Author: Mohd M. Khan
Not heard of sepsis before? You’re not alone. Unfortunately, many people, including heavyweight champion Muhammad Ali and Broadway rock musical “Hair” original cast member Steve Curry, lost their lives to blood poisoning (sepsis). Infants, the elderly, trauma victims, chemotherapy patients, or immunocompromised individuals (HIV, autoimmune diseases, leukemia) are at the highest risk of developing sepsis after contracting an infection. In the U.S. alone, sepsis-related hospitalizations cost more than $20 billion/year—the most costly condition for hospitals to treat—with associated deaths exceeding those due to AIDS, breast cancer, and prostate cancer combined.
So far over 100 phase 2 and 3 clinical trials for sepsis therapeutics have failed, and there is no approved drug on the market that could specifically be used in treating severe sepsis. For instance, small-molecule drug TAK-242 and synthetic anti-sepsis molecule Eritoran failed in clinical trials, whereas the Food and Drug Administration-approved biotherapeutic Xigris was removed from the market, as it showed no efficacy against sepsis complications in clinical settings.
Sepsis is a life-threatening condition that can occur when the body’s immune system responds to an infection (bacteria, viruses, or fungi) in an overwhelming and dysregulated fashion. As you can see in the diagram I drew, dissemination of bacteria in the blood results in a cytokine storm, which converts a healthy immune system, which normally functions to control blood-borne infections into a liability for the patient. Sepsis caused by Gram-negative bacteria is, in part, dependent on stimulation of toll-like receptor-4 (TLR4) by the bacterial membrane component lipopolysaccharide (LPS). Structurally, endotoxins consists of lipid A, a core oligosaccharide and, sometimes, a large polysaccharide (O-antigen) with lipid A binding to the TLR4 complex leading to activation of the immune system.
My thesis research, supported by the AAPS Foundation, will focus on determining the relationship between LPS structure and receptor binding and activation using immunological, microbiological, mass spectrometry-based proteomic, and systems biology approaches. To block receptor activation and subsequent inflammation, lipid A mimetics can be designed to act as a receptor antagonist, thereby dampening or blocking bacterial endotoxin-mediated inflammation. Structurally, lipid A mimetics look like an endotoxin molecule, effectively bind to receptor, but don’t activate the receptor. A better understanding of this process will help in designing powerful anti-sepsis lipid A mimetics; our lab and collaborators have shown the possible therapeutic potential of this approach.
What makes endotoxin biology even more interesting is that some bacteria can modify their lipid A part in response to environmental signals; bacteria can remodel their lipid A in order to produce either strong pro-inflammatory effects or become completely invisible to the host immune system. For instance, Yersinia pestis — the highly pathogenic bacterium that causes plague — can grow in the body without an effective restrain from body’s immune system. Y. pestis accomplishes this by producing lipid A structures that have a feeble stimulatory effect on human innate immune signaling. Interestingly, some remodeled LPS (endotoxin) can even block receptor activation. LPS remodeling is one of the strategies by which bacteria survive and in many cases develop antibiotic resistance. For example, one of the most prevalent organisms associated with sepsis is Pseudomonas aeruginosa, which is widespread among patients with cystic fibrosis (CF), burn/ trauma, and organ transplants. In CF patients, P. aeruginosa produces a variety of LPS structures that can influence disease severity, progression, and associated inflammation. In contrast, patients without cystic fibrosis mostly produce a single version of LPS that is comparatively less stimulatory.
A graduate fellowship from AAPS has enabled me in advancing my thesis research and graduate training goals. The knowledge obtained in my thesis research project is expected to assist in designing effective anti-sepsis molecules that can be tested to treat sepsis and improve patient outcomes while decreasing hospital burdens. Stay tuned for the near-future updates!