Dynamics and Internal Control of Body Temperature in Response to Infectious Agents and other Causal Factors

Abstract

Thermoregulation is crucial to homeostasis, but the mechanisms of its dysfunction are still largely mysterious, including fever, which is generally the most disconcerting sign of a serious infection or disease. Theories on body temperature dynamics that aim to explain a fever, such as changes in an internal setpoint, have been proposed, but none can identify the fundamental molecular pathways that produce a fever. Here, potential molecular pathways resultant in fever are identified, modeled, and compared to experimental temperature response data. Based on recent developments made by this lab, which has shown that the pyrogen prostaglandin E2 (PGE2) possesses similar binding affinity as the hormone cortisol (CORT) at the critical ligand binding domain (LBD) of glucocorticoid receptors (GR); molecular modeling, mathematical modeling and a case study for validation is used to indicate that competitive inhibition of CORT by PGE2 as a fundamental reason for dysfunctional dynamics of body temperature, including fever. Comprised of a superposition of proportional and derivative terms of signals representing temperature receptors, CORT concentration, and PGE2 concentration, the internal temperature control model characterizes dynamics associated with the cardiovascular, immune, and neural systems in response to infectious agents, triggering events, and other causal factors. The model is validated by examination of the transient and spectral characteristics of a three-day case history involving temperature trajectories after physical activity protocols in response to a standard vaccination of pneumococcal and influenza species.