Macrophages are a first line of defense against pathogens. However, certain invading microbes modify macrophage responses to promote their own survival and growth. Mycobacterium tuberculosis (M.tb) is a human-adapted intracellular pathogen that exploits macrophages as an intracellular niche. It was previously reported that M.tb rapidly activates cAMP Response Element Binding Protein (CREB), a transcription factor that regulates diverse cellular responses in macrophages. However, the mechanism(s) underlying CREB activation and its downstream roles in human macrophage responses to M.tb are largely unknown. Herein we determined that M.tb-induced CREB activation is dependent on signaling through MAPK p38 in human monocyte-derived macrophages (MDMs). Using a CREB-specific inhibitor, we determined that M.tb-induced CREB activation leads to expression of immediate early genes including COX2, MCL-1, CCL8 and c-FOS, as well as inhibition of NF-kB p65 nuclear localization. These early CREB-mediated signaling events predicted that CREB inhibition would lead to enhanced macrophage control of M.tb growth, which we observed over days in culture. CREB inhibition also led to phosphorylation of RIPK3 and MLKL, hallmarks of necroptosis. However, this was unaccompanied by cell death at the time points tested. Instead, bacterial control corresponded with increased colocalization of M.tb with the late endosome/lysosome marker LAMP-1. Increased phagolysosomal fusion detected during CREB inhibition was dependent on RIPK3-induced pMLKL, indicating that M.tb-induced CREB signaling limits phagolysosomal fusion through inhibition of the necroptotic signaling pathway. Altogether, our data show that M.tb induces CREB activation in human macrophages early post-infection to create an environment conducive to bacterial growth. Targeting certain aspects of the CREB-induced signaling pathway may represent an innovative approach for development of host-directed therapeutics to combat TB.

Quorum sensing (QS) was historically described as a mechanism by which bacteria detect and optimize their population density via gene regulation based on dynamic environmental cues. Recently, it was proposed that QS or similar mechanisms may have broader applications across different species and cell types. Indeed, emerging evidence shows that the mammalian immune system can also elicit coordinated responses on a population level to regulate cell density and function, thus suggesting that QS-like mechanisms may also be a beneficial trait of the immune system. In this review, we explore and discuss potential QS-like mechanisms deployed by the immune system to coordinate cellular-level responses, such as T cell responses mediated via the common gamma chain (γc) receptor cytokines and the aryl hydrocarbon receptors (AhRs). We present evidence regarding a novel role of QS as a multifunctional mechanism coordinating CD4+ and CD8+ T cell behavior during steady state and in response to infection, inflammatory diseases, and cancer. Successful clinical therapies such as adoptive cell transfer for cancer treatment may be re-evaluated to harness the effects of the QS mechanism(s) and enhance treatment responsiveness. Moreover, we discuss how signaling threshold perturbations through QS-like mediators may result in disturbances of the complex crosstalk between immune cell populations, undesired T cell responses, and induction of autoimmune pathology. Finally, we discuss the potential therapeutic role of modulating immune-system-related QS as a promising avenue to treat human diseases.

Renal Angiomyolipomas (AMLs) are benign neoplastic entities paradigmatically composed of smooth muscle, blood vessels, and adipose tissue. The cornerstone of renal AML identification fundamentally entails imaging; however, findings may rarely resemble malignancy and subsequently obfuscate diagnosis. Compellingly, the comorbid effect of viral diseases such as COVID-19 on neoplasm integrity and morphology remains incompletely understood. The following case reports a 46-year-old female presenting with intermittent right flank pain persisting for three weeks. Preliminary sonographic studies revealed a predominantly echogenic, space-occupying lesion with well-defined margins in the right renal cortex undergoing angiogenesis. Shortly thereafter, the patient contracted COVID-19, and the right flank pain progressed to a debilitatingly constant nature described as sharp, stabbing, and aggravating to an eight on a scale of ten. Recovery was uncomplicated; however, the patient presented with mild thrombocytopenia. Contrast-enhanced CT scans elucidated a compelling hypodense mass center suggesting the presence of an encapsulated thrombus accompanied by further invasion of Morison’s pouch 25 days post-initial identification. Histopathological examination of the surgically excised specimen confirmed the likely diagnosis of a centrally thrombosed renal angiomyolipoma. Severe Acute Respiratory Syndrome Coronavirus-2 (SARSCoV-2) infection may have ostensibly contributed to neoplasm morphology alterations and subsequent thrombosis, as intrinsic renal cell damage is welldocumented in the literature. Consequently, clinicians must remain vigilant that radiographic abnormalities may emerge secondary to comorbid viral diseases such as COVID-19 via incompletely understood mechanism(s).