TEAM UFLORIDA 2023
Sepsis is the body’s dysregulated immune response to microbial invasion, or the body’s extreme response to infection. This immune dysregulation can cause a cascade of changes that can lead to systemic inflammation, damage to multiple organ systems, and eventually organ failure and death.There were approximately 49 million sepsis cases globally in 2017 with 11 million sepsis-related deaths accounting for 19.7% of all global deaths (WHO, 2023). Sepsis disproportionately affects vulnerable populations like newborns, pregnant women, and people living in low-income settings.
In the past two decases, there has been a consistent decline in in-patient mortality rates associated with sepsis (Zimmerman, 2013). However, the overarching prognosis for individuals diagnosed with sepsis remains largely unchanged. A significant portion of sepsis survivors endure prolonged stays in the Intensive Care Unit (ICU), with many ultimately succumbing to the complications of the condition. Recent data indicates a potential surge in sepsis-related mortalities (Prest, 2022). This is disconcerting, as it contrasts with the general positive trajectory observed in ICU patient outcomes, suggesting that the improvements in healthcare may not be benefiting sepsis patients equivalently. To bridge this evident disparity in patient outcomes, there is an imperative need for an enhanced understanding of the immunopathology underlying sepsis, coupled with the development of refined clinical tools and methodologies.
WHAT IS SEPSIS?
Sepsis is an extreme reaction to an infection. These infections can be fungal and viral but are generally bacterial. When the body tries to fight off an infection, patients with sepsis undergo immune dysregulation that can lead to tissue failure, organ failure, or even death. Sepsis requires immediate medical attention and treatment.
There is no coherent and confirmative diagnosis process for patients with sepsis. Instead, a sepsis diagnosis requires a combination of several tests and confirmation that the patient displays the signs and symptoms of this disease. Apart from the initial infection causing sepsis, doctors examine patients for elevated white blood cell counts, evidence of organ failure, lactic acid build-up, fast heart rate, and low blood pressure. Diagnosis before the onset of symptoms is unfeasible. Therefore, patients only receive a diagnosis and thus treatment once they are already undergoing severe bodily dysfunction.
Patients with sepsis struggle to maintain the production and formation of the cellular components of blood and plasma. While infected, patients rapidly produce myeloid and lymphoid progenitor cells that engender hematopoietic stem cell (HSC) cycling. HSCs reside in peripheral blood and can contribute to improper immune regulation in patients with sepsis.
Every 2.8 seconds, someone dies from sepsis. Sepsis is found worldwide and impacts many. Septic patients who survive may exhibit debilitating side effects, even after hospitalization. Eighty-five percent of sepsis cases are in low and middle-income countries, so although sepsis is everywhere, its dispersal is disparate. There are over 1.7 million cases of sepsis reported each year. These numbers are astounding and do not factor in family and friends impacted as well.
Immune-deficient patients are more vulnerable to developing sepsis due to their increased risk of infection. This fact disproportionately impacts those sixty-five and older, those with chronic medical conditions, previous sepsis recoverers, and infants. Populations living in underdeveloped and impoverished areas are also more likely to acquire sepsis and are less likely to receive proper care and a timely diagnosis.
Septic shock is the most severe form of sepsis that can manifest in the body. The risk of septic shock increases from four to nine percent every hour treatment is prolonged. Septic shock results in a dramatic drop in blood pressure and can contribute to organ failure and even death in some cases. Patients with septic shock must be intensely monitored in hospital settings and are at high risk for organ failure and death.
Our team has developed a multifaceted approach combining wet and dry lab models to study sepsis mechanisms, which can be used as a clinical tool in the future. Inspired by previous research using organoids as disease models (Khan, et al., 2023) our team has decided to create a human bone marrow organoid to mimic the bone-marrow environment in-vitro to lay the foundation for further immune and sepsis related studies. In conjunction, to further our understanding of the immune system and septic conditions, we built a mechanistic model to simulate and predict hematopoeietc dynamics. Through a series of stepwise, directed-differentiation steps, we will recapitulate bone-marrow conditions in-vitro that display key features of the endosteal and perivascular niche of bone marrow, including myeloid cell lineages affected by sepsis to study the effects of hematopoiesis and immune response in sepsis. The structural and chemical similarity of our organoids to human bone-marrow will allow for further studies of the immune system and septic conditions without harming a living test subject.
To further our understanding of the immune system and septic conditions, we also built an in silico mechanistic model This model allowed us to simplify the complex immune system through differential equations by treating the immune system as a set of nodes that each have a positive or negative “force” on the other nodes. Our model differs from other attempts in literature because it takes into account the number of hematopoietic stem and progenitor cells (HSPCs) along with pro-inflammatory leukocytes and anti-inflammatory leukocytes. Integrating HSPC’s into our model has given us insight into the nature of how the level of stem cells in our immune system can affect the overall immune response.