gap junctions In summary Scholz et al have tackled a critica

In summary, Scholz et al. have tackled a critical issue in biomedicine relating to human CD4 and CD8 T memory stem cell generation and function. Although the molecular mechanism(s) of T cell generation remain nebulous vis-à-vis the relative role of WNT/β-catenin or mTOR modulation, the current report certainly provides a nidus of information that will guide subsequent investigations. Hopefully, with the attainment of a refined molecular understanding and the development of alternative pharmacologic inhibitors, an ability to effectively modulate T gap junctions for therapeutic purposes will be realized.
(Mtb) is one of the most successful 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 (; ; ; ). 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 the macrophage 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 (). Mtb also interferes with immune signaling by secreting another bacterial-derived second messenger, cyclic-di-adenosine monophosphate (c-di-AMP) (). 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 (). 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). The failure to control the global TB epidemic despite the availability of curative drug regimens is partly driven by the inherent difficulties of maintaining continuous chemotherapy over at least six months (). Moreover, even when patients are cured from the disease, lung function is often never fully recovered. As such, adjunctive host-directed therapies (HDTs) for TB are currently being explored to improve treatment outcomes by restoring effective host immunity, achieving an appropriate degree of inflammation, and preventing disease-associated lung pathology (). Success in modulating immunity may also lead to treatment shortening by reducing granulomatous pathology and the bacterial persister-state associated with granulomas.
In the last 10–20years, access to antiretroviral therapy (ART) has improved worldwide, resulting in substantial reduction in HIV-associated mortality and increased life expectancy, especially in low and middle-income countries. However, immune reconstitution inflammatory syndrome (IRIS), the clinical deterioration in patients with HIV initiating ART, is a common complication of ART initiation. The manifestations of IRIS depend on the type of opportunistic infection. With HIV-1 as the strongest predisposing factor to tuberculosis (TB) and TB as the commonest cause of death in HIV-1 infected persons in Africa, the otherwise beneficial dual therapy for HIV-1 and TB is frequently complicated by the occurrence of TB-immune reconstitution inflammatory syndrome (TB-IRIS) (). Two forms of TB-IRIS are recognized: paradoxical, which occurs in patients established on anti-tuberculosis therapy before ART, but who develop recurrent or new TB symptoms and clinical features after ART initiation; and unmasking TB-IRIS in patients not receiving treatment for TB when ART is started, but who present with active TB within 3months of starting ART (). Paradoxical TB-IRIS affects approximately 15.7% of all HIV-1-infected patients commencing ART while on TB treatment, and up to 52% in some populations, causing considerable morbidity and mortality ().