Publications

Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis, remains one of the major causes of death from infection worldwide, with over a million associated deaths each year. The study of biomarkers for TB is critical for advancing our understanding and management of the disease. Biomarkers, defined as measurable indicators of biological states or conditions, are invaluable for the diagnosis, prognosis and treatment monitoring of TB. Clinical studies have provided critical knowledge on the matter but are also notoriously constrained by economical, ethical and sampling limitations. The use of animal models provides a simpler, more controllable, cost-effective setting with great potential for translation to humans. They also allow the evaluation of biomarkers within the respiratory compartment, when available, which is of particular interest due to the nature of TB pathogenesis. This Review focuses on the current landscape of TB biomarker discovery in several animal models, from invertebrates to large mammals. Here we summarize the basics of host-pathogen immune interaction, describe the main methodological approaches used and highlight the most substantial findings for each animal model studied. Furthermore, we discuss the advantages, challenges and limitations associated with species-specific differences in animal models. We conclude that integrating the data obtained from animal models and human studies is absolutely required to advance the TB field to accelerate the management of this disease.

JTD Keywords: Cd4 t-cells, Drosophila-melanogaster, Experimental airborne tuberculosis, Gamma release assay, Guinea-pig, Host-parasite relationships, Ifn-gamma, Mycobacterium-tuberculosis, Nitric-oxide synthase, Pulmonary tuberculosis

The ability to engineer complex multicellular systems has enormous potential to inform our understanding of biological processes and disease and alter the drug development process. Engineering living systems to emulate natural processes or to incorporate new functions relies on a detailed understanding of the biochemical, mechanical, and other cues between cells and between cells and their environment that result in the coordinated action of multicellular systems. On April 3-6, 2022, experts in the field met at the Keystone symposium "Engineering Multicellular Living Systems" to discuss recent advances in understanding how cells cooperate within a multicellular system, as well as recent efforts to engineer systems like organ-on-a-chip models, biological robots, and organoids. Given the similarities and common themes, this meeting was held in conjunction with the symposium "Organoids as Tools for Fundamental Discovery and Translation".

JTD Keywords: computational, engineered living, engineered organs, multicellular, Brain organoids, Cell diversity, Computational, Dynamics, Engineered living, Engineered organs, Heart, Maturation, Model, Multicellular, Mycobacterium-tuberculosis, Quantitative-analysis, Systems, Tissue deformation

The Streptococcus pyogenes genome harbors two clusters of class Ib ribonucleotide reductase genes, nrdHEF and nrdF*I*E*, and a second stand-alone nrdI gene, designated nrdI2. We show that both clusters are expressed simultaneously as two independent operons. The NrdEF enzyme is functionally active in vitro, while the NrdE*F* enzyme is not. The NrdF* protein lacks three of the six highly conserved iron-liganding side chains and cannot form a dinuclear iron site or a tyrosyl radical. In vivo, on the other hand, both operons are functional in heterologous complementation in Escherichia coli. The nrdF*I*E* operon requires the presence of the nrdI* gene, and the nrdHEF operon gained activity upon cotranscription of the heterologous nrdI gene from Streptococcus pneumoniae, while neither nrdI* nor nrdI2 from S. pyogenes rendered it active. Our results highlight the essential role of the flavodoxin NrdI protein in vivo, and we suggest that it is needed to reduce met-NrdF, thereby enabling the spontaneous reformation of the tyrosyl radical. The NrdI* flavodoxin may play a more direct role in ribonucleotide reduction by the NrdF*I*E* system. We discuss the possibility that the nrdF*I*E* operon has been horizontally transferred to S. pyogenes from Mycoplasma spp.

JTD Keywords: Group-a streptococcus, Bacillus-subtilis genes, Escherichia-coli, Corynebacterium-ammoniagenes, Mycobacterium-tuberculosis, Expression analysis, Genome sequence, Small-subunit, Salmonella-typhimurium, Iron center