Phosphodiesterase inhibitors as adjunctive therapies for tuberculosis

Mycobacterium tuberculosis (Mtb) is one of the most successful The failure to control the global TB epidemic despite the availability human pathogens, and a key mechanism in its virulence arsenal is its ability to influence host immune responses to its advantage. In recent years it has become clear that one such mechanism pivots on bacterial-derived, secreted small molecules that are released from the intracellular phagosome of macrophages into the host cell cytosol where they interfere with host cell signaling and downstream cytokine responses. Using small molecules such as cyclic nucleotides, Mtb subverts the host's innate bactericidal responses to remodel the intracellular niche to an environment favorable for mycobacterial survival or growth (Agarwal et al., 2009; Dey et al., 2015; Tobin et al., 2012; Wallis and Hafner, 2015). A key bacterial-derived, secreted small molecule is the well-known second messenger cyclic adenosine monophosphate (cAMP). Upon infection Mtb produces a burst of cAMP within macrophages. Through a microbial adenylate cyclase gene, bacterial-derived cAMP is delivered to themacrophage cytoplasm increasing cytosolic cAMP levels 3–5-fold above baseline and triggering the PKA-CREB pathway to upregulate NFκB transcription. One consequence of bacterial subversion of host cAMP signaling is the elevated TNF-α secretion at the early stages of infection promoting necrosis and granuloma formation—outcomes that foster bacterial survival (Agarwal et al., 2009). Mtb also interferes with immune signaling by secreting another bacterial-derived second messenger, cyclic-di-adenosine monophosphate (c-di-AMP) (Dey et al., 2015). This pathogen-associated molecular pattern (PAMP) which is recognized by the macrophage cytosolic surveillance pathway behaves as a double-edged sword in Mtb pathogenesis. On the one hand, it contributes to the induction of Type I interferon levels through the STING-IRF3 signaling pathway, enhancing immunopathology and thus benefiting the microbe. On the other hand, c-di-AMP also enhances autophagy and bacterial killing. Mtb expressing excess c-di-AMP displays a loss of pathogenicity in animal models indicating that the dominant impact of microbial c-di-AMP production is its stimulation of autophagy to benefit the host (Dey et al., 2015). This latter observation suggests that measures to prevent the breakdown of Mtb-derived c-di-AMP might be beneficial for host control of tuberculosis (TB).