Symbiotic Science: Unveiling Host-Microbe Interactions on a Chip

The study of host-microbe interactions has been an ongoing field of study since the inception of ‘germ theory.’ It involves the investigation of the symbiotic interactions between microorganisms and their hosts, including plants and animals. Some microorganisms are beneficial to their host, providing nutrients, stimulation needed for biological development, protection from disease, and for some organisms, bioluminescent capabilities used to attract prey or avoid predation. Other symbiotic microorganisms have adverse effects on their host, which we refer to as pathogens. As a function of host protection against pathogenic microbes, beneficial microorganisms have developed numerous strategies to disrupt or kill pathogens through their production of antimicrobial peptides. These antimicrobial peptides serve as a template for the development of novel antimicrobial therapeutics, which are needed for combatting the rise of antimicrobial resistance. To advance our understanding of symbiotic interactions between hosts and microbes, the application of 3D tissue-on-a-chip technology offers new approaches for investigating of host-microbe interactions. We developed one such system, called an engineered microvessel (EMV) to reveal new insights into the interactions between host endothelial tissues and two pathogens, invasive Group A Streptococcus (GAS) and SARS-CoV-2. In our investigation of GAS, we described the transcriptional response of GAS to fibrin immobilization, as well as the role of virulence factor streptokinase (SK2b) in directing this transcriptional response. We found that during fibrin immobilization, GAS enters a latency state, which is altered in GAS deficient of functional SK2b. We also showed that the temporal dynamics of this response are altered in a biomimetic EMV system, compared to GAS-fibrin immobilization in a dish. In our investigation of SARS-CoV-2, we examined the effects of viral Spike (S)-protein on endothelial cells (ECs). We found that S-protein alters cytokine production of ECs within the EMV, resulting in the release of pro-inflammatory cytokines, such as IL-6. Furthermore, we described the pro-angiogenic activity of S-protein-treated ECs and angiogenic tube formation within the EMV system, detected through live imaging. This work highlights the benefits and limitations of the application of tissue-on-a-chip systems in the study of host-microbial interactions.