MicroRNAs Contribute to the Host Response to Coxiella burnetii

MicroRNAs (miRNAs), a class of small non-coding RNAs, are critical to gene regulation in eukaryotes. They are involved in modulating a variety of physiological processes, including the host response to intracellular infections. Little is known about miRNA functions during infection by Coxiella burnetii, the causative agent of human Q fever. This bacterial pathogen establishes a large replicative vacuole within macrophages by manipulating host processes such as apoptosis and autophagy. We investigated miRNA expression in C. burnetii-infected macrophages and identified several miRNAs that were down- or up-regulated during infection. We further explored the functions of miR-143-3p, an miRNA whose expression is down-regulated in macrophages infected with C. burnetii, and show that increasing the abundance of this miRNA in human cells results in increased apoptosis and reduced autophagy – conditions that are unfavorable to C. burnetii intracellular growth. In sum, this study demonstrates that C. burnetii infection elicits a robust miRNA-based host response, and because miR-143-3p promotes apoptosis and inhibits autophagy, down-regulation of miR-143-3p expression during C. burnetii infection likely benefits the pathogen

Exploring miRNA Function and Host Response to \u3ci\u3eCoxiella burnetii\u3c/i\u3e Infection

Alveolar macrophages attempt to control bacterial infection through a spectrum of defense processes, including induction of apoptosis, autophagy, inflammatory response, and nutrient sequestration. MicroRNAs (miRNAs), a class of small non-coding RNAs, are involved in a spectrum of physiological processes, including immune response to intracellular infections. However, whether microRNAs have any functions in host response to Coxiella burnetii infection is unknown. Coxiella burnetii is a highly infectious intracellular pathogen that causes Q fever, a zoonosis with a worldwide occurrence. In this work, I investigated the functions of miRNAs in host response to C. burnetii infection and found that miRNAs are an integral component of macrophages\u27 stage-specific response to C. burnetii infection, and inhibition of miR-143-3p likely facilitates the pathogen\u27s intracellular growth. I also examined how different isolates of C. burnetii impact host inflammatory responses, and using single-cell analysis discovered that certain subpopulations of infected macrophages are likely more pathogen friendly than others. Additionally, I determined that gallium-protoporphyrin IX (GaPPIX), a heme analog, inhibits C. burnetii\u27s axenic and intracellular growth, and could potentially be used as a therapeutic agent. Together, these results could contribute to the development of novel miRNA- or GaPPIX-based therapeutic agents and could be applied to better understand the virulence strategies of other intracellular pathogens

\u3ci\u3eCoxiella Burnetii\u3c/i\u3e and Related Tick Endosymbionts Evolved from Pathogenic Ancestors

Both symbiotic and pathogenic bacteria in the family Coxiellaceae cause morbidity and mortality in humans and animals. For instance, Coxiella-like endosymbionts (CLEs) improve the reproductive success of ticks—a major disease vector, while Coxiella burnetii causes human Q fever, and uncharacterized coxiellae infect both animals and humans. To better understand the evolution of pathogenesis and symbiosis in this group of intracellular bacteria, we sequenced the genome of a CLE present in the soft tick Ornithodoros amblus (CLEOA) and compared it to the genomes of other bacteria in the order Legionellales. Our analyses confirmed that CLEOA is more closely related to C. burnetii, the human pathogen, than to CLEs in hard ticks, and showed that most clades of CLEs contain both endosymbionts and pathogens, indicating that several CLE lineages have evolved independently from pathogenic Coxiella. We also determined that the last common ancestorof CLEOA and C. burnetii was equipped to infect macrophages and that even though horizontal gene transfer (HGT) contributed significantly to the evolution of C. burnetii, most acquisition events occurred primarily in ancestors predating the CLEOA–C. burnetii divergence. These discoveries clarify the evolution of C. burnetii, which previously was assumed to have emerged when an avirulent tick endosymbiont recently gained virulence factors via HGT. Finally, we identified several metabolic pathways, including heme biosynthesis, that are likely critical to the intracellular growth of the human pathogen but not the tick symbiont, and show that the use of heme analog is a promising approach to controlling C. burnetii infections