| 1. |
- Borriello, F., et al.
(författare)
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Identification and Characterization of Stimulator of Interferon Genes As a Robust Adjuvant Target for Early Life Immunization
- 2017
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Immunization is key to preventing infectious diseases, a leading cause of death early in life. However, due to age-specific immunity, vaccines often demonstrate reduced efficacy in newborns and young infants as compared to adults. Here, we combined in vitro and in vivo approaches to identify adjuvant candidates for early life immunization. We employed newborn and adult bone marrow-derived dendritic cells (BMDCs) to perform a screening of pattern recognition receptor agonists and found that the stimulator of interferon genes ligand 2' 3'-cGAMP (hereafter cGAMP) induces a comparable expression of surface maturation markers in newborn and adult BMDCs. Then, we utilized the trivalent recombinant hemagglutinin (rHA) influenza vaccine, Flublok, as a model antigen to investigate the role of cGAMP in adult and early life immunization. cGAMP adjuvantation alone could increase rHA-specific antibody titers in adult but not newborn mice. Remarkably, as compared to alum or cGAMP alone, immunization with cGAMP formulated with alum (Alhydrogel) enhanced newborn rHA-specific IgG2a/ c titers similar to 400-fold, an antibody subclass associated with the development of IFN gamma-driven type 1 immunity in vivo and endowed with higher effector functions, by 42 days of life. Highlighting the amenability for successful vaccine formulation and delivery, we next confirmed that cGAMP adsorbs onto alum in vitro. Accordingly, immunization early in life with (cGAMP(+) alum) promoted IFN. production by CD4(+) T cells and increased the proportions and absolute numbers of CD4(+) CXCR5(+) PD-1(+) T follicular helper and germinal center (GC) GL-7(+) CD138(+) B cells, suggesting an enhancement of the GC reaction. Adjuvantation effects were apparently specific for IgG2a/c isotype switching without effect on antibody affinity maturation, as there was no effect on rHA-specific IgG avidity. Overall, our studies suggest that cGAMP when formulated with alum may represent an effective adjuvantation system to foster humoral and cellular aspects of type 1 immunity for early life immunization.
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| 2. |
- Gravina, Giacomo, et al.
(författare)
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Staphylococcus epidermidis Sensitizes Perinatal Hypoxic-Ischemic Brain Injury in Male but Not Female Mice
- 2020
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Staphylococcus epidermidis is the most common nosocomial infection and the predominant pathogen in late-onset sepsis in preterm infants. Infection and inflammation are linked to neurological and developmental sequelae and bacterial infections increase the vulnerability of the brain to hypoxia-ischemia (HI). We thus tested the hypothesis that S. epidermidis exacerbates HI neuropathology in neonatal mice. Methods: Male and female C57Bl/6 mice were injected intraperitoneally with sterile saline or 3.5 x 10(7) colony-forming units of S. epidermidis on postnatal day (PND) 4 and then subjected to HI on PND5 (24 h after injection) or PND9 (5 d after injection) by left carotid artery ligation and exposure to 10% O-2. White and gray matter injury was assessed on PND14-16. In an additional group of animals, the plasma, brain, and liver were collected on PND5 or PND9 after infection to evaluate cytokine and chemokine profiles, C5a levels and C5 signaling. Results: HI induced 24 h after injection of S. epidermidis resulted in greater gray and white matter injury compared to saline injected controls in males, but not in females. Specifically, males demonstrated increased gray matter injury in the cortex and striatum, and white matter loss in the subcortical region, hippocampal fimbria and striatum. In contrast, there was no potentiation of brain injury when HI occurred 5 d after infection in either sex. In the plasma, S. epidermidis-injected mice demonstrated increased levels of pro- and anti-inflammatory cytokines and chemokines and a reduction of C5a at 24 h, but not 5 d after infection. Brain CCL2 levels were increased in both sexes 24 h after infection, but increased only in males at 5 d post infection. Conclusion: Ongoing S. epidermidis infection combined with neonatal HI increases the vulnerability of the developing brain in male but not in female mice. These sex-dependent effects were to a large extent independent of expression of systemic cytokines or brain CCL2 expression. Overall, we provide new insights into how systemic S. epidermidis infection affects the developing brain and show that the time interval between infection and HI is a critical sensitizing factor in males.
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| 3. |
- Lai, Jacqueline, 1980, et al.
(författare)
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Immune responses in perinatal brain injury.
- 2017
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 63, s. 210-223
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Forskningsöversikt (refereegranskat)abstract
- The perinatal period has often been described as immune deficient. However, it has become clear that immune responses in the neonate following exposure to microbes or as a result of tissue injury may be substantial and play a role in perinatal brain injury. In this article we will review the immune cell composition under normal physiological conditions in the perinatal period, both in the human and rodent. We will summarize evidence of the inflammatory responses to stimuli and discuss how neonatal immune activation, both in the central nervous system and in the periphery, may contribute to perinatal hypoxic-ischemic brain injury.
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| 4. |
- Lai, Jacqueline, 1980, et al.
(författare)
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Vancomycin Is Protective in a Neonatal Mouse Model of Staphylococcus epidermidis-Potentiated Hypoxic-Ischemic Brain Injury
- 2020
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Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 64:3
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Tidskriftsartikel (refereegranskat)abstract
- Infection is correlated with increased risk of neurodevelopmental sequelae in preterm infants. In modeling neonatal brain injury, Toll-like receptor agonists have often been used to mimic infections and induce inflammation. Using the most common cause of bacteremia in preterm infants, Staphylococcus epidermidis, we present a more clinically relevant neonatal mouse model that addresses the combined effects of bacterial infection together with subsequent hypoxic-ischemic brain insult. Currently, there is no neuroprotective treatment for the preterm population. Hence, we tested the neuroprotective effects of vancomycin with and without adjunct therapy using the anti-inflammatory agent pentoxifylline. We characterized the effects of S. epidermidis infection on the inflammatory response in the periphery and the brain, as well as the physiological changes in the central nervous system that might affect neurodevelopmental outcomes. Intraperitoneal injection of postnatal day 4 mice with a live clinical isolate of S. epidermidis led to bacteremia and induction of proinflammatory cytokines in the blood, as well as transient elevations of neutrophil and monocyte chemotactic cytokines and caspase 3 activity in the brain. When hypoxia-ischemia was induced postinfection, more severe brain damage was observed in infected animals than in saline-injected controls. This infection-induced inflammation and potentiated brain injury was inoculum dose dependent and was alleviated by the antibiotic vancomycin. Pentoxifylline did not provide any additional neuroprotective effect. Thus, we show for the first time that live S. epidermidis potentiates hypoxic-ischemic preterm brain injury and that peripheral inhibition of inflammation with antibiotics, such as vancomycin, reduces the extent of brain injury.
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| 5. |
- Nazmi, Arshed, et al.
(författare)
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Lymphocytes Contribute to the Pathophysiology of Neonatal Brain Injury
- 2018
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Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 9, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Periventricular leukomalacia (PVL) is the most common form of preterm brain injury affecting the cerebral white matter. This type of injury involves a multiphase process and is induced by many factors, including hypoxia-ischemia (HI) and infection. Previous studies have suggested that lymphocytes play a significant role in the pathogenesis of brain injury, and the aim of this study was to determine the contribution of lymphocyte subsets to preterm brain injury.Immunohistochemistry on brain sections from neonatal mice was performed to evaluate the extent of brain injury in wild-type and T cell and B cell-deficient neonatal mice (Rag1-/- mice) using a mouse model of HI-induced preterm brain injury. Flow cytometry was performed to determine the presence of different types of immune cells in mouse brains following HI. In addition, immunostaining for CD3 T cells and CD20 B cells was performed on postmortem preterm human infant brains with PVL.Mature lymphocyte-deficient Rag1- / - mice showed protection from white matter loss compared to wild type mice as indicated by myelin basic protein immunostaining of mouse brains. CD3+ T cells and CD20+ B cells were observed in the postmortem preterm infant brains with PVL. Flow cytometry analysis of mouse brains after HI-induced injury showed increased frequency of CD3+ T, αβT and B cells at 7days after HI in the ipsilateral (injured) hemisphere compared to the contralateral (control, uninjured) hemisphere.Lymphocytes were found in the injured brain after injury in both mice and humans, and lack of mature lymphocytes protected neonatal mice from HI-induced brain white matter injury. This finding provides insight into the pathology of perinatal brain injury and suggests new avenues for the development of therapeutic strategies.
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| 6. |
- Nguyen, D. N., et al.
(författare)
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Elevated levels of circulating cell-free DNA and neutrophil proteins are associated with neonatal sepsis and necrotizing enterocolitis in immature mice, pigs and infants
- 2017
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Ingår i: Innate Immunity. - : SAGE Publications. - 1753-4259 .- 1753-4267. ; 23:6, s. 524-536
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Tidskriftsartikel (refereegranskat)abstract
- Preterm infants are highly susceptible to late-onset sepsis (LOS) and necrotizing enterocolitis (NEC), but disease pathogenesis and specific diagnostic markers are lacking. Circulating cell-free DNA (cfDNA) and immune cell-derived proteins are involved in multiple immune diseases in adults but have not been investigated in preterm neonates. We explored the relation of circulating neutrophil-associated proteins and cfDNA to LOS and/or NEC. Using a clinically relevant preterm pig model of spontaneous LOS and NEC development, we investigated neutrophil-associated proteins and cfDNA in plasma, together with cytokines in gut tissues. The changes in cfDNA levels were further studied in preterm pigs and neonatal mice with induced sepsis, and in preterm infants with or without LOS and/or NEC. Fifteen of 114 preterm pigs spontaneously developed both LOS and NEC, and they showed increased intestinal levels of IL-6 and IL-1 and plasma levels of cfDNA, neutrophil-associated proteins, and proteins involved in platelet-neutrophil interaction during systemic inflammation. The abundance of neutrophil-associated proteins highly correlated with cfDNA levels. Further, Staphylococcus epidermidis challenge of neonatal mice and preterm pigs increased plasma cfDNA levels and bacterial accumulation in the spleen. In infants, plasma cfDNA levels were elevated at LOS diagnosis and 1-6d before NEC. In conclusion, elevated levels of plasma cfDNA and neutrophil proteins are associated with LOS and NEC diagnosis.
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