Connecting the (Sp)ots: Cytokines and the Cure to Sepsis

Illustrated by: Angela Chen

In the Clinical Sciences Research Building at Washington University School of Medicine, every day brings exciting opportunities for discoveries at the cutting edge of medicine. For Dr. Richard Hotchkiss, a professor and researcher in the Department of Anesthesiology, those opportunities lie deep within the multitude of septic blood samples and immunoassay wells waiting to be analyzed in his laboratory everyday.

 “Sepsis is a complex host response involving multiple interacting systems, such as both proinflammatory and anti-inflammatory systems, and blood coagulation system.” Hotchkiss describes, “Your respiratory system, your neurological system, virtually every organ is in some way or other impacted by severe sepsis… It is hard to treat because it is such a systemic disorder.”

Primarily characterized by life threatening organ dysfunction as a result of a dysregulated immune response, Sepsis remains the leading cause of death in the Intensive Care Unit (ICU) [5]. Before the 90’s, sepsis was established almost exclusively to be caused by gram-negative bacteria; since the turn of the century, many additional categories of pathogens have been found to incite a septic response, while a third of septic patients lack pathogenic causes altogether [5]. Consistent with the broad range of infections and diseases plaguing septic patients is an overwhelmingly heterogeneous array of symptomatic manifestations: from fever, shock and significant cardiovascular dysfunction to low body temperatures and lethargy, specialists are challenged by these diverse phenotypes [3]. Yet, for septic patients, the race towards rapid diagnosis and early treatment with broad spectrum antibiotics is key.

            “Diagnosis of the invading pathogen is a major step forward in the hospital.” Hotchkiss says, “What has clearly come from clinical trials is that the most important thing you can do in sepsis is rapid administration of broad-spectrum antibiotics. Source control, if a patient has an infection, like appendicitis, in getting the infection drained is important. Then, continuing supportive care with volume resuscitation and medications to raise patients’ blood pressures.”

Such treatment standards have become staples in improving patient outcomes as well as further elucidating the complexities in immune response. Immune status changes and individual variability has been a focal point of sepsis research for decades; however, early theories emphasized the need for a reduction in the initial surge in innate immune response, referred to as a “cytokine storm” after the characteristic release of pro-inflammatory immune signalling molecules called cytokines, and thus advocated for immunosuppressive therapies [2].

“We see some patients that come in with meningococcemia or toxic shock syndrome or some of these Group A Beta-Hemolytic Strep infections, and they can die from excessive inflammation in the cytokine storm.” Hotchkiss says, “On the other hand, we’ve gotten better at supporting the patient over the years and we can get them through that hyperinflammatory phase. Many of the patients are actually evolving into an immunosuppressed phase.”

This interplay between immune suppression and overactivation has become a centerpoint of scientific inquiry, and the immunosuppressive phase of sepsis, spurred by a crippled adaptive immune response, suggests a novel direction in understanding the mechanisms of sepsis pathogenesis. “Sepsis causes compromise of your immune system by killing many of your immune effector cells. Your lymphocytes, in particular, undergo apoptosis… as you become more immune-compromised. This makes patients susceptible to secondary hospital acquired infections, which they often die from.” Hotchkiss describes.

And it is this failure to mount a secondary immune response which has guided the Hotchkiss Laboratory in crafting a novel approach yielding promising results: a functional bioassay assessing the degree of activation in patients’ immune systems and providing opportunities to test and integrate various immune therapies for individualized treatment approaches [4]. This immunoassay allows patients’ blood to be artificially stimulated to reproduce both their baseline immune function as well as modulate this immune status with various reagents and drug therapies. To quantify the number of immune cells, as well as their capability in mounting an effective response, the membranes upon which these cells are plated are equipped with specialized receptors to bind to specific cell-secreted cytokines. Upon dyeing these membranes, locations of significant quantities of cytokine production, visualized as dark spots on a lighter background, are counted to represent the number of activated immune cells. Compared to previous proteomic or genomic measures of immune status, such functional endotyping allows for a dynamic assessment of the time-sensitive variations in immune function.

Such innovation has been the product of many years of trial and error, as well as a network of funding and support from various sectors of the healthcare system. “In addition to having NIH funding in addition to over a quarter of the century, I have worked with ‘big pharma’ probably equally as long.” Hotchkiss says, “I have had great collaborations with Merck, Bristol Myers Squibb, Pfizer, and it takes something like that to figure out the big problems in sepsis and develop new therapies to test in clinical trials.”

And what about the biggest “problem” on the drawing board today? Amidst increasing insight into the presentation of COVID as a form of viral sepsis, the Hotchkiss laboratory remains hard at work mining new discoveries at the cutting edge of medicine [1].

“COVID has been critical in reactivating the National Institutes of Health and investigators to attack infectious disorders. In our lab, we have done studies with probably over 100 COVID patients… and have published several papers.” Hotchkiss says, “We have unbelievably great collaborators, and it is a really good team effort moving forward.”

Edited by: Rehan Mehta
Illustrated by: Angela Chen

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