Mycobacterium tuberculosis H37Rv Induces Gene Expression of PDE4A and PDE7A in Human Macrophages

The World Health Organization reported that one-fourth of the global population is infected with Mycobacterium tuberculosis (M.tb), the causative agent of an airborne infectious disease known as tuberculosis (TB). In 2017, TB alone caused 1.6 million deaths. M.tb is an intracellular pathogen equipped with specialized evolutionary traits to evade immune mechanisms. Upon inhalation, macrophages phagocytose M.tb and become a niche due to their inability to resolve the infection. The intracellular growth of M.tb is influenced, in part, by host transcription factors and immunosuppressive second messengers like cyclic adenosine monophosphate (cAMP). The importance of cAMP as an inflammatory response mediator derives from its ability to suppress innate immunity functions in macrophages, monocytes, and neutrophils by limiting pro-inflammatory cytokine release. Despite its known effects, the mechanisms underlying cAMP activation in response to M.tb are incompletely understood, particularly in human macrophages. Preliminary data indicate that cAMP levels are increased in human monocyte-derived macrophages (hMDMs) following infection with virulent M.tb H37Rv and attenuated M.tb H37Ra. Phosphodiesterases (PDEs) comprise a group of enzymes that degrade cAMP to regulate signal transduction. We hypothesize that elevated cAMP levels induce gene expression of certain PDEs as a host response mechanism to degrade M.tb-induced cAMP. Gene expression studies demonstrated that transcription of PDE4A and PDE7A increased 48 and 72 h after infection, whereas PDE3A and PDE5A remained unaltered. These data suggest that human macrophages up-regulate PDE expression to limit M.tb from dampening the immune response via high cAMP levels. Further studies will demonstrate the clinical feasibility of cAMP degradation as a novel host-directed therapy to reduce M.tb pathogenesis.