Coxiella burnetii inhibits nuclear translocation of TFEB, the master transcription factor for lysosomal biogenesis.

Coxiella burnetii is a highly infectious, Gram-negative, obligate intracellular bacterium and the causative agent of human Q fever. The Coxiella Containing Vacuole (CCV) is a modified phagolysosome that forms through fusion with host endosomes and lysosomes. While an initial acidic pH < 4.7 is essential to activate Coxiella metabolism, the mature, growth-permissive CCV has a luminal pH of ~5.2 that remains stable throughout infection. Inducing CCV acidification to a lysosomal pH (~4.7) causes Coxiella degradation, suggesting that Coxiella regulates CCV pH. Supporting this hypothesis, Coxiella blocks host lysosomal biogenesis, leading to fewer host lysosomes available to fuse with the CCV. Host cell lysosome biogenesis is primarily controlled by the transcription factor EB (TFEB), which binds Coordinated Lysosomal Expression And Regulation (CLEAR) motifs upstream of genes involved in lysosomal biogenesis and function. TFEB is a member of the microphthalmia/transcription factor E (MiT/TFE) protein family, which also includes MITF, TFE3, and TFEC. This study examines the roles of MiT/TFE proteins during Coxiella infection. We found that in cells lacking TFEB, both Coxiella growth and CCV size increase. Conversely, TFEB overexpression or expression in the absence of other family members leads to significantly less bacterial growth and smaller CCVs. TFE3 and MITF do not appear to play a significant role during Coxiella infection. Surprisingly, we found that Coxiella actively blocks TFEB nuclear translocation in a Type IV Secretion System-dependent manner, thus decreasing lysosomal biogenesis. Together, these results suggest that Coxiella inhibits TFEB nuclear translocation to limit lysosomal biogenesis, thus avoiding further CCV acidification through CCV-lysosomal fusion. IMPORTANCE: The obligate intracellular bacterial pathogen Coxiella burnetii causes the zoonotic disease Q fever, which is characterized by a debilitating flu-like illness in acute cases and life-threatening endocarditis in patients with chronic disease. While Coxiella survives in a unique lysosome-like vacuole called the Coxiella Containing Vacuole (CCV), the bacterium inhibits lysosome biogenesis as a mechanism to avoid increased CCV acidification. Our results establish that transcription factor EB (TFEB), a member of the microphthalmia/transcription factor E (MiT/TFE) family of transcription factors that regulate lysosomal gene expression, restricts Coxiella infection. Surprisingly, Coxiella blocks TFEB translocation from the cytoplasm to the nucleus, thus downregulating the expression of lysosomal genes. These findings reveal a novel bacterial mechanism to regulate lysosomal biogenesis.

Tick abundance and infection with three zoonotic bacteria are heterogeneous in a Belgian peri-urban forest.

Ixodes ricinus is a vector of several pathogens of public health interest. While forests are the primary habitat for I. ricinus, its abundance and infection prevalence are expected to vary within forest stands. This study assesses the spatio-temporal variations in tick abundance and infection prevalence with three pathogens in and around a peri-urban forest where human exposure is high. Ticks were sampled multiple times in 2016 and 2018 in multiple locations with a diversity of undergrowth, using the consecutive drags method. Three zoonotic pathogens were screened for, Borrelia burgdorferi s.l., Coxiella burnetii, and Francisella tularensis. The influence of season, type of site and micro-environmental factors on tick abundance were assessed with negative binomial generalized linear mixed-effects models. We collected 1642 nymphs and 181 adult ticks. Ticks were most abundant in the spring, in warmer temperatures, and where undergrowth was higher. Sites with vegetation unaffected by human presence had higher abundance of ticks. Forest undergrowth type and height were significant predictors of the level of tick abundance in a forest. The consecutive drags method is expected to provide more precise estimates of tick abundance, presumably through more varied contacts with foliage. Borrelia burgdorferi s.l. prevalence was estimated from pooled ticks at 5.33%, C. burnetii was detected in six pools and F. tularensis was not detected. Borrelia afzelii was the dominant B. burgdorferi genospecies. Tick abundance and B. burgdorferi s.l. infection prevalence were lower than other estimates in Belgian forests.

Fiebre Q: todavía muchas preguntas por resolver / Q fever: still many unanswered questions

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