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Emerging Roles of Autophagy and Inflammasome in Ehrlichiosis
Tyler R Tominello1, Edson R A Oliveira2, Shah S Hussain2
1Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.
Abstract:
Human monocytic ehrlichiosis (HME) is a potentially life-threatening tick-borne rickettsial disease (TBRD) caused by the obligate intracellular Gram-negative bacteria, Ehrlichia. Fatal HME presents with acute ailments of sepsis and toxic shock-like symptoms that can evolve to multi-organ failure and death. Early clinical and laboratory diagnosis of HME are problematic due to non-specific flu-like symptoms and limitations in the current diagnostic testing. Several studies in murine models showed that cell-mediated immunity acts as a "double-edged sword" in fatal ehrlichiosis. Protective components are mainly formed by CD4 Th1 and NKT cells, in contrast to deleterious effects originated from neutrophils and TNF-α-producing CD8 T cells. Recent research has highlighted the central role of the inflammasome and autophagy as part of innate immune responses also leading to protective or pathogenic scenarios. Recognition of pathogen-associated molecular patterns (PAMPS) or damage-associated molecular patterns (DAMPS) triggers the assembly of the inflammasome complex that leads to multiple outcomes. Recognition of PAMPs or DAMPs by such complexes can result in activation of caspase-1 and -11, secretion of the pro-inflammatory cytokines IL-1β and IL-18 culminating into dysregulated inflammation, and inflammatory cell death known as pyroptosis. The precise functions of inflammasomes and autophagy remain unexplored in infections with obligate intracellular rickettsial pathogens, such as Ehrlichia. In this review, we discuss the intracellular innate immune surveillance in ehrlichiosis involving the regulation of inflammasome and autophagy, and how this response influences the innate and adaptive immune responses against Ehrlichia. Understanding such mechanisms would pave the way in research for novel diagnostic, preventative and therapeutic approaches against Ehrlichia and other rickettsial diseases.
Insights
Human monocytic ehrlichiosis (HME) is a dangerous tick-borne illness. This review explores how inflammasomes and autophagy impact immune responses to Ehrlichia, offering insights for new treatments.
Area of Science:
- Infectious Diseases
- Immunology
- Microbiology
Background:
- Human monocytic ehrlichiosis (HME) is a severe tick-borne rickettsial disease (TBRD) caused by Ehrlichia bacteria.
- Fatal HME can lead to sepsis, toxic shock, multi-organ failure, and death, with diagnosis complicated by non-specific symptoms.
- Immune responses, including CD4 Th1, NKT cells, neutrophils, and CD8 T cells, play a complex role in HME outcomes.
Purpose of the Study:
- To review the role of inflammasome and autophagy in innate immune responses during Ehrlichia infections.
- To explore how these innate mechanisms influence both innate and adaptive immunity against Ehrlichia.
- To identify potential targets for novel diagnostic, preventative, and therapeutic strategies against ehrlichiosis and other rickettsial diseases.
Main Methods:
- This review synthesizes current research on inflammasome and autophagy pathways in the context of Ehrlichia infections.
- It discusses the recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).
- The review examines the activation of caspase-1/-11, secretion of IL-1β and IL-18, pyroptosis, and their implications in ehrlichiosis.
Main Results:
- Inflammasome and autophagy are key components of innate immunity in ehrlichiosis, with dual roles in protection and pathogenesis.
- Dysregulated inflammation and pyroptosis are outcomes of inflammasome activation in response to Ehrlichia.
- The precise functions of inflammasomes and autophagy in Ehrlichia infections are not fully understood but are critical.
Conclusions:
- Understanding inflammasome and autophagy regulation in Ehrlichia infections is crucial for developing effective interventions.
- Targeting these innate immune pathways could lead to novel diagnostics and therapeutics for HME and related rickettsial diseases.
- Further research is needed to elucidate the specific mechanisms of inflammasome and autophagy in Ehrlichia pathogenesis.
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