Pathways associated with secondary fatigue. Prolonged and or excessive stimulation of membrane bound Toll-like receptors (TLRs) results in the production of pro-inflammatory cytokines (PICs) and reactive oxygen and nitrogen species (ROS/RNS) at sufficiently high concentrations to cause macromolecule damage leading to the production of redox-derived damage-associated molecular patterns (DAMPs). The presence of such DAMPs leads to chronic engagement of TLRs and a spiraling, self-amplifying pattern of increasing ROS/RNS and PICs in a TLR radical cycle. Increasing levels of ROS/RNS damage mitochondrial lipids and proteins leading to dissipation of the mitochondrial membrane potential and inhibition of the electron transport chain. This leads to compromised oxidative phosphorylation and the production of ROS making another major contribution to the inflammatory milieu and another element in the development of a vicious spiral of bioenergetics decline. Elevated levels of PICs in the periphery activate microglia and astrocytes in the brain leading to the production of elevated PICs and ROS/RNS causing mitochondrial and metabolic dysfunction. This figure is original.