Abstract

Fever is a common clinical symptom in patients with tuberculosis (TB). During fever, heat-shock proteins (HSPs) such as HSP70 are expressed, which are molecular chaperones regulating protein folding and may also have immunomodulatory properties. How fever modulates immune responses during TB and by which mechanisms are unknown. In this study, we investigated the effects of fever, and specifically the role of HSP70, on Mycobacterium tuberculosis (Mtb)-induced macrophage inflammatory responses. Human monocyte-derived macrophages (MDM) were infected with Mtb at 37°C or 40°C to mimic febrile conditions. Fever suppresses Mtb-induced IL-1β and IL-10 gene expression and secretion from MDM, but enhances Mtb-induced HSP70 secretion and intracellular accumulation in MDM. Extracellular HSP70 and HSP70-expressing macrophages are abundant in granulomas in TB patient biopsies. HSP70 antagonism decreased Mtb-induced IL-1β secretion during febrile conditions, but has no significant effect on IL-10 secretion. Pre-treatment of MDM with recombinant HSP70 significantly increased Mtb-induced IL-1β at 37°C. Finally, extracellular HSP70 negatively regulated further HSP70 secretion from MDM during Mtb infection. Overall, fever and subsequent HSP70 expression modulates pro-inflammatory innate immune response in TB, which may have implications for the development of host-directed therapies.