AMPK-Targeted Effector Networks in Mycobacterial Infection

AMP-activated protein kinase (AMPK), a key metabolic regulator, plays an essential role in the maintenance of energy balance in response to stress. Tuberculosis (TB), primarily caused by the pathogen Mycobacterium tuberculosis (Mtb), remains one of the most important infectious diseases worldwide, characterized by both high incidence and mortality. Development of new preventive and therapeutic strategies against TB requires a profound understanding of the various host-pathogen interactions that occur during infection. Emerging data suggest that AMPK plays an essential regulatory role in host autophagy, mitochondrial biogenesis, metabolic reprogramming, fatty acid β-oxidation, and the control of pathologic inflammation in macrophages during Mtb infection. As described in this review, recent studies have begun to define the functional properties of AMPK modulators capable of restricting intracellular bacteria and promoting host defenses. Several host defense factors in the context of AMPK activation also participate in autophagic and non-autophagic pathways in a coordinated manner to enhance antimicrobial responses against Mtb infection. A better understanding of these AMPK-targeted effector networks offers significant potential for the development of novel therapeutics for human TB and other infectious diseases

Peroxisome Proliferator-Activated Receptor-Targeted Therapies: Challenges upon Infectious Diseases

Peroxisome proliferator-activated receptors (PPARs) α, β, and γ are nuclear receptors that orchestrate the transcriptional regulation of genes involved in a variety of biological responses, such as energy metabolism and homeostasis, regulation of inflammation, cellular development, and differentiation. The many roles played by the PPAR signaling pathways indicate that PPARs may be useful targets for various human diseases, including metabolic and inflammatory conditions and tumors. Accumulating evidence suggests that each PPAR plays prominent but different roles in viral, bacterial, and parasitic infectious disease development. In this review, we discuss recent PPAR research works that are focused on how PPARs control various infections and immune responses. In addition, we describe the current and potential therapeutic uses of PPAR agonists/antagonists in the context of infectious diseases. A more comprehensive understanding of the roles played by PPARs in terms of host-pathogen interactions will yield potential adjunctive personalized therapies employing PPAR-modulating agents

AMP-Activated Protein Kinase and Host Defense against Infection

5′-AMP-activated protein kinase (AMPK) plays diverse roles in various physiological and pathological conditions. AMPK is involved in energy metabolism, which is perturbed by infectious stimuli. Indeed, various pathogens modulate AMPK activity, which affects host defenses against infection. In some viral infections, including hepatitis B and C viral infections, AMPK activation is beneficial, but in others such as dengue virus, Ebola virus, and human cytomegaloviral infections, AMPK plays a detrimental role. AMPK-targeting agents or small molecules enhance the antiviral response and contribute to the control of microbial and parasitic infections. In addition, this review focuses on the double-edged role of AMPK in innate and adaptive immune responses to infection. Understanding how AMPK regulates host defenses will enable development of more effective host-directed therapeutic strategies against infectious diseases

Cellular Senescence in Intervertebral Disc Aging and Degeneration: Molecular Mechanisms and Potential Therapeutic Opportunities

Closely associated with aging and age-related disorders, cellular senescence (CS) is the inability of cells to proliferate due to accumulated unrepaired cellular damage and irreversible cell cycle arrest. Senescent cells are characterized by their senescence-associated secretory phenotype that overproduces inflammatory and catabolic factors that hamper normal tissue homeostasis. Chronic accumulation of senescent cells is thought to be associated with intervertebral disc degeneration (IDD) in an aging population. This IDD is one of the largest age-dependent chronic disorders, often associated with neurological dysfunctions such as, low back pain, radiculopathy, and myelopathy. Senescent cells (SnCs) increase in number in the aged, degenerated discs, and have a causative role in driving age-related IDD. This review summarizes current evidence supporting the role of CS on onset and progression of age-related IDD. The discussion includes molecular pathways involved in CS such as p53-p21CIP1, p16INK4a, NF-κB, and MAPK, and the potential therapeutic value of targeting these pathways. We propose several mechanisms of CS in IDD including mechanical stress, oxidative stress, genotoxic stress, nutritional deprivation, and inflammatory stress. There are still large knowledge gaps in disc CS research, an understanding of which will provide opportunities to develop therapeutic interventions to treat age-related IDD

Ohmyungsamycin promotes M1-like inflammatory responses to enhance host defence against Mycobacteroides abscessus infections

Ohmyungsamycin A (OMS) is a newly identified cyclic peptide that exerts antimicrobial effects against Mycobacterium tuberculosis. However, its role in nontuberculous mycobacteria (NTMs) infections has not been clarified. Mycobacteroides abscessus (Mabc) is a rapidly growing NTM that has emerged as a human pathogen in both immunocompetent and immunosuppressed individuals. In this study, we demonstrated that OMS had significant antimicrobial effects against Mabc infection in both immunocompetent and immunodeficient mice, and in macrophages. OMS treatment amplified Mabc-induced expression of M1-related proinflammatory cytokines and inducible nitric oxide synthase, and significantly downregulated arginase-1 expression in murine macrophages. In addition, OMS augmented Mabc-mediated production of mitochondrial reactive oxygen species (mtROS), which promoted M1-like proinflammatory responses in Mabc-infected macrophages. OMS-induced production of mtROS and nitric oxide was critical for OMS-mediated antimicrobial responses during Mabc infections. Notably, the combination of OMS and rifabutin had a synergistic effect on the antimicrobial responses against Mabc infections in vitro, in murine macrophages, and in zebrafish models in vivo. Collectively, these data strongly suggest that OMS may be an effective M1-like adjunctive therapeutic against Mabc infections, either alone or in combination with antibiotics.Y

Gamma-aminobutyric acid type A receptor alpha 4 coordinates autophagy, inflammation, and immunometabolism to promote innate immune activation

Gamma-aminobutyric acid type A receptor (GABAAR), the ionotropic receptor of GABA, is expressed in macrophages and in the nervous system; however, its role in innate immunity is unknown. Herein, we identified myeloid GABAAR subunit α4 (Gabra4) as a critical regulator of autophagy and a promoter of host innate defense during infection and inflammation. Myeloid Gabra4 deficiency led to defective mycobacterial clearance during infection and increased susceptibility to septic shock. Gabra4 deletion exaggerated inflammatory responses and suppressed the activation of autophagy in macrophages upon infectious and inflammatory stimuli. Mechanistically, Gabra4-mediated signaling led to upregulation of autophagy in macrophages via intracellular calcium release and AMP-activated protein kinase (AMPK) signaling activation, which was required for linking autophagy and antimicrobial responses. Additionally, Gabra4 was required to generate mitochondrial reactive oxygen species, thereby triggering autophagy and antimicrobial responses to mycobacteria. Metabolomics analysis showed that Gabra4 was critical for glucose metabolism and aerobic glycolysis in macrophages. Our findings demonstrate that myeloid Gabra4 coordinates autophagy, inflammation, and immunometabolism to promote innate host defense against pathogenic and dangerous stimuli. Abbreviation AM: Alveolar macrophage; AMPK: AMP-activated protein kinase; ASC: Apoptosis-associated speck-like protein containing a CARD; ATP: Adenosine 5’-triphosphate; BAL: Bronchoalveolar lavage; BCG: Mycobacterium bovis Bacillus Calmette–Guérin; BMDM: Bone marrow-derived macrophage; CCL: CC motif chemokine ligand; CFU: Colony forming unit; CKO: Conditional knock out; CXCL: C-X-C motif ligand; Dpi: Days post-infection; ECAR: Extracellular acidification rate; EGFP: Enhanced green fluorescent protein; FOXO3: Forkhead box O3; GABA: Gamma-aminobutyric acid; GABAAR: GABA type A receptor; Gabarap: GABA type A receptor-associated protein; Gabarapl1: GABA type A receptor-associated protein like 1; GABRA4: Gamma-aminobutyric acid type A receptor subunit alpha4; HIF-1α: Hypoxia-inducible factor-1 alpha; IL: Interleukin; i.n.: Intranasal; i.p.: Intraperitoneal; LDHA: Lactate dehydrogenase A; LPS: Lipopolysaccharide; Mabc: Mycobacteroides abscessus subsp. abscessus; MOI: Multiplicities of infection; Mtb: Mycobacterium tuberculosis; mtROS: Mitochondrial reactive oxygen species; OCR: Oxygen consumption rate; OXPHOS: Oxidative phosphorylation; PM: Peritoneal macrophage; TNF: Tumor necrosis factor; WT: Wild typ