energetic cost of immunity. The present study assessed the metabolic costs of an antibody response. Adult and aged male C5BL/6J mice were implanted with either empty Silastic capsules or capsules filled with melatonin and injected with either saline or keyhole limpet hemocyanin (KLH). O2 consumption was monitored periodically throughout antibody production using indirect calorimetry. KLH-injected mice mounted significant immunoglobulin G (IgG) responses and consumed more O2 compared with animals injected with saline. Melatonin treatment increased O2 consumption in mice injected with saline but suppressed the increased metabolic rate associated with an immune response in KLH-injected animals. Melatonin had no effect on immune response to KLH. Adult and aged mice did not differ in antibody response or metabolic activity. Aged mice appear unable to maintain sufficient heat production despite comparable O2 production to adult mice. These results suggest that mounting an immune response requires significant energy and therefore requires using resources that could otherwise be allocated to other physiological processes. Energetic trade-offs are likely when energy demands are high (e.g., during winter, pregnancy, or lactation). Melatonin appears to play an adaptive role in coordinating reproductive, immunologic, and energetic processes.

scholarly journals Acute Myeloid Leukemia: Is it T Time?

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2385
Author(s):  
Meriem Ben Khoud ◽  
Tiziano Ingegnere ◽  
Bruno Quesnel ◽  
Suman Mitra ◽  
Carine Brinster
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Adaptive Immune Response ◽  
The Elderly ◽  
Leukemic Cells ◽  
Thymic Function ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a heterogeneous disease driven by impaired differentiation of hematopoietic primitive cells toward myeloid lineages (monocytes, granulocytes, red blood cells, platelets), leading to expansion and accumulation of “stem” and/or “progenitor”-like or differentiated leukemic cells in the bone marrow and blood. AML progression alters the bone marrow microenvironment and inhibits hematopoiesis’ proper functioning, causing sustained cytopenia and immunodeficiency. This review describes how the AML microenvironment influences lymphoid lineages, particularly T lymphocytes that originate from the thymus and orchestrate adaptive immune response. We focus on the elderly population, which is mainly affected by this pathology. We discuss how a permissive AML microenvironment can alter and even worsen the thymic function, T cells’ peripheral homeostasis, phenotype, and functions. Based on the recent findings on the mechanisms supporting that AML induces quantitative and qualitative changes in T cells, we suggest and summarize current immunotherapeutic strategies and challenges to overcome these anomalies to improve the anti-leukemic immune response and the clinical outcome of patients.

scholarly journals Toxin Levels in Serum Correlate with the Development of Staphylococcal Scalded Skin Syndrome in a Murine Model

2001 ◽  
Vol 69 (8) ◽  
pp. 5193-5197 ◽  
Author(s):  
Lisa R. W. Plano ◽  
Becky Adkins ◽  
Markus Woischnik ◽  
Ruth Ewing ◽  
Carleen M. Collins
Keyword(s):  
Immune Response ◽  
Time Course ◽  
Adaptive Immune Response ◽  
Critical Factor ◽  
Staphylococcal Scalded Skin Syndrome ◽  
Exfoliative Dermatitis ◽  
Adaptive Immune ◽  
Exfoliative Toxin ◽  
Adult Mice ◽  
Old Mice

ABSTRACT Staphylococcal scalded skin syndrome (SSSS) is an exfoliative dermatitis that results from infection with exfoliative toxin-producingStaphylococcus aureus. SSSS is seen primarily in infants and children. Here we ask if there is a specific maturation process that protects healthy adults from this syndrome. For these studies, an active recombinant exfoliative toxin A (rETA) was used in a neonatal mouse model. A time course generated on the susceptibility to the toxin as a function of mouse age indicated that BALB/c mice developed the characteristic symptoms of SSSS until day 7 of life. Between day 7 and day 8 of life there was a dramatic decrease in susceptibility, such that mice at day 9 of life were resistant to the effects of the toxin. This time course corresponds approximately to the time needed for maturation of the adaptive immune response, and SSSS in adults is often identified with immunocompromised states. Therefore, mice deficient in this response were examined. Adult mice thymectomized at birth and adult SCID mice did not develop the symptoms of SSSS after injection with the toxin, indicating that the adaptive immune response is not responsible for the lack of susceptibility observed in the older mice. SSSS in adults is also associated with renal disorders, suggesting that levels of toxin in serum are important in the development of the disease. rETA was not cleared as efficiently from the serum of 1-day-old mice compared to clearance from 10-day-old mice. Ten-day-old mice were given repeated injections of toxin so that the maximal level of toxin was maintained for a sustained period of time, and exfoliation occurred in these mice. Thus, whereas the adaptive immune response is not needed for protection of adult mice from SSSS, efficient clearance of the toxin from the bloodstream is a critical factor.

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