2020 IARS Mentored Research Award

Catharina Conrad, MD, PhD
Postdoctoral Researcher
University of California, San Francisco
San Francisco, CA

Dr. Conrad’s Research

Protease Profiling for Rapid Phenotyping and Monitoring of ARDS

Acute respiratory distress syndrome (ARDS) is a life-threatening condition of critically ill patients, characterized by excessive lung inflammation and pulmonary edema resulting in lung failure. The Covid19 crisis has exposed a significant weakness of standard care for patients with ARDS, and that is shortcomings in ARDS risk assessment, prevention and treatment. A key to overcome these challenges may be molecular phenotyping to predict prognosis and mortality of ARDS patient subgroups. Several classes of proteases, including serine, cysteine and metalloproteases, are instrumental in the pathogenesis of lung injury and modulate the immune response. This proposal intends to determine real-time protease profiles in lung fluids of ARDS patients as a correlate of inflammation to dynamically track disease progression and develop personalized therapeutic approaches. Our consideration is that the activities of inflammatory mediators predict their biological relevance more precisely than mere expression levels. In Aim 1 of this application we will use fluorescent reporters based on known cleavage sites to detect multiple protease activities (>10) by the change of fluorescence over time. Pilot data suggests that proteolytic signatures of ARDS survivors significantly differ from cleavage patterns of non-survivors within 30 minutes, pointing towards a great potential of protease activities for rapid risk assessment of patients with lung inflammation. In Aim 2 we will attribute the activities to particular proteases derived from specific cell types at different phases of inflammation during the course of ARDS. To validate these proteases as therapeutic targets for ARDS, we will perform genetic and pharmacological in vivo studies to neutralize proteolytic activity in murine models of acute lung injury. In vitro cell-culture models will provide mechanistic insight and complement our mouse studies.

Related Publications

ADAM8 signaling drives neutrophil migration and ARDS severity
Catharina Conrad et al.

Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent, unmet need for improved early recognition and therapeutic development. Neutrophil influx is a hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins (ADAMs). Through this research, the authors propose that in acute inflammatory lung diseases such as pneumonia and ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain.

Is neutrophilic inflammation treatable in COVID-19?
Catharina Conrad, Mark R Looney

As the world is entering the third year of the COVID-19 pandemic, the discovery of effective treatments continues to be a global health priority. Despite vaccination success, promising antiviral drugs, and benefits of pharmacological immunomodulation for patients who are hospitalised with severe COVID-19, systemic hyperinflammation currently cannot be fully controlled and remains a major cause of morbidity and mortality.

Neutrophils in people with severe COVID-19 show increased abundance, altered phenotypes, and dysregulated functionality.

As first responder innate immune cells, neutrophils release several classes of proteases that are essential for microbe destruction but can also cause collateral tissue damage when neutrophil proteolytic activity becomes excessive. Neutrophil serine proteases, such as neutrophil elastase, proteinase 3, and cathepsin G, have been recognised as such so-called double-edged immune modulators, and elevated concentrations of these markers in the blood and lung fluid are associated with poor outcomes in patients with COVID-19.

However, no COVID-19 therapies specifically targeting neutrophilic inflammation have been investigated in large-scale clinical trials.