Upregulated Complement Protein Predisposes Patients to Fungal Infections

Major fungal infections have become more common across the globe. One unexpected phenomenon among the rise of fungi is life-threatening infections as a result of a complication of certain immunotherapies and small molecule kinase inhibitors. 

A scientist at the Hackensack Meridian Health’s Center for Discovery and Innovation (CDI) has identified the specific mechanistic cause of one such phenomenon, which could be life-saving in the future. The study was recently published in Cell. “Our findings will assist clinicians in their understanding of how these life-threatening infections are emerging,” said Jigar Desai, PhD, assistant member of the CDI, assistant professor of medical sciences at the Hackensack Meridian School of Medicine, and first author of the paper. “These findings may help doctors and scientists alike better understand how some of these cases arise and how to avoid them.”

The role and therapeutic significance of C5a protein 

The team of scientists established that component 5a (C5a) protein—the penultimate effector constituent of the complement pathway—is key to the body's innate ability to fight systemic fungal infections. The team also identified that an enhanced complement pathway signature acts as a predictive biomarker for systemic candidiasis. 

With the use of animal models, patient data, and sera, the team showed how C5a and its downstream effects are crucial for the body’s immune cells, specifically neutrophils and macrophages, to clear the fungus, Candida albicans, when it has overtaken the body’s natural defenses. Desai and the team showed this in stages, both in animal models and in patient sera by isolating what roles the C5a plays. 

In addition to uncovering induced complement signature as a potential biomarker for systemic candidiasis, this work will be highly impactful in the clinical setting, where complement C5-targeted therapeutics, such as the anti-C5 monoclonal antibodies eculizumab/ravulizumab (as well as the C5a receptor inhibitor, avacopan) are the treatment of choice. In these settings, findings from this work emphasize the importance of surveillance for opportunistic fungal infections, where early diagnosis can improve patient outcomes.

"Our findings establish a new paradigm in immunobiology, demonstrating for the first time the direct critical role of cell-intrinsic complement generation for effective host defense against Candida,” write the authors. "The multifaceted translation of our work shows promise for the development of individualized risk stratification and prognostication strategies in patients at risk for invasive fungal disease."

- This press release was originally published on the Center for Discovery and Innovation website