| 1. |
- Ardalan, Maryam, 1979, et al.
(författare)
-
Reelin cells and sex-dependent synaptopathology in autism following postnatal immune activation
- 2022
-
Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 179:17, s. 4400-4422
-
Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: Autism spectrum disorders (ASD) are heterogeneous neurodevelopmental disorders with considerably increased risk in male infants born preterm and with neonatal infection. Here, we investigated the role of postnatal immune activation on hippocampal synaptopathology by targeting Reelin+ cells in mice with ASD-like behaviours. Experimental Approach: C57/Bl6 mouse pups of both sexes received lipopolysaccharide (LPS, 1mg·kg−1) on postnatal day (P) 5. At P45, animal behaviour was examined by marble burying and sociability test, followed by ex vivo brain MRI diffusion kurtosis imaging (DKI). Hippocampal synaptogenesis, number and morphology of Reelin+ cells, and mRNA expression of trans-synaptic genes, including neurexin-3, neuroligin-1, and cell-adhesion molecule nectin-1, were analysed at P12 and P45. Key Results: Social withdrawal and increased stereotypic activities in males were related to increased mean diffusivity on MRI-DKI and overgrowth in hippocampus together with retention of long-thin immature synapses on apical dendrites, decreased volume and number of Reelin+ cells as well as reduced expression of trans-synaptic and cell-adhesion molecules. Conclusion and Implications: The study provides new insights into sex-dependent mechanisms that may underlie ASD-like behaviour in males following postnatal immune activation. We identify GABAergic interneurons as core components of dysmaturation of excitatory synapses in the hippocampus following postnatal infection and provide cellular and molecular substrates for the MRI findings with translational value.
|
|
| 2. |
- Gravina, Giacomo, et al.
(författare)
-
Association of N-Acetyl Asparagine with QTc in Diabetes: A Metabolomics Study
- 2022
-
Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:8
-
Tidskriftsartikel (refereegranskat)abstract
- Changes in the cardio-metabolomics profile and hormonal status have been associated with long QT syndrome, sudden cardiac death and increased mortality. The mechanisms underlying QTc duration are not fully understood. Therefore, an identification of novel markers that complement the diagnosis in these patients is needed. In the present study, we performed untargeted metabolomics on the sera of diabetic patients at a high risk of cardiovascular disease, followed up for 2.55 [2.34-2.88] years (NCT02431234), with the aim of identifying the metabolomic changes associated with QTc. We used independent weighted gene correlation network analysis (WGCNA) to explore the association between metabolites clusters and QTc at T1 (baseline) and T2 (follow up). The overlap of the highly correlated modules at T1 and T2 identified N-Acetyl asparagine as the only metabolite in common, which was involved with the urea cycle and metabolism of arginine, proline, glutamate, aspartate and asparagine. This analysis was confirmed by applying mixed models, further highlighting its association with QTc. In the current study, we were able to identify a metabolite associated with QTc in diabetic patients at two chronological time points, suggesting a previously unrecognized potential role of N-Acetyl asparagine in diabetic patients suffering from long QTc.
|
|
| 3. |
- Gravina, Giacomo
(författare)
-
Perinatal Staphylococcus epidermidis infection and the immature brain: a neuroinflammatory link
- 2022
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Preterm birth and its associated complications are among the most serious global health issues that modern society faces. Due to the prolonged medical care and immature immune system, preterm infants have a higher susceptibility to infections, which puts them at a higher risk of developing neurological impairments as well as neurodevelopmental diseases. S. epidermidis is one of the most common nosocomial infections in preterm infants. Despite being considered a harmless commensal for a long time, S. epidermidis has emerged as the predominant pathogen of neonatal sepsis, leading to inflammation-related morbidities. Moreover, the incomplete maturation of the preterm infants´ organs might lead to an increased risk of episodes of hypoxia and it is believed that the ongoing infection can worsen the effects of cerebral hypoxia-ischemia (HI), further increasing the risk for perinatal brain injury. The hypothesis of this doctoral thesis is that systemic inflammation induced by S. epidermidis infection leads to immune reactions in the periphery and the brain, which increases vulnerability to brain injury, leading to neurological impairments. Thus, the overall aim of this thesis was to explore the different aspects of the pathogenesis associated with S. epidermidis infection, ranging from its sensitizing effects to the neuroinflammatory responses. Using our established animal model for S. epidermidis infection and Hypoxia-ischemia (HI), in Paper I we induced HI 24 hours or 5 days after S. epidermidis infection, demonstrating a sex-dependent sensitization 24 hours after infection in male, but not female mice. We also found a dramatic upregulation of peripheral cytokines, brain Chemokine ligand 2 (CCL2) together with decreased plasma levels of Complement protein 5a. As neuroinflammation contributes to perinatal brain injury, in Paper II we analyzed hippocampal microglia activation both at morphological and transcriptional levels. We found that S. epidermidis induced significant changes in microglial morphology as well as in their transcriptional programs. We also found that microglial inflammasome activation might act in synergy with blood-brain barrier alterations as well as leukocyte infiltration into the brain. To further characterize the neuroinflammatory response in the hippocampus of S. epidermidis infected mice, in Paper III we carried out hippocampal global protein expression analysis, revealing astrocytic activation as well as vascular changes. These alterations were associated with increased lipocalin 2 levels in both plasma and brain. We also demonstrated that a similar pattern of events might occur in a cohort of preterm infants with signs of infection by analyzing plasma levels of lipocalin 2. To conclude, this thesis clearly highlights a previously unrecognized and important contribution of S. epidermidis in triggering neuroinflammation in the developing brain. Overall, the findings in this thesis shed new light on how S. epidermidis affects the immature brain, representing a suitable platform for the development of novel treatment or preventative strategies in babies who experience S. epidermidis infection.
|
|
| 4. |
- Gravina, Giacomo, et al.
(författare)
-
Proteomics identifies lipocalin-2 in neonatal inflammation associated with cerebrovascular alteration in mice and preterm infants
- 2023
-
Ingår i: iScience. - 2589-0042. ; 26:7
-
Tidskriftsartikel (refereegranskat)abstract
- Staphylococcus (S.) epidermidis is the most common nosocomial coagulase-negative staphylococci infection in preterm infants. Clinical signs of infection are often unspecific and novel markers to complement diagnosis are needed. We investigated proteomic alterations in mouse brain after S. epidermidis infection and in preterm infant blood. We identified lipocalin-2 (LCN2) as a crucial protein associated with cerebrovascular changes and astrocyte reactivity in mice. We further proved that LCN2 protein expression was associated with endothelial cells but not astrocyte reactivity. By combining network analysis and differential expression approaches, we identified LCN2 linked to blood C-reactive protein levels in pre term infants born <28 weeks of gestation. Blood LCN2 levels were associated with similar alterations of cytokines and chemokines in both infected mice and human preterm infants with increased levels of C-reactive protein. This experimental and clinical study suggests that LCN2 may be a marker of preterm infection/inflammation associated with cerebrovascular changes and neuroinflammation.
|
|
| 5. |
- Gravina, Giacomo, et al.
(författare)
-
Staphylococcus epidermidis Sensitizes Perinatal Hypoxic-Ischemic Brain Injury in Male but Not Female Mice
- 2020
-
Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
-
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.
|
|
| 6. |
- Gravina, Giacomo, et al.
(författare)
-
Survivin in autoimmune diseases.
- 2017
-
Ingår i: Autoimmunity reviews. - : Elsevier BV. - 1873-0183 .- 1568-9972. ; 16:8, s. 845-855
-
Forskningsöversikt (refereegranskat)abstract
- Survivin is a protein functionally important for cell division, apoptosis, and possibly, for micro-RNA biogenesis. It is an established marker of malignant cell transformation. In non-malignant conditions, the unique properties of survivin make it indispensable for homeostasis of the immune system. Indeed, it is required for the innate and adaptive immune responses, controlling differentiation and maintenance of CD4(+) and CD8(+) memory T-cells, and in B cell maturation. Recently, survivin has emerged as an important player in the pathogenesis of autoimmune diseases. Under the conditions of unreserved inflammation, survivin enhances antigen presentation, maintains persistence of autoreactive cells, and supports production of autoantibodies. In this context, survivin takes its place as a diagnostic and prognostic marker in rheumatoid arthritis, psoriasis, systemic sclerosis and pulmonary arterial hypertension, neuropathology and multiple sclerosis, inflammatory bowel diseases and oral lichen planus. In this review, we summarise the knowledge about non-malignant properties of survivin and focus on its engagement in cellular and molecular pathology of autoimmune diseases. The review highlights utility of survivin measures for clinical applications. It provides rational for the survivin inhibiting strategies and presents results of recent reports on survivin inhibition in modern therapies of cancers and autoimmune diseases.
|
|
| 7. |
- Gravina, Giacomo, et al.
(författare)
-
Transcriptome network analysis links perinatal Staphylococcus epidermidis infection to microglia reprogramming in the immature hippocampus
- 2023
-
Ingår i: Glia. - 0894-1491. ; 71:9, s. 2234-2249
-
Tidskriftsartikel (refereegranskat)abstract
- Staphylococcus epidermidis (S. epidermidis) is the most common nosocomial pathogen in preterm infants and associated with increased risk of cognitive delay, however, underlying mechanisms are unknown. We employed morphological, transcriptomic and physiological methods to extensively characterize microglia in the immature hippocampus following S. epidermidis infection. 3D morphological analysis revealed activation of microglia after S. epidermidis. Differential expression combined with network analysis identified NOD-receptor signaling and trans-endothelial leukocyte trafficking as major mechanisms in microglia. In support, active caspase-1 was increased in the hippocampus and using the LysM-eGFP knock-in transgenic mouse, we demonstrate infiltration of leukocytes to the brain together with disruption of the blood-brain barrier. Our findings identify activation of microglia inflammasome as a major mechanism underlying neuroinflammation following infection. The results demonstrate that neonatal S. epidermidis infection share analogies with S. aureus and neurological diseases, suggesting a previously unrecognized important role in neurodevelopmental disorders in preterm born children.
|
|
