The Role of Central Metabolic Plasticity and Molecular Iron in Coxiella burnetii Intracellular Replication and Pathogenesis

Savannah Elizabeth Sanchez

doi:10.7273/000002391

Coxiella burnetii is a Gram-negative bacterial obligate intracellular parasite (BOIP) and the cause of Query (Q) fever. Q fever typically manifests as an acute, self-limiting febrile illness; however, ~1–5% of infected individuals develop chronic Q fever that can lead to severe diseases (e.g., hepatitis and endocarditis). Many BOIPs are host-specific, nutrient parasites as a consequence of preferential loss in metabolic genes during a hallmark parasitic lifestyle process of genome streamlining. The relatively reduced C. burnetii genome (i.e., ~2 Mb) encodes for a near complete central metabolic machinery and the pathogen naturally infects a broad range of host organisms (e.g., mammals and arthropods) and cell types. This amphotropic nature of C. burnetii, in combination with its ability to utilize both glycolytic and gluconeogenic substrates, suggests that the pathogen relies on metabolic plasticity to replicate in nutritionally diverse intracellular environments. While infecting a broad range of host cell types, C. burnetii exhibits tropism for tissues directly involved in iron storage and recycling (e.g., the liver and splenic red pulp) during natural infections. Cultured host cells infected with C. burnetii were shown to increase expression of transferrin receptors, suggesting a demand for iron, a micronutrient reported to have a limited role in C. burnetii virulence regulation. Despite a near complete central metabolic machinery the oxidative branch of the pentose phosphate pathway (oxPPP), a major mechanism for regeneration of the reducing equivalent NADPH, appears dispensable to C. burnetii. The absence of genes related to this pathway have been suggested as a metabolic limitation of C. burnetii and explanation for its slow growth rate. Elucidating the metabolic potential (i.e., metabolic strategies, adaptations, and limitations) of bacterial pathogens deepens our understanding of their physiology and provides important insight into bacterial pathogenesis. This work aims to investigate the metabolic potential of C. burnetii as it relates to plasticity in central metabolism, the utilization of molecular iron, and the absence of the oxPPP using both in vitro (i.e., a combination of host cell and axenic (host cell-free) techniques) and in vivo (i.e., the Drosophila melanogaster animal model for C. burnetii infection) models.

The Role of Central Metabolic Plasticity and Molecular Iron in Coxiella burnetii Intracellular Replication and Pathogenesis

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