MMI News

Sanghyun Lee selected as a recipient for the 2021 Smith Family Awards Program for Excellence in Biomedical Research!
Congratulations to Dr. Sanghyun Lee on recieving the 2021 Smith Family Awards Program for Excellence in Biomedical Research for his research project titled "A Focused Approach to Identify Entry Factors for Pathogenic Enteric Viruses Using CRISPR Activation Screening"

For the past 29 years, the Smith Family Foundation has been supporting groundbreaking medical research through the Smith Family Awards Program for Excellence in Biomedical Research. Its mission is to launch the careers of newly independent biomedical researchers with the ultimate goal of achieving medical breakthroughs. This award provides $300,000 over three years to support research. 

Amanda Jamieson awarded the 2021 Dean's Award for Excellence in Undergraduate Teaching, Advising and Mentoring in Biological Sciences!
Congratulations to Professor Amanda Jamieson on recieving the 2021 Dean's Award for Excellence in Undergraduate Teaching, Advising, and Mentoring in Biological Sciences! 

This annual award recognizes a faculty member in the Division of Biology and Medicine for his/her outstanding teaching, advising and mentoring of students in the Undergraduate Divisional programs in the Biological Sciences.  Nominees may be recognized for teaching excellence within courses; for advising (freshman, sophomore and especially, concentration advising); other services enhancing service to undergraduates (e.g., participation in special programs, presentations, events, etc.). Additional service/teaching activity is also regarded, such as mentoring directed research and independent studies including thesis and Honors supervision.

First Author Kellyanne Duncan: Spatial analysis of gut microbiome reveals a distinct ecological niche associated with the mucus layer
Congrats to Kellyanne Duncan, former Pathobiology graduate student and former Vaishnava Lab member, for her recent first author publication! "Spatial analysis of gut microbiome reveals a distinact ecological niche associated with the muscus layer" was published in the February 2021 journal, Gut Microbes. Dr. Duncan is currently a post-doc in the Xavier Lab at the Broad Insitute. 

Evaluation of the Microbiome in Men Taking Pre-exposure Prophylaxis for HIV Prevention
Tenofovir-based regimens as pre-exposure prophylaxis (PrEP) are highly effective at preventing HIV infection. The most common side-effect is gastrointestinal (GI) distress which may be associated with changes in the microbiome. Dysbiosis of the microbiome can have numerous health-related consequences. To understand the effect of PrEP on dysbiosis, we evaluated 27 individuals; 14 were taking PrEP for an average of 171 weeks. Sequencing of 16S rRNA was performed using self-collected rectal swabs. Mixed beta diversity testing demonstrated significant differences between PrEP and non-PrEP users with Bray–Curtis and unweighted UniFrac analyses (p = 0.05 and 0.049, respectively). At the genus level, there was a significant reduction in Finegoldia, along with a significant increase in Catenibacterium and Prevotella in PrEP users. Prevotella has been associated with inflammatory pathways, insulin resistance and cardiovascular disease, while Catenibacterium has been associated with morbid obesity and metabolic syndrome. Overall, these results suggest that PrEP may be associated with some degree of microbiome dysbiosis, which may contribute to GI symptoms. Long-term impact of these changes is unknown.

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The Invariant NKT Cell Response Has Differential Signaling Requirements during Antigen-Dependent and Antigen-Independent Activation
Invariant NKT (iNKT) cells are an innate-like population characterized by their recognition of glycolipid Ags and rapid cytokine production upon activation. Unlike conventional T cells, which require TCR ligation, iNKT cells can also be stimulated independently of their TCR. This feature allows iNKT cells to respond even in the absence of glycolipid Ags, for example, during viral infections. Although the TCR-dependent and -independent activation of iNKT cells have been relatively well established, the exact contributions of IL-12, IL-18, and TLRs remain unclear for these two activation pathways. To definitively investigate how these components affect the direct and indirect stimulation of iNKT cells, we used mice deficient for either MyD88 or the IL-12Rβ2 in the T cell lineage. Using these tools, we demonstrate that IL-12, IL-18, and TLRs are completely dispensable for the TCR activation pathway when a strong agonist is used. In contrast, during murine CMV infection, when the TCR is not engaged, IL-12 signaling is essential, and TLR signaling is expendable. Importantly, to our knowledge, we discovered an intrinsic requirement for IL-18 signaling by splenic iNKT cells but not liver iNKT cells, suggesting that there might be diversity, even within the NKT1 population.

Alternate histories of cytokinesis: lessons from the trypanosomatids
Popular culture has recently produced several “alternate histories” that describe worlds where key historical events had different outcomes. Beyond entertainment, asking “could this have happened a different way?” and “what would the consequences be?” are valuable approaches for exploring molecular mechanisms in many areas of research, including cell biology. Analogous to alternate histories, studying how the evolutionary trajectories of related organisms have been selected to provide a range of outcomes can tell us about the plasticity and potential contained within the genome of the ancestral cell. Among eukaryotes, a group of model organisms has been employed with great success to identify a core, conserved framework of proteins that segregate the duplicated cellular organelles into two daughter cells during cell division, a process known as cytokinesis. However, these organisms provide relatively sparse sampling across the broad evolutionary distances that exist, which has limited our understanding of the true potential of the ancestral eukaryotic toolkit. Recent work on the trypanosomatids, a group of eukaryotic parasites, exemplifies alternate historical routes for cytokinesis that illustrate the range of eukaryotic diversity, especially among unicellular organisms.

Andrew G. Campbell elected as AAAS fellow
Congratulations to Andrew G. Campbell, Brown University Dean of the Graduate School, Professor of Medical Science and IMSD Program Director on being elected AAAS Fellow. 

Dr. Campbell was elected for research in infectious diseases in neglected populations, administrative leadership, and service to increase the full participation of all in science.  AAAS Fellows are elected each year by their peers serving on the Council of AAAS, the organization’s member-run governing body.
The title recognizes important contributions to STEM disciplines, including pioneering research, leadership within a given field, teaching and mentoring, fostering collaborations, and advancing public understanding of science.

Consumption of a Western-Style Diet Modulates the Response of the Murine Gut Microbiome to Ciprofloxacin
Due to the growing incidence of disorders related to antibiotic-induced dysbiosis, it is essential to determine how our “Western”-style diet impacts the response of the microbiome to antibiotics. While diet and antibiotics have profound impacts on gut microbiome composition, little work has been done to examine their combined effects. Previous work has shown that nutrient availability, influenced by diet, plays an important role in determining the extent of antibiotic-induced disruption to the gut microbiome. Thus, we hypothesize that the Western diet will shift microbiota metabolism toward simple sugar and mucus degradation and away from polysaccharide utilization. Because of bacterial metabolism’s critical role in antibiotic susceptibility, this change in baseline metabolism will impact how the structure and function of the microbiome are impacted by ciprofloxacin exposure. Understanding how diet modulates antibiotic-induced microbiome disruption will allow for the development of dietary interventions that can alleviate many of the microbiome-dependent complications of antibiotic treatment.

Lalit Beura named 2020 Searle Scholar
Congratulations to Assistant Professor, Lalit Beura, for being one of 15 scientists named as Searle Scholars for 2020 for his research project "Adaptation of resident memory CD8 T lymphocytes in the reproductive mucosa". Beura studies the role played by T-cells in establishing an immune barrier in mucosal surfaces, which are common bacterial points of entry into the body. The Searle Scholars Program makes grants to selected universities and research centers to support the independent research of exceptional young faculty in the biomedical sciences and chemistry who have recently been appointed as assistant professors on a tenure-track appointment. The award provides $300,000 over three years to support research.

Reductions in anti-inflammatory gut bacteria are associated with depression in a sample of young adults
We assessed the gut microbiota of 90 American young adults, comparing 43 participants with major depressive disorder (MDD) and 47 healthy controls, and found that the MDD subjects had significantly different gut microbiota compared to the healthy controls at multiple taxonomic levels. At the phylum level, participants with MDD had lower levels of Firmicutes and higher levels of Bacteroidetes, with similar trends in the at the class (Clostridia and Bacteroidia) and order (Clostridiales and Bacteroidales) levels. At the genus level, the MDD group had lower levels of Faecalibacterium and other related members of the family Ruminococcaceae, which was also reduced relative to healthy controls. Additionally, the class Gammaproteobacteria and genus Flavonifractor were enriched in participants with MDD. Accordingly, predicted functional differences between the two groups include a reduced abundance of short-chain fatty acid production pathways in the MDD group. We also demonstrated that the magnitude of taxonomic changes was associated with the severity of depressive symptoms in many cases, and that most changes were present regardless of whether depressed participants were taking psychotropic medications. Overall, our results support a link between MDD and lower levels of anti-inflammatory, butyrate-producing bacteria, and may support a connection between the gut microbiota and the chronic, low-grade inflammation often observed in MDD patients.

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.