Bloodstream Infections from Combat Injuries Focus of DARPA-Funded Prophylactic Approach

Bloodstream infections (BSIs) can be uniquely challenging in trauma victims who are affected by burn and blast injuries—and this is particularly true for fungal infections.

DARPA’s (Defense Advanced Research Projects Agency) new SHIELD (Synthetic Hemo-technologies to Locate and Disinfect) program is honing in on this issue, with an aim to develop a prophylactic treatment that can be broadly administered to trauma victims in combat casualty care scenarios. The goal is to rapidly clear multiple bloodborne bacterial and fungal pathogens, limit morbidity and mortality, and protect recipients for up to seven days.

A new contract from SHIELD will give researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University up to $12M to develop such a treatment.

“Our goal is to develop a pathogen-agnostic treatment for defending human health in situations when the pathogen identity is unknown or there is insufficient time to identify the pathogen,” said Samir Mitragotri, PhD, Wyss core faculty member and the principal investigator on the project.

The Wyss project proposes an innovative solution for this challenge by combining two key technologies, “FcMBL-mediated pathogen-binding” and “macrophage-activating cellular backpacks” that individually have been validated in multiple medical applications and together could synergistically enable a powerful new approach against infectious pathogens.

The combination—known as FcMBL backpack therapeutics—that will be developed under the new DARPA-SHIELD-funded project can be safely and rapidly applied to prevent and treat BSIs in individuals who, due to trauma to various parts of the body, are at high risk of developing sepsis and organ failures and don’t have access to care facilities. FcMBL backpacks, injected directly into the blood circulation, bind to macrophages to keep them activated over days due to a constant stream of backpack-released cytokines. Backpack-carrying macrophages can then patrol the bloodstream as well as internal organs, such as the spleen and liver, which are the major natural pathogen-clearance sites, to eliminate pathogens before they can become a threat.

“The beauty of this groundbreaking project is that it combines two extremely powerful technologies that enable pathogen capture and immune cell activation, which synergize with each other when they are assembled into a living pathogen-killing machinery that can patrol inside the bodies of infected individuals,” said Donald Ingber, MD, PhD, Wyss founding director. “Easily to manufacture, store, and deploy, FcMBL backpacks could save the lives of many by enabling superior pathogen clearance in trauma patients at the site of injury.”

Cellular backpacks, developed by Mitragotri, are micrometer-scale disk-shaped microparticles engineered to quickly and tightly bind to the surface of specific types of immune cells, including macrophages, outside and inside the body, without being engulfed by the cells. When loaded with slowly released cytokine molecules and bound to macrophages in mice, cellular backpacks continuously activate immune cells for days, unleash their tumor cell-killing potential, and control tumor growth. As an important additional benefit, the close proximity of backpacks to immune cells such as macrophages, also avoids known systemic toxicities of the released cytokines. Beyond cancer applications, Mitragotri and his team have developed easily deployable cellular backpack devices to also control autoimmune disorders such as multiple sclerosis, and as key components of noninvasive diagnostics and therapeutics for “silent” traumatic brain injuries, among other disease targets.

The FcMBL pathogen-binding technology was developed with prior DARPA support by a Wyss team led by Ingber and Michael Super, PhD, director of immunomaterials at the Wyss Institute, to enable various pathogen-agnostic therapeutic and diagnostic applications. It consists of a genetically engineered version of the human blood opsonin, Mannose Binding Lectin, which is linked to the Fc portion of an immunoglobulin. After demonstrating that FcMBL bound to more than 130 different types of pathogens, including all major bacterial and fungal species that cause BSI and sepsis, the team engineered fast and effective FcMBL-based pathogen-clearing devices for sepsis, as well as diagnostic assays for use in different infectious disease settings. More recently, the researchers showed that FcMBL-coated liposomes that were loaded with antifungal drugs successfully concentrated the drug at sites of fungal infections to provide enhanced pathogen clearance while preventing unwanted side effects of antifungals.

“It was a logical step to combine the FcMBL pathogen-binding technology with the cellular backpacks advanced in Professor Samir Mitragotri’s group as this would harness the powers of FcMBL inside the bodies of infected individuals by activating critical cells of the innate immune system that are the body’s first line of defense,” said Super.