| 1. |
- Ammanath, Aparna Viswanathan, et al.
(författare)
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Antimicrobial Evaluation of Two Polycyclic Polyprenylated Acylphloroglucinol Compounds: PPAP23 and PPAP53.
- 2024
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Ingår i: International Journal of Molecular Sciences. - 1422-0067. ; 25:15
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Tidskriftsartikel (refereegranskat)abstract
- Polycyclic polyprenylated acylphloroglucinols (PPAPs) comprise a large group of compounds of mostly plant origin. The best-known compound is hyperforin from St. John's wort with its antidepressant, antitumor and antimicrobial properties. The chemical synthesis of PPAP variants allows the generation of compounds with improved activity and compatibility. Here, we studied the antimicrobial activity of two synthetic PPAP-derivatives, the water-insoluble PPAP23 and the water-soluble sodium salt PPAP53. In vitro, both compounds exhibited good activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Both compounds had no adverse effects on Galleria mellonella wax moth larvae. However, they were unable to protect the larvae from infection with S. aureus because components of the larval coelom neutralized the antimicrobial activity; a similar effect was also seen with serum albumin. In silico docking studies with PPAP53 revealed that it binds to the F1 pocket of human serum albumin with a binding energy of -7.5 kcal/mol. In an infection model of septic arthritis, PPAP23 decreased the formation of abscesses and S. aureus load in kidneys; in a mouse skin abscess model, topical treatment with PPAP53 reduced S. aureus counts. Both PPAPs were active against anaerobic Gram-positive gut bacteria such as neurotransmitter-producing Clostridium, Enterococcus or Ruminococcus species. Based on these results, we foresee possible applications in the decolonization of pathogens.
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| 2. |
- Ammanath, Aparna Viswanathan, et al.
(författare)
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From an Hsp90 - binding protein to a peptide drug.
- 2022
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Ingår i: microLife. - : Oxford University Press (OUP). - 2633-6693. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- The Lpl proteins represent a class of lipoproteins that was first described in the opportunistic bacterial pathogen Staphylococcus aureus, where they contribute to pathogenicity by enhancing F-actin levels of host epithelial cells and thereby increasing S. aureus internalization. The model Lpl protein, Lpl1 was shown to interact with the human heat shock proteins Hsp90α and Hsp90ß, suggesting that this interaction may trigger all observed activities. Here we synthesized Lpl1-derived peptides of different lengths and identified two overlapping peptides, namely, L13 and L15, which interacted with Hsp90α. Unlike Lpl1, the two peptides not only decreased F-actin levels and S. aureus internalization in epithelial cells but they also decreased phagocytosis by human CD14+ monocytes. The well-known Hsp90 inhibitor, geldanamycin, showed a similar effect. The peptides not only interacted directly with Hsp90α, but also with the mother protein Lpl1. While L15 and L13 significantly decreased lethality of S. aureus bacteremia in an insect model, geldanamycin did not. In a mouse bacteremia model L15 was found to significantly decreased weight loss and lethality. Although the molecular bases of the L15 effect is still elusive, in vitro data indicate that simultaneous treatment of host immune cells with L15 or L13 and S. aureus significantly increase IL-6 production. L15 and L13 represent not antibiotics but they cause a significant reduction in virulence of multidrug-resistant S. aureus strains in in vivo models. In this capacity, they can be an important drug alone or additive with other agents.
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| 3. |
- Bergmann, Berglind, et al.
(författare)
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Pre-treatment with IL2 gene therapy alleviates Staphylococcus aureus arthritis in mice.
- 2020
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Ingår i: BMC infectious diseases. - : Springer Science and Business Media LLC. - 1471-2334. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Staphylococcus aureus (S. aureus) arthritis is one of the most detrimental joint diseases known and leads to severe joint destruction within days. We hypothesized that the provision of auxiliary immunoregulation via an expanded compartment of T regulatory cells (Tregs) could dampen detrimental aspects of the host immune response whilst preserving its protective nature. Administration of low-dose interleukin 2 (IL2) preferentially expands Tregs, and is being studied as a treatment choice in several autoimmune conditions. We aimed to evaluate the role of IL2 and Tregs in septic arthritis using a well-established mouse model of haematogenously spred S. aureus arthritis.C57BL/6 or NMRI mice we intravenously (iv) injected with a defined dose of S. aureus LS-1 or Newman and the role of IL2 and Tregs were assessed by the following approaches: IL2 was endogenously delivered by intraperitoneal injection of a recombinant adeno-associated virus vector (rAAV) before iv S. aureus inoculation; Tregs were depleted before and during S. aureus arthritis using antiCD25 antibodies; Tregs were adoptively transferred before induction of S. aureus arthritis and finally, recombinant IL2 was used as a treatment starting day 3 after S. aureus injection. Studied outcomes included survival, weight change, bacterial clearance, and joint damage.Expansion of Tregs induced by IL2 gene therapy prior to disease onset does not compromise host resistance to S. aureus infection, as the increased proportions of Tregs reduced the arthritis severity as well as the systemic inflammatory response, while simultaneously preserving the host's ability to clear the infection.Pre-treatment with IL2 gene therapy dampens detrimental immune responses but preserves appropriate host defense, which alleviates S. aureus septic arthritis in a mouse model.
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| 4. |
- Deshmukh, Megshree, et al.
(författare)
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Gene expression of S100a8/a9 predicts Staphylococcus aureus-induced septic arthritis in mice.
- 2023
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Ingår i: Frontiers in microbiology. - 1664-302X. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Septic arthritis is the most aggressive joint disease associated with high morbidity and mortality. The interplay of the host immune system with the invading pathogens impacts the pathophysiology of septic arthritis. Early antibiotic treatment is crucial for a better prognosis to save the patients from severe bone damage and later joint dysfunction. To date, there are no specific predictive biomarkers for septic arthritis. Transcriptome sequencing analysis identified S100a8/a9 genes to be highly expressed in septic arthritis compared to non-septic arthritis at the early course of infection in an Staphylococcus aureus septic arthritis mouse model. Importantly, downregulation of S100a8/a9 mRNA expression at the early course of infection was noticed in mice infected with the S. aureus Sortase A/B mutant strain totally lacking arthritogenic capacity compared with the mice infected with parental S. aureus arthritogenic strain. The mice infected intra-articularly with the S. aureus arthritogenic strain significantly increased S100a8/a9 protein expression levels in joints over time. Intriguingly, the synthetic bacterial lipopeptide Pam2CSK4 was more potent than Pam3CSK4 in inducing S100a8/a9 release upon intra-articular injection of these lipopeptides into the mouse knee joints. Such an effect was dependent on the presence of monocytes/macrophages. In conclusion, S100a8/a9 gene expression may serve as a potential biomarker to predict septic arthritis, enabling the development of more effective treatment strategies.
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| 5. |
- Fei, Ying, et al.
(författare)
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Commensal Bacteria Augment Staphylococcus aureus septic Arthritis in a Dose-Dependent Manner.
- 2022
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Ingår i: Frontiers in cellular and infection microbiology. - : Frontiers Media SA. - 2235-2988. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Septic arthritis is considered one of the most dangerous joints diseases and is mainly caused by the Gram-positive bacterium Staphylococcus aureus (S. aureus). Human skin commensals are known to augment S. aureus infections. The aim of this study was to investigate if human commensals could augment S. aureus-induced septic arthritis.NMRI mice were inoculated with S. aureus alone or with a mixture of S. aureus together with either of the human commensal Staphylococcus epidermidis (S. epidermidis) or Streptococcus mitis (S. mitis). The clinical, radiological and histopathological changes due to septic arthritis were observed. Furthermore, the serum levels of chemokines and cytokines were assessed.Mice inoculated with a mixture of S. aureus and S. epidermidis or S. mitis developed more severe and frequent clinical arthritis compared to mice inoculated with S. aureus alone. This finding was verified pathologically and radiologically. Furthermore, the ability of mice to clear invading bacteria in the joints but not in kidneys was hampered by the bacterial mixture compared to S. aureus alone. Serum levels of monocyte chemoattractant protein 1 were elevated at the early phase of disease in the mice infected with bacterial mixture compared with ones infected with S. aureus alone. Finally, the augmentation effect in septic arthritis development by S. epidermidis was bacterial dose-dependent.The commensal bacteria dose-dependently augment S. aureus-induced septic arthritis in a mouse model of septic arthritis.
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| 6. |
- Gupta, Priti, et al.
(författare)
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Local Immune Activation and Age Impact on Humoral Immunity in Mice, with a Focus on IgG Sialylation.
- 2024
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Ingår i: Vaccines. - 2076-393X. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Age alters the host's susceptibility to immune induction. Humoral immunity with circulating antibodies, particularly immunoglobulin G (IgG), plays an essential role in immune response. IgG glycosylation in the fragment crystallizable (Fc) region, including sialylation, is important in regulating the effector function by interacting with Fc gamma receptors (FcγRs). Glycosylation is fundamentally changed with age and inflammatory responses. We aimed to explore the regulation of humoral immunity by comparing responses to antigen-induced immune challenges in young and adult mice using a local antigen-induced arthritis mouse model. This study examines the differences in immune response between healthy and immune-challenged states across these groups. Our initial assessment of the arthritis model indicated that adult mice presented more severe knee swelling than their younger counterparts. In contrast, we found that neither histological assessment, bone mineral density, nor the number of osteoclasts differs. Our data revealed an age-associated but not immune challenge increase in total IgG; the only subtype affected by immune challenge was IgG1 and partially IgG3. Interestingly, the sialylation of IgG2b and IgG3 is affected by age and immune challenges but not stimulated further by immune challenges in adult mice. This suggests a shift in IgG towards a pro-inflammatory and potentially pathogenic state with age and inflammation.
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| 7. |
- Gupta, Priti, et al.
(författare)
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The impact of TLR2 and aging on the humoral immune response to Staphylococcus aureus bacteremia in mice.
- 2023
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Ingår i: Scientific reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Aging alters immunoglobulin production, affecting the humoral immune response. Toll-like receptor 2 (TLR2) recognizes Staphylococcus aureus (S. aureus) which causes bacteremia with high mortality in the elderly. To understand how TLR2 and aging affect the humoral immune response in bacteremia, four groups of mice (wild type-young, wild type-old, TLR2-/--young, and TLR2-/--old) were used to analyze immunoglobulin levels in healthy conditions as well as 10days after intravenous injection with S. aureus. We found that aging increased the levels of both IgM and IgG. Increased IgG in aged mice was controlled by TLR2. In bacteremia infection, aged mice failed to mount proper IgM response in both wild-type (WT) and TLR2-/- mice, whereas IgG response was impaired in both aged and TLR2-/- mice. Aged mice displayed reduced IgG1 and IgG2a response irrespective of TLR2 expression. However, impaired IgG2b response was only found in agedWT mice and not in TLR2-/- mice. Both aging and TLR2-/- increased the levels of anti-staphylococcal IgM in bacteremia. Aging increased sialylated IgG in WT mice but not in TLR2-/- mice. IgG sialylation was not affected by the infection in neither of the mice. In summary, aging increases all immunoglobulins except IgG1. However, aged mice fail to mount a proper antibody response to S. aureus bacteremia. TLR2 plays the regulatory role in IgG but not IgM response to infection.
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| 8. |
- Hanna, Balsam, et al.
(författare)
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Osteopenia/osteoporosis develops in the early phase of disease in patients with idiopathic inflammatory myopathies
- 2021
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Ingår i: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 0300-9742 .- 1502-7732. ; 50:5, s. 398-401
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To study the relationship between different disease-related variables and bone mineral density (BMD) in patients with idiopathic inflammatory myopathies (IIMs). Method: Demographic and clinical data were retrospectively collected from the medical records of all patients diagnosed with IIMs during 2003-2018 in the Rheumatology Department, Sahlgrenska University Hospital, Gothenburg, Sweden. BMD measurements by dual-energy X-ray absorptiometry (DXA) were compared among three patient groups categorized according to the time when DXA was performed in relation to the diagnosis: during the first month, 2-6 months, and 7-24 months after diagnosis. Results: In total, 48 patients were included in the study. BMD correlated positively with body mass index and the presence of myositis-specific autoantibodies. As expected, age and diseases duration had negative associations with BMD. Importantly, osteopenia and osteoporosis were significantly more common in patients who underwent DXA at later time-points of the disease than in those who underwent DXA during the first month after diagnosis. Conclusions: Reduced BMD is common in patients with IIMs. The development of osteopenia/osteoporosis starts in the early phase of myositis (within 6 months), and immediate osteoporosis prophylaxis at diagnosis is necessary.
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| 9. |
- Hu, Zhicheng, et al.
(författare)
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Phenol-soluble modulin α and β display divergent roles in mice with staphylococcal septic arthritis.
- 2022
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Phenol-soluble modulin α (PSMα) is identified as potent virulence factors in Staphylococcus aureus (S. aureus) infections. Very little is known about the role of PSMβ which belongs to the same toxin family. Here we compared the role of PSMs in S. aureus-induced septic arthritis in a murine model using three isogenic S. aureus strains differing in the expression of PSMs (Newman, Δpsmα, and Δpsmβ). The effects of PSMs on neutrophil NADPH-oxidase activity were determined in vitro. We show that the PSMα activates neutrophils via the formyl peptide receptor (FPR) 2 and reduces their NADPH-oxidase activity in response to the phorbol ester PMA. Despite being a poor neutrophil activator, PSMβ has the ability to reduce the neutrophil activating effect of PSMα and to partly reverse the effect of PSMα on the neutrophil response to PMA. Mice infected with S. aureus lacking PSMα had better weight development and lower bacterial burden in the kidneys compared to mice infected with the parental strain, whereas mice infected with bacteria lacking PSMβ strain developed more severe septic arthritis accompanied with higher IL-6 and KC. We conclude that PSMα and PSMβ play distinct roles in septic arthritis: PSMα aggravates systemic infection, whereas PSMβ protects arthritis development.
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| 10. |
- Hu, Zhicheng, et al.
(författare)
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The impact of aging and TLR2 deficiency on the clinical outcomes of Staphylococcus aureus bacteremia.
- 2023
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Ingår i: The Journal of infectious diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 228:3, s. 332-342
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Tidskriftsartikel (refereegranskat)abstract
- Staphylococcus aureus (S. aureus) causes a broad range of infections. TLR2 senses the S. aureus lipoproteins in S. aureus infections. Aging raises the risk of infection. Our aim was to understand how aging and TLR2 impact the clinical outcomes of S. aureus bacteremia. Four groups of mice (Wild type/young, Wild type/old, TLR2-/-/young, and TLR2-/-/old) were intravenously infected with S. aureus, and the infection course was followed. Both TLR2 deficiency and aging enhanced the susceptibility to disease. Increased age was the main contributing factor to mortality and changes in spleen weight, whereas other clinical parameters such as weight loss and kidney abscess formation were more TLR2 dependent. Importantly, aging increased mortality without relying on TLR2. In vitro, both aging and TLR2 deficiency downregulated cytokine/chemokine production of immune cells with distinct patterns. In summary, we demonstrate that aging and TLR2 deficiency impair the immune response to S. aureus bacteremia in distinct ways.
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