Scholarly Work - Microbiology & Cell Biology
Permanent URI for this collectionhttps://scholarworks.montana.edu/handle/1/3494
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Item Host Lung Environment Limits Aspergillus fumigatus Germination through an SskA-Dependent Signaling Response(American Society for Microbiology, 2021-12) Kirkland, Marina E.; Stannard, McKenzie; Kowalski, Caitlin H.; Mould, Dallas; Caffrey-Carr, Alayna; Temple, Rachel M.; Ross, Brandon S.; Lofgren, Lotus A.; Stajich, Jason E.; Cramer, Robert A.; Obar, Joshua J.Aspergillus fumigatus isolates display significant heterogeneity in growth, virulence, pathology, and inflammatory potential in multiple murine models of invasive aspergillosis. Previous studies have linked the initial germination of a fungal isolate in the airways to the inflammatory and pathological potential, but the mechanism(s) regulating A. fumigatus germination in the airways is unresolved. To explore the genetic basis for divergent germination phenotypes, we utilized a serial passaging strategy in which we cultured a slow germinating strain (AF293) in a murine-lung-based medium for multiple generations. Through this serial passaging approach, a strain emerged with an increased germination rate that induces more inflammation than the parental strain (herein named LH-EVOL for lung homogenate evolved). We identified a potential loss-of-function allele of Afu5g08390 (sskA) in the LH-EVOL strain. The LH-EVOL strain had a decreased ability to induce the SakA-dependent stress pathway, similar to AF293 ΔsskA and CEA10. In support of the whole-genome variant analyses, sskA, sakA, or mpkC loss-of-function strains in the AF293 parental strain increased germination both in vitro and in vivo. Since the airway surface liquid of the lungs contains low glucose levels, the relationship of low glucose concentration on germination of these mutant AF293 strains was examined; interestingly, in low glucose conditions, the sakA pathway mutants exhibited an enhanced germination rate. In conclusion, A. fumigatus germination in the airways is regulated by SskA through the SakA mitogen-activated protein kinase (MAPK) pathway and drives enhanced disease initiation and inflammation in the lungs.Item Molecular Mechanisms for Regulation of Neutrophil Apoptosis under Normal and Pathological Conditions(Pleiades Publishing Ltd, 2021-05) Noseykina, E. M.; Schepetkin, I. A.; Atochin, D. N.Neutrophils are one of the main cells of innate immunity that perform a key effector and regulatory function in the development of the human inflammatory response. Apoptotic forms of neutrophils are important for regulating the intensity of inflammation and restoring tissue homeostasis. This review summarizes current data on the molecular mechanisms of modulation of neutrophil apoptosis by the main regulatory factors of the inflammatory response—cytokines, integrins, and structural components of bacteria. Disturbances in neutrophil apoptosis under stress are also considered, molecular markers of changes in neutrophil lifespan associated with various diseases and pathological conditions are presented, and data on pharmacological agents for modulating apoptosis as potential therapeutics are also discussed.