Fig 1.
Coxiella burnetii: A model system to study host–pathogen interaction and zoonotic infectious diseases.
Technological advances in the field of C. burnetii research, including the development of axenic media, availability of virulent and attenuated strains for laboratory research, in silico and experimental tools to predict and functionally characterize T4SS-secreted effectors (SecReT4, DeepSecE, T4SEpp) [92–94], enhanced genetic toolkit [21–24,88,89,95,96] and other resources (example: CoxBase) [97], as listed on the right panel, have facilitated better understanding of interaction between host and C. burnetii at a molecular, cellular, and organism level. Bottom panel depicts some of the experimental host systems employed, including, epithelial cells/ fibroblasts, macrophages of different animal origins, Drosophila melanogaster, Caenorhabditis elegans, Galleria mellonella, wildtype and SCID mice, guinea pigs, human ex vivo lung model, and non-human primates. These models are characterized by a spectrum of advantages and limitations, as highlighted by green and red text, respectively. These developments are expected to promote modeling of zoonotic disease biology in natural hosts (top panel) and research efforts in several key focus areas including dysregulation of lysosome biology by pathogens, placental immunity [98], effector functions, molecular mechanisms underlying chronic sequelae, environmental stability of Coxiella, impact of rising climate change, and vaccine development (left panel). Created with Biorender.com.
Fig 2.
Factors promoting or restricting Coxiella burnetii infection.
Development of bacterial replication-permissive, lysosome-derived compartment and intracellular bacterial proliferation (shown in the central boxed panel) is supported by the Coxiella T4SS and the translocation of numerous effectors into the host cell, M2 transcriptional program including upregulation of immunosuppressive cytokines TGF-β and IL-10, autophagy, and host anti-oxidative mechanisms. Further, the smooth LPS variants produced by the C. burnetii NMI strain mask the bacterial surface lipoproteins and prevent TLR2 activation, thus inhibiting pathogen sensing in the host and allowing the establishment of disease. At the same time, the host restricts Coxiella through activation of innate, adaptive, and cell-autonomous immune mechanisms including multiple pathogen recognition receptor-based pathways, activation of T and NK cells, secretion of pro-inflammatory cytokines, especially IFNγ, TNF, and IL-17, production of ROS and RNS, activation of the M1 program in macrophages, tryptophan depletion, production of itaconate, expression of STX11, antimicrobial peptide production, hypoxic conditions, and apoptosis. MiT/TFE family of transcription factors regulate Coxiella vacuole biogenesis and intracellular bacterial replication and the precise contribution of each, in promoting or restricting different stages of infection, requires further investigation. Central Boxed panel: Immunofluorescent images of TPA-differentiated THP1 cells infected with C. burnetii NMII for 3 days and fixed with 4% PFA. LAMP1, lysosome-associated membrane protein-1; TPA: 12-O-tetradecanoylphorbol-13-acetate; THP1: human monocyte cell line. Figure created with Biorender.com. Credit for immunofluorescent images in the central boxed panel: Ms. Amrita Bhattacharya, IISER Thiruvananthapuram.