MMI News

Electronic Nicotine Delivery System Aerosol-induced Cell Death and Dysfunction in Macrophages and Lung Epithelial Cells
Electronic nicotine delivery system (ENDS) use is outpacing our understanding of its potential harmful effects. Homeostasis of the lung is maintained through proper balance of cell death, efferocytic clearance, and phagocytosis of pathogens. To investigate whether ENDS use has the potential to alter this balance, we developed physiologically relevant ENDS exposure paradigms for lung epithelial cells and primary macrophages. In our studies, cells were exposed directly to aerosol made from carefully controlled components with and without nicotine. We found that ENDS aerosol exposure led to apoptosis, secondary necrosis, and necrosis in lung epithelial cell models. In contrast, macrophages died mostly by apoptosis and inflammatory caspase–mediated cell death when exposed to ENDS aerosol. The clearance of dead cells and pathogens by efferocytosis and phagocytosis, respectively, is an important process in maintaining a healthy lung. To investigate the impact of ENDS aerosol on macrophage function independent of general toxicity, we used an exposure time that did not induce cell death in primary macrophages. Exposure to ENDS aerosol containing nicotine inhibited nearly all phagocytic and greatly reduced the efferocytic abilities of primary macrophages. When challenged with a bacterial pathogen, there was decreased bacterial clearance. The presence of nicotine in the ENDS aerosol increased its toxicity and functional impact; however, nicotine exposure alone did not have any deleterious effects. These data demonstrate that ENDS aerosol exposure could lead to increased epithelial cell and macrophage death in the lung and impair important macrophage functions that are essential for maintenance of lung function.


Competitive Cell Death Interactions in Pulmonary Infection: Host Modulation Versus Pathogen Manipulation
In the context of pulmonary infection, both hosts and pathogens have evolved a multitude of mechanisms to regulate the process of host cell death. The host aims to rapidly induce an inflammatory response at the site of infection, promote pathogen clearance, quickly resolve inflammation, and return to tissue homeostasis. The appropriate modulation of cell death in respiratory epithelial cells and pulmonary immune cells is central in the execution of all these processes. Cell death can be either inflammatory or anti-inflammatory depending on regulated cell death (RCD) modality triggered and the infection context. In addition, diverse bacterial pathogens have evolved many means to manipulate host cell death to increase bacterial survival and spread. The multitude of ways that hosts and bacteria engage in a molecular tug of war to modulate cell death dynamics during infection emphasizes its relevance in host responses and pathogen virulence at the host pathogen interface. This narrative review outlines several current lines of research characterizing bacterial pathogen manipulation of host cell death pathways in the lung. We postulate that understanding these interactions and the dynamics of intracellular and extracellular bacteria RCD manipulation, may lead to novel therapeutic approaches for the treatment of intractable respiratory infections.


Assessment of Acute Wound Healing using the Dorsal Subcutaneous Polyvinyl Alcohol Sponge Implantation and Excisional Tail Skin Wound Models
Wound healing is a complex process that requires the orderly progression of inflammation, granulation tissue formation, fibrosis, and resolution. Murine models provide valuable mechanistic insight into these processes; however, no single model fully addresses all aspects of the wound healing response. Instead, it is ideal to use multiple models to address the different aspects of wound healing. Here, two different methods that address diverse aspects of the wound healing response are described. In the first model, polyvinyl alcohol sponges are subcutaneously implanted along the mouse dorsum. Following sponge retrieval, cells can be isolated by mechanical disruption, and fluids can be extracted by centrifugation, thus allowing for a detailed characterization of cellular and cytokine responses in the acute wound environment. A limitation of this model is the inability to assess the rate of wound closure. For this, a tail skin excision model is utilized. In this model, a 10 mm x 3 mm rectangular piece of tail skin is excised along the dorsal surface, near the base of the tail. This model can be easily photographed for planimetric analysis to determine healing rates and can be excised for histological analysis. Both described methods can be utilized in genetically altered mouse strains, or in conjunction with models of comorbid conditions, such as diabetes, aging, or secondary infection, in order to elucidate wound healing mechanisms.


Antimicrobial Resistance Gene Prevalence in a Population of Patients with Advanced Dementia Is Related to Specific Pathobionts
Long-term care facilities are significant reservoirs of antimicrobial-resistant organisms, and patients with advanced dementia are particularly vulnerable to multidrug-resistant organism (MDRO) acquisition and antimicrobial overuse. In this study, we longitudinally examined a group of patients with advanced dementia using metagenomic sequencing. We found significant inter- and intra-subject heterogeneity in microbiota composition, suggesting temporal instability. We also observed a link between the antimicrobial resistance gene density in a sample and the relative abundances of several pathobionts, particularly Escherichia coliProteus mirabilis, and Enterococcus faecalis, and used this relationship to predict resistance gene density in samples from additional subjects. Furthermore, we used metagenomic assembly to demonstrate that these pathobionts had higher resistance gene content than many gut commensals. Given the frequency and abundances at which these pathobionts were found in this population and the underlying vulnerability to MDRO of patients with advanced dementia, attention to microbial blooms of these species may be warranted.


 

Andrew G. Campbell recognized as one of 100 inspiring black scientists in America 
Andrew G. Campbell, Dean of the Graduate School and Professor of Medical Science, is one of three researchers at Brown who is being recognized as one of 100 inspiring black scienctists in America. Congratulations, Dean Campbell! 


Mae Staples awarded F31 Fellowship
Congratulations to Mae Staples who has been awarded an F31 Fellowship from the NIH for her research proposal "Transcriptional regulation of C. albicans biofilms by formation of phase-separated condensates".  This Ruth L. Kirschstein Predoctoral Individual National Research Service Award (NRSA) is granted to 'promising predoctoral students with potential to develop into a productive, independent research scientist, to obtain mentored research training while conducting dissertation research'.   Mae is currently a 4th-year student in the Richard Bennett lab.  


American Academy of Microbiology: 2020 Fellows
Congratulations to Professor Richard Bennett who has been elected as a Fellow into the American Academy of Microbiology.  These Fellows are elected annually through a highly selective, peer-review process, based on their records of scientific achievement and original contributions that have advanced microbiology.  The 2020 Class is comprised of 68 Fellows.