1K25AI175668-01A1: Tuning Complement-Mediated Immunity in Aspergillosis: A Systems Medicine Approach

Luis Sordo Vieira, PhD

Project Summary

Invasive aspergillosis is one of the most common fungal infections in immunocompromised patients. With the increasing number of susceptible patients and the threat of antifungal-resistance, the development of host- centric interventions is of paramount importance. Complement, a potent component of the innate immune system, is protective against many infections. On the other hand, complement overactivation has been shown to drive lung injury and inflammation. Pulmonary hemorrhage is a characteristic feature of invasive aspergillosis, and the interactions between pulmonary hemorrhage and complement activation are poorly understood. Intervening in the interactions between hemorrhage and complement may prove beneficial as a novel therapeutic intervention to manage pulmonary aspergillosis, and a number of complement inhibitors are either FDA- approved or in late-phase development. The overarching hypothesis in this project is that pulmonary hemorrhage in invasive aspergillosis leads to complement overactivation, leading to tissue injury and further hemorrhage. The dynamics of complement activation are complex and span multiple sites, making it difficult to predict how and when to intervene. We propose that mathematical modeling-based design of effective therapies in pulmonary aspergillosis can help in the discovery phase of understanding mechanisms of complement-mediated injury in pulmonary aspergillosis, and possible interventions of such mechanisms. As such we will leverage the power of mathematical modeling, closely coupled with in vivo models of pulmonary aspergillosis, to unravel the interactions of hemorrhage and complement in the lung and to systematically interrogate the model to determine possible points of intervention. In Aim 1, we will mechanistically explore the effects of the terminal component of the complement cascade in pulmonary aspergillosis. In Aim 2, we will build a multiscale mathematical model of pulmonary aspergillosis to capture the mechanisms that connect hemorrhage and complement activity, validating these mechanisms in vivo. We will then use the model to derive a prioritized set of interventions that will be validated in mouse models of pulmonary aspergillosis. This research is intended to train a PhD mathematician with a background in mathematical modeling in experimental biology and facilitate his transition to an independent investigator. He will be mentored by a physician-scientist with expertise in lung host defense and a complement biologist and overseen by an advisory committee composed of experts in computational modeling, lung biology, and mycology. This training will be enhanced by the rich scientific environment at the University of Florida, together with rigorous coursework in advanced immunology, mycology, and microbiology, and training in grant writing and scientific rigor. Taken together, this project will train a transdisciplinary scientist for an independent investigative career.

Relevance Statement

Invasive pulmonary aspergillosis, a common fungal infection among immunocompromised patients, has poor outcomes including a high mortality rate. The increasing number of susceptible patients and the threat of antifungal-resistant strains makes the development of host-centric interventions a high priority for public health. This project will use mathematical modeling and experimental data to determine new potential treatments in this infection.