Bacterial sepsis occurs when viral coated proteins bind and activate Toll-like receptors (TLR) 2 and 4 on white blood cells and is taken up by macrophages. Due to this ingestion by these macrophages activating TLR receptors which are directly correlated to the activation of the innate immune response. This causes the activation and production of many interleukins, transcription factors and cytokines. One of these interactions is the NF-kβ protein that enters the nucleus and activates nitric oxide synthase (iNOS), Irg1, tumor necrosis factor (TNF), interleukin 6 (IL-6) and interleukin 1 beta (IL-1β). These are pro inflammatory cytokines that can oxidize tyrosines such as nitrotyrosine, and move into the bloodstream which transports them to the brain. At the brain the proinflammatory cytokines activate the hypothalamus, releasing hypothalamic corticotropin releasing hormone (CRH) into the hypophyseal portal system. CRH acts on the anterior pituitary releasing adrenocorticohormone (ACTH), this hormone travels in the bloodstream to the adrenal glands releasing cortisol and epinephrine. This stimulates the sympathetic nervous system into a "fight or flight" response, increasing glucose production, release short chain acylcarnitines, beta oxidation of fatty acids in order to allow cells to produce and develop immune cells such as macrophages and neutrophils. In turn also stimulates the liver to produce even more proinflammatory cytokines like IL-6, TNF and NO to strengthen the innate immune response. The increased concentration of nitric oxide causes blood vessels to dilate, reducing blood pressure, disrupting mitochondrial tricarboxylic acid (TCA) cycle this leads to accumulation of byproducts of the cycle such as citrate and production of acylcarnitines and fatty acids. Succinate also begins to accumulate resulting in a downstream effect production of pro inflammatory cytokine. This deactivates oxidative phorphorylation in mitochondria and white blood cells shifting them to aerobic glycolysis leading to more reactive oxygen species (ROS) being produced as a byproduct and oxidation of amino acids. Aerobic glycolysis in white blood cells lead to its division and propagation in a quick time frame, causing a highly exagerrated response. This highly inflammatory response leads to a harmful postive feedback leading to more glucose and arginine consumed and more lactate and NO produced further exacerbating this aerobic glycolytic pathway. Ultimately causing a reduction in amino acids and gluconeogenic acids causing the body to act on amino acid reservoirs such as myosin in the muscle or serum albumin in the blood. Detrimental in some cases as low levels of serum albumin can lead to hypoalbuminemia leading to swelling as albumin is responsible for keeping fluid within the blood vessels. Throughout this activation of the innate immune response the pathway for kynurenine thrown into dysregulation, that is suspected to be due to stimulation from interferon gamma. Hyperstimulation leads to activation of indole dioxygenase (IDO) enzyme leading to reductions of tryptophan. Subsequently activation of IDO leads to increased concentration of kynurenine and its metabolites leading to a self stimulating autocrine process. Kynurenine then binds to arylhydrocarbon receptor (AhR) on immune cells, this bounded compound will travel to the nucleus to bind NF-kβ causing more production of IDO enzyme, reduction of tryosine and production of kynurenine. High levels of kynurenine and low levels of tryptophan leads T cell differentiation to shift to an anti-inflammtory response, inhibition of T cell proliferation and T cell apoptosis. Overall leading to a blunted immune response, causing the infection to continue to spread and contributing to a futile cycle. As the energy needed to sustain the immune response exhausts the body and ends up being damaged by the kynurenine pathway. This ultimately can result in hypotension, lactic acidosis, damaging of barriers, pulmonary edema, hypoalbuminemia, build up of uremic toxins, organ injury, organ failure and in extreme cases death.

Bacterial Sepsis References