Publications by authors named "K A Shirey"
Influenza, as well as other respiratory viruses, can trigger local and systemic inflammation resulting in an overall "cytokine storm" that produces serious outcomes such as acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). We hypothesized that gene therapy platforms could be useful in these cases if the production of an anti-inflammatory protein reflects the intensity and duration of the inflammatory condition. The recombinant protein would be produced and released only in the presence of the inciting stimulus, avoiding immunosuppression or other unwanted side effects that may occur when treating infectious diseases with anti-inflammatory drugs.
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- Researchers developed an analog of a small molecule called UM101, named GEn-1124, which has better solubility and binding affinity to the p38a MAPK protein, known for its role in inflammation.
- GEn-1124 shows significant improvements over UM101, such as an 18-fold increase in binding affinity, enhanced stability, and better lung protection, resulting in improved survival rates in mouse models of acute lung injury.
- The study reveals that GEn-1124 operates through a novel mechanism by destabilizing the p38a:MK2 complex, altering gene expression, and promoting enhanced signaling within the cell's nucleus.
Article Synopsis
- A Controlled Human Infection Model (CHIM) with wild-type Salmonella Typhi was set up to study immunity development, revealing that about 55% of volunteers met typhoid diagnosis criteria after infection.
- Intestinal macrophages, which play a crucial role in gut defense, are derived from circulating monocytes rather than tissue-resident progenitors, making them unique compared to macrophages in other organs.
- Changes in circulating monocytes were tracked post-infection, showing that typhoid diagnosis participants had increased activation markers, indicating a heightened immune response, and upregulated molecules to interact with both bacterial antigens and adaptive immune cells.
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, impacts millions of individuals worldwide and severely impairs the quality of life for patients. Dysregulation of innate immune signaling pathways reduces barrier function and exacerbates disease progression. Macrophage (Mφ) signaling pathways are potential targets for IBD therapies.
View Article and Find Full Text PDFGastrin-releasing peptide (GRP), an evolutionarily conserved neuropeptide, significantly contributes to influenza-induced lethality and inflammation in rodent models. Because GRP is produced by pulmonary neuroendocrine cells (PNECs) in response to γ-aminobutyric acid (GABA), we hypothesized that influenza infection promotes GABA release from PNECs that activate GABA receptors on PNECs to secrete GRP. Oxidative stress was increased in the lungs of influenza A/PR/8/34 (PR8)-infected mice, as well as serum glutamate decarboxylase 1, the enzyme that converts L-glutamic acid into GABA.
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