Biology subjects

Sachan, M.

Publications and source records attributed to Sachan, M..

3 recordsLinked to original sources

bioRxiv2025

Coxiella burnetii strains elicit distinct inflammatory responses in human macrophages

Coxiella burnetii, the causative agent of human Q fever, subverts macrophage antimicrobial functions to establish an intracellular replicative niche. To better understand the host-pathogen interactions, we investigated the transcriptional responses of human alveolar macrophages (hAMs) infected with virulent (NMI, G), attenuated (NMII), and avirulent (Dugway) strains of C. burnetii. RNA sequencing analysis revealed that all strains activated proinflammatory pathways, particularly IL-17 signaling, though the magnitude and nature of the response varied by strain. Dugway infection induced the most robust transcriptional response and consistent M1-like macrophage polarization, while responses to NMI and NMII were more variable. Cytokine assays confirmed significant secretion of effectors downstream of IL-17 signaling, but only at later stages of infection. Single-cell RNA sequencing further revealed heterogeneity in macrophage response to C. burnetii infection, with distinct subpopulations exhibiting divergent inflammatory profiles. These findings highlight the complexity of macrophage responses to C. burnetii and underscore the importance of strain-specific and cell-specific factors in shaping host immunity. Understanding these dynamics may inform the development of targeted therapies for Q fever.

microbiology↗

bioRxiv2022

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.

microbiology↗

bioRxiv2020

Ticks convert pathogenic Coxiella into endosymbionts

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 is the etiological agent of human Q fever and uncharacterized coxiellae cause infections in 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 ancestor of CLEOA and C. burnetii was equipped to infect macrophages, and that even though 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 analogs is a promising approach to controlling C. burnetii infections.

microbiology↗