Person:

Bonham, Kevin

In multicellular organisms, communication between cells relies on transmitting information across membrane barriers. Different cell types interrogate particular aspects of their surrounding environment through protein receptors that span membranes and upon ligand binding, trigger enzymatic signaling cascades that culminate in the activation of one or more transcription factors. Information transmission is bidirectional, as individual cells must be able to sense unique aspects of their surroundings, relay their specialized knowledge with others, and receive the collective knowledge of surrounding cells and tissues. This two-way communication is particularly important in the innate immune system, where potentially infectious organisms must be readily detected and identified, and their presence communicated to other cells in the vicinity. Because of the rapid generation time of microorganisms, delays between any of these steps - detection, information processing or information transmission - can make the difference between successful control of infection and pathogen outgrowth. For this reason, the receptors that identify potential pathogens must be able to detect pathogens wherever they are found, be exquisitely sensitive, and initiate a robust response. At the same time, the inflammatory response to infection is itself damaging. This requires that the same receptors are tightly controlled, both by modulating their sensitivity and by rapidly turning off responses through negative feedback pathways. Here, I show that the toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) plays a critical role in controlling the sensitivity of toll-like receptor (TLR) signaling. First, TIRAP controls the assembly of the myddosome, a protein complex that activates signal transduction, from both the plasma membrane and within endosomes of macrophages. Though TIRAP's role at the cell surface was previously described, its endosomal function was previously unknown. Second, TIRAP is an important target for negative regulation. After stimulation with the TLR4 ligand lipopolysaccharide (LPS), macrophages induce a state known as endotoxin tolerance, in which they are refractory for additional LPS stimulation. Many mechanisms for endotoxin tolerance have been proposed, but here I show that TIRAP is degraded in endotoxin tolerance, and that the mechanism of TIRAP degradation also has implications for viral/bacterial superinfection.

Inflammatory bowel diseases (IBD), which include Crohn’s disease (CD) and ulcerative colitis (UC), affect several million individuals worldwide. CD and UC are complex diseases and heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Extensive study has focused on individual contributing factors. As part of the Integrative Human Microbiome Project (HMP2), 132 subjects were followed one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each, in total 2,965 stool, biopsy, and blood specimens). These provide a comprehensive view of the gut microbiome’s functional dysbiosis during IBD activity, showing a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (e.g. among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and host serum antibody levels. Disease was also marked by greater temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to the dysregulation. The study’s infrastructure resources, results, and data, available through the Inflammatory Bowel Disease Multi'omics Database (http://ibdmdb.org), provide the most comprehensive description to date of host and microbial activities in IBD.

While women are generally underrepresented in STEM fields, there are noticeable differences between fields. For instance, the gender ratio in biology is more balanced than in computer science. We were interested in how this difference is reflected in the interdisciplinary field of computational/quantitative biology. To this end, we examined the proportion of female authors in publications from the PubMed and arXiv databases. There are fewer female authors on research papers in computational biology, as compared to biology in general. This is true across authorship position, year, and journal impact factor. A comparison with arXiv shows that quantitative biology papers have a higher ratio of female authors than computer science papers, placing computational biology in between its two parent fields in terms of gender representation. Both in biology and in computational biology, a female last author increases the probability of other authors on the paper being female, pointing to a potential role of female PIs in influencing the gender balance.