The Shock of Sepsis: The Struggle to Treat SIRS
Scientists and clinicians have studied sepsis since the mid-1880s. Physician-scientists like Ignaz Semmelweiss, Joseph Lister, Hugo Schottmüller, and Louis Pasteur launched the fields of immunology and related diseases that researchers still study today. But even as our knowledge of sepsis grows, diagnosis and treatment remain difficult1,2.
We saw this play out just last year. A 12-year-old boy, Rory Staunton, developed an infection that led to fatal septic shock. Doctors missed the early signs of SIRS (systemic inflammatory response syndrome)3. His death led to the founding of the Rory Staunton Foundation. It also led to reforms of emergency protocols in his home state of New York, known as “Rory’s Laws”3.
Hospital policy reform is only part of the solution. Sepsis affects more than 700,000 people in North America every year, with a 30-50% mortality rate4. To date, no FDA-approved drugs exist to treat SIRS4. In fact, after 20 years of intense translational research into sepsis, none of the proposed treatments have worked well enough to become standard care1.
We need to change how we care for sepsis patients, and we need to better understand the biology behind sepsis. That understanding could lead to more accurate detection and better therapies.
How Sepsis Affects the Innate Immune System
Sepsis happens when an infection triggers a systemic inflammatory response5. This throws the immune system off balance, changes the body’s blood flow, and can lead to coagulation, heart ischemia, and multi-organ failure1.
Researchers first thought sepsis came from overactivation of the innate immune system. But many patients don’t die from this first wave of inflammation. Instead, they die during a later stage of immune suppression, called “immunoparalysis,” which lets opportunistic viruses and bacteria take over the body1.
We can understand sepsis’s effects by looking at the different cell types it touches:
- The innate immune system
- The adaptive immune system
- Non-immune cells
Because sepsis stems from bacterial and viral infection, the innate immune system is the most well-studied part of its biology. During SIRS, innate immune cells — macrophages, dendritic cells, and natural killer (NK) cells — become pathologically affected.
During the initial infection, the body builds up more pathogen-associated molecular pattern (PAMP) and damage-associated molecular pattern (DAMP) molecules. Toll-like receptors (TLRs) on innate immune cells, such as TLR4 and TLR9, recognize these molecules and trigger an inflammatory response. This inflammation increases adhesion molecules on both innate and adaptive immune cells4, which signals these cells to migrate toward the infection site.
At the same time, the complement cascade activates and raises C5a protein levels. This higher C5a drives more migration of innate immune cells and boosts macrophages’ ability to engulf pathogens (phagocytosis)4.
Prolonged exposure to C5a throws off macrophage activation and eventually triggers cell death (apoptosis)1. As macrophages die, they release high-mobility group protein B1 (HMGB1), which can increase inflammation further5.
Other innate immune cells are affected too:
- Neutrophils: Sepsis triggers an abnormally long proliferation period5, which can lead to organ damage and more inflammation. Sustained neutrophil activation may also contribute to immunoparalysis — activated neutrophils raise reactive oxygen species, which are known to suppress immunity, and macrophages that consume dying neutrophils release anti-inflammatory cytokines5.
- Dendritic cells: Prolonged sepsis reduces their pro-inflammatory ability. SIRS depletes splenic and myeloid dendritic cells, and the ones that remain function poorly4.
- NK cells: Best known for anti-viral immunity, but also involved in responses to bacterial infection. NK cells play two different roles across the phases of sepsis. Early on, they add to overactive immune responses and systemic inflammation4. Later, weakened NK cells may allow secondary bacterial or viral infections, which worsens inflammation during SIRS4.
How Sepsis Affects the Adaptive Immune System
Sepsis doesn’t just throw off the innate immune system — it also affects the adaptive immune system’s T cells and B cells.
- Sepsis lowers overall T-cell receptor function and shifts Th1 (pro-inflammatory) T cells toward a Th2 (immunosuppressive) response1.
- It increases CD25+Foxp3+ T cells, also known as regulatory T cells, during SIRS5.
- Interferon-gamma, a pro-inflammatory cytokine active during sepsis, increases innate response activator (IRA) B cells. These B cells recognize PAMPs, block infection clearance, and speed up septic shock4,6.
- Rising C5a levels also cause T-cell and B-cell apoptosis during sepsis4, which drives further immunosuppression4.
Non-Immunological Effects of Sepsis
Sepsis also affects the body beyond the immune system.
- It raises coagulation, and this heightened clotting state can lead to ischemic injury5.
- It causes cytopathic hypoxia5 and cardiomyopathy4.
- SIRS also affects the autonomic nervous system: more apoptosis of adrenal medullary cells throws off the endocrine system that controls the autonomic nervous system1.
Current Research and Treatment Approaches
Researchers are studying how sepsis develops, with the goal of finding effective treatments.
- Recent studies have looked at the role of STIM17 and PI3K activation in starting sepsis5.
- Researchers are also studying host deficiencies that may lead to sepsis, including zinc8 and ADAMS-T5 deficiencies, to learn more about sepsis’s underlying imbalance.
Medical scientists are working with clinicians to better understand the balance between hyper-responsiveness and systemic immune suppression4. These studies have led to several proposed immunotherapies:
- Dendritic cell implantation4
- Regulatory T-cell implantation4
- Modifying the immune system with TLR antagonists4
- Injecting the pro-inflammatory cytokines IL-15 and IL-174
- Limiting adaptive immune system exhaustion by blocking PD-14
However, several of these approaches — including T-reg implantation and TLR antagonists — showed limited clinical benefit and were stopped early4. This may be because researchers still lack a good model for studying human sepsis before clinical trials.
The Search for Better Sepsis Models
Current research methods for studying sepsis have real limits, which points to a need for reform in SIRS research. A recent article by Seok et al. in the Proceedings of the National Academy of Sciences outlined the limits of using mouse models to study human inflammation9. Seok et al. found differences in timing, gene signatures, and regulated pathways in the inflammatory response after various injuries9.
These differences may come from several sources: evolutionary gaps between mouse and human immune systems, the inbred nature of research mice, and a tendency for mouse studies to focus on one mechanism. In a real body, though, immune responses actually overlap heavily. The authors suggest two paths forward:
- Studying genetic and epigenetic changes in patient samples during sepsis, to find more appropriate mouse models9
- Recreating the inflammatory response in vitro using diseased tissue9
Unfortunately, in vitro models have their own limits. This simplified approach may miss a key cell, cellular event, or spatial/timing pattern that matters for sepsis.
Non-human primates might offer a more accurate sepsis model than either approach, but the ethical and cost concerns of using them remain a deterrent.
A final model that may help sepsis researchers is the humanized mouse. This is a severely immunocompromised mouse given a rebuilt adaptive and/or innate immune system, used to study human diseases in vivo. Unsinger et al. proposed using humanized mice to study sepsis.
They transplanted two-day-old NOD-scid IL2 receptor-gamma knockout mice with hCD34+ enriched hematopoietic cord blood stem cells. After building a human immune system in these mice, the researchers used the cecal ligation puncture (CLP) model of intra-abdominal peritonitis and measured changes in immune response10.
These mice developed a working human innate and adaptive immune system that mirrored the human immune response to sepsis. Some differences remain between the humanized mouse model and the real human immune response, such as differences in bowel bacterial flora10. Even so, this model is still a useful tool.
Combined with more genetic and epigenetic data from patient studies, it should lead to better preclinical studies, and hopefully, FDA-approved drugs to treat sepsis in the clinic.
References:
1. Rittirsch, D., Flierl, M. A. & Ward, P. A. Harmful molecular mechanisms in sepsis. Nat Rev Immunol 8, 776-787, doi:10.1038/nri2402 (2008).
2. Stearns-Kurosawa, D. J., Osuchowski, M. F., Valentine, C., Kurosawa, S. & Remick, D. G. The pathogenesis of sepsis. Annu Rev Pathol 6, 19-48, doi:10.1146/annurev-pathol-011110-130327 (2011).
3. Dwyer, J. Death of a Boy Prompts New Medical Efforts Nationwide, October 26, 2012).
4. Ward, P. A. & Bosmann, M. A historical perspective on sepsis. Am J Pathol 181, 2-7, doi:10.1016/j.ajpath.2012.05.003 (2012).
5. Cinel, I. & Opal, S. M. Molecular biology of inflammation and sepsis: a primer. Crit Care Med 37, 291-304, doi:10.1097/CCM.0b013e31819267fb (2009).
6. Rauch, P. J. et al. Innate response activator B cells protect against microbial sepsis. Science 335, 597-601, doi:10.1126/science.1215173
7. Gandhirajan, R. K. et al. Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation. J Clin Invest, doi:10.1172/jci65647 (2013).
8. Liu, M. J. et al. ZIP8 Regulates Host Defense through Zinc-Mediated Inhibition of NF-κB. Cell Rep, doi:10.1016/j.celrep.2013.01.009 (2013).
9. Seok, J. et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A, doi:10.1073/pnas.1222878110 (2013).
10. Unsinger, J., McDonough, J. S., Shultz, L. D., Ferguson, T. A. & Hotchkiss, R. S. Sepsis-induced human lymphocyte apoptosis and cytokine production in “humanized” mice. J Leukoc Biol 86, 219-227, doi:10.1189/jlb.1008615 (2009).
