Inflammasomes, Autophagy, and Cell Death: The Trinity of Innate Host Defense against Intracellular Bacteria

Abstract

Inflammasome activation is an innate host defense mechanism initiated upon sensing pathogens or danger in the cytosol. Both autophagy and cell death are cell autonomous processes important in development, as well as in host defense against intracellular bacteria. Inflammasome, autophagy, and cell death pathways can be activated by pathogens, pathogen-associated molecular patterns (PAMPs), cell stress, and host-derived damage-associated molecular patterns (DAMPs). Phagocytosis and toll-like receptor (TLR) signaling induce reactive oxygen species (ROS), type I IFN, NFκB activation of proinflammatory cytokines, and the mitogen-activated protein kinase cascade. ROS and IFNγ are also prominent inducers of autophagy. Pathogens, PAMPs, and DAMPs activate TLRs and intracellular inflammasomes, inducing apoptotic and inflammatory caspases in a context-dependent manner to promote various forms of cell death to eliminate pathogens. Common downstream signaling molecules of inflammasomes, autophagy, and cell death pathways interact to initiate appropriate measures against pathogens and determine host survival as well as pathological consequences of infection. The integration of inflammasome activation, autophagy, and cell death is central to pathogen clearance. Various pathogens produce virulence factors to control inflammasomes, subvert autophagy, and modulate host cell death in order to evade host defense. This review highlights the interaction of inflammasomes, autophagy, and host cell death pathways in counteracting Burkholderia pseudomallei, the causative agent of melioidosis. Contrasting evasion strategies used by B. pseudomallei, Mycobacterium tuberculosis, and Legionella pneumophila to avoid and dampen these innate immune responses will be discussed.

Necroptosis: a crucial pathogenic mediator of human disease

“…The necroptosis pathway has been implicated as both an adaptive and pathogenic component of many human pathologies that involve inflammatory processes, including atherosclerosis, cardiac ischemia/reperfusion (I/R) injury, sepsis, inflammatory bowel disease, and neurodegenerative diseases (7)(8)(9)13). Necroptosis has also emerged as an instrument of innate immunity during infectious diseases and is considered a protective mode of cell death that eliminates pathogen-infected cells (10,14). Furthermore, necroptosis activation is an integral component of autoimmune and autoinflammatory diseases (15,16) and may also contribute to the pathogenesis of genetic diseases, such as Duchenne's muscular dystrophy and lysosomal storage disorders (17,18).…”

Deficiency in the autophagy modulator Dram1 exacerbates pyroptotic cell death of Mycobacteria-infected macrophages

“…This is especially true for tuberculosis (TB), the most lethal infectious disease worldwide. The causative agents of human TB or TBlike disease in poikilothermic animals, Mycobacterium tuberculosis (Mtb) and Mycobacterium marinum (Mm), are widely studied to increase understanding of the role of autophagy in host defense 3,[6][7][8][9][10] .…”

Innate Immunity and Neuroinflammation in Neuropsychiatric Conditions Including Autism Spectrum Disorders: Role of Innate Immune Memory

“…Since the existence of the immune system was recognized more than 50 years ago, the immune system has been thought to be comprised of two components, innate immunity and adaptive immunity. Innate immunity is the arm that mounts nonspecific, acute immune responses, by sensing microbial by-products called pathogen-associated molecular patterns (PAMPs) or by-products derived from tissue injuries called damage-associated molecular patterns (DAMPs) [5]. Signaling through PAMPs and DAMPs are thought to play a major role in plant immunity [6].…”