21 September 2018
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and a major public health concern, particularly for the very young and very old. Around the world, sepsis kills more people than AIDS, breast cancer and prostate cancer combined. The mortality rate can be as high as 50%, and those who survive are often left with long-term consequences that may include physical and psychological disabilities.
Sepsis becomes fatal as a consequence of multiple organ failure caused by an overwhelming cascade of inflammatory mediators released into the bloodstream. But exactly how this response to infection is regulated, and whether it is in fact a regulated response, remains uncertain. Some authors have suggested that the body goes through different immune states while fighting sepsis, starting by activation of immunity and then reaching immune paralysis or exhaustion. Current treatments have shown limited efficacy and patient outcome is in most cases unpredictable.
Mice are the most frequently used animal to study sepsis. However, the utility of animals as models of sepsis has been questioned: A recent review has pointed out that “To date, not a single therapeutic agent demonstrating efficacy in preclinical animal models for sepsis… is currently utilized in clinical practice.” As such, it is hard to see how mice can be of any help in improving our understanding of sepsis in humans, even with refinement or standardisation of them as models. For a start, there are many significant differences between a mouse’s response to deliberate sepsis and the human disease. It is well known that mice are highly resistant to endotoxin and that it takes around 2,000 times more endotoxin in mice than the equivalent dose in humans to induce low blood pressure, high heart rate and signs of inflammation that resemble the symptoms of sepsis in humans. This murine resilience may be explained by the fact that mice usually inhabit environments full of pathogens and contaminants, against which the species has evolved defence mechanisms. In fact, a component was recently discovered in mouse blood that suppresses the damaging response to endotoxin. In addition to the difference between humans and mice regarding their resilience to endotoxin, a study in 2013 showed that the genes activated in the human response to endotoxin bore little resemblance to the mouse genes switched on or off under similar circumstances. Thus, the pathways involved in the response to endotoxin (and, by inference, sepsis) are likely to be quite different in mice and humans – further calling into question the use of mice as ‘models’ of human disease.
In an attempt to gain some much-needed insights into sepsis progression in humans and to enable more accurate predictions of patient outcome, de Camargo and colleagues have developed an in silico simulation model of toll-like receptor 4 (TLR4) trafficking. The model evaluates TLR4 mRNA in blood samples taken from patients diagnosed with sepsis. TLR4 is the LPS receptor and responsible for detection of, and response to, Gram negative pathogens. de Camargo’s model showed that when the initially high levels of TLR4 on the cell surface are rapidly internalised, this constitutes a pro-inflammatory role resulting in the resolution of sepsis. However, when TLR4 expression is amplified and the receptor oscillates between the cell surface and intracellular compartments, there is no signal resolution and the outcome is bleak. The study shows that whether or not the patient will survive sepsis can be defined by the cellular route taken by TLR4, and within the cohort tested, the deaths due to sepsis were all predicted by this simulation.
Sepsis treatment has remained the same for the last 30 years, despite extensive research involving hundreds of thousands of animals in attempts to understand the mechanism(s) of sepsis in humans and develop effective treatments. Novel, human-specific approaches such as the in silico modelling strategy above provide insights into what could be a useful, cheap and quick biomarker for sepsis diagnosis, progression, and recovery, helping us better understand the disease in humans, and ultimately reduce the mortality rates for sepsis and septic shock.