Analysis of Cell Signaling Perturbations in Response to Chronic Localized Infections

The tissue-level response to pathogens involves an intricate series of signal transduction events, influenced by immune and healing mediators that alert the host to danger and eliminate the infection. Disruptions to normal signaling events can compromise the host’s ability to respond and lead to the development of chronic infections that cannot be resolved without clinical intervention. Prolonged inflammation due to chronic infection can damage tissues and compromise healing processes, thus, the interactions of immune and healing mediators in signaling cascades are intimately linked to tissue health outcomes. Studying signaling networks relevant to these responses provided a more thorough understanding of localized tissue health to identify the drivers of disruptions to signaling cascades, and this knowledge can lead to the development of improved diagnostic and therapeutic biomarkers to combat chronic infections. The work presented here focused on elucidating the relationships between immune and wound healing factors in an in vivo rodent model and a clinical cohort to understand the tissue-level responses to chronic inflammation and infection. Specifically, extracellular inflammatory immune responses (i.e., cytokines and chemokines) related to intracellular signaling (i.e., phosphorylation of proteins) were investigated to identify alterations in native responses compared to those provoked by chronic inflammation and infection. Reponses in native tissues were compared to tissues with inflammatory and infectious stimuli to test if levels of immune related cytokines were elevated in response to chronic joint infections. Wound healing phosphoproteins were also included to look for shifts in wound healing-related processes across groups. Traditional statistical approaches and network analysis were used to dissect these complex biological datasets and identified drivers of network disruptions in response to inflammation and infection. The spatial analysis suggested that changes in biological responses were related to proximity to inflammation and infection, and the degree of response differed across spatial gradients, which demonstrated the ability for these chronic insults to affect disparate tissues in a clinically-relevant manner. The objective of this research and future related research is to facilitate new clinical strategies to combat chronic infection, and monitoring alterations to cell signaling pathways in this work highlighted the value of using network analysis to approach biological interrogation of signal disruptions related to these insults.