Clinician Assessment for<i>Coxiella burnetii</i>Infection in Hospitalized Patients with Potentially Compatible Illnesses During Q Fever Outbreaks and Following a Health Alert, Montana, 2011

Nett, Randall J.; Helgerson, Steven D.; Anderson, Alicia D.

doi:10.1089/vbz.2012.1007

Cited by 4 publications

(3 citation statements)

References 9 publications

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Section: Introductionmentioning

confidence: 99%

Coxiella burnetii-containing vacuoles interact with host recycling-endosomal proteins Rab11a and Rab35 for vacuolar expansion

Hall,

Senior,

Ocampo

et al. 2024

Preprint

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Coxiella burnetiiis a gram-negative obligate intracellular bacterium and a zoonotic pathogen that causes human Q fever. Although acute Q fever manifests as atypical pneumonia, chronic infection may lead to life-threatening endocarditis. The lack of effective antibiotics and a licensed vaccine forCoxiellain the U.S. warrants further research intoCoxiellapathogenesis. Within the host cells,Coxiellareplicates in an acidic phagolysosome-like vacuole termedCoxiella-containing vacuole (CCV). Previously, we have shown that the CCV pH is critical forCoxiellasurvival and that theCoxiellaType 4B secretion system regulates CCV pH by inhibiting the host endosomal maturation pathway. However, the trafficking pattern of the ‘immature’ endosomes inCoxiella-infected cells remained unclear. Our recent CCV localization screen with host Rab proteins revealed that recycling endosome-associated proteins Rab11a and Rab35 localize to the CCV during infection, suggesting that CCV interacts with host recycling endosomes during maturation. Interestingly, only a subset of CCVs were Rab11a or Rab35-positive at any given time point. A quantitation of Rab11a/Rab35-positive CCVs at 3- and 6-days post-infection (dpi) revealed that at 3 dpi, ∼52% of CCVs were positive for Rab11a, whereas only ∼39% CCVs were positive for Rab35. This pattern reversed at 6-dpi, when only ∼22% of CCVs were positive for Rab11a and ∼64% of CCVs were positive for Rab35. These data suggest that the CCV preferentially interacts with Rab11a and Rab35-positive recycling endosomes depending on the stage of maturation. Furthermore, we observed a significant increase in Rab11a and Rab35 fluorescent intensity inCoxiella-infected cells compared to mock cells suggesting thatCoxiellaincreases the recycling endosome content in infected cells. Finally, a siRNA-mediated knockdown of both Rab11a and Rab35 resulted in significantly smaller CCVs, suggesting that recycling endosomal Rab proteins are essential for CCV expansion. Overall, our data, for the first time, show that the CCV dynamically interacts with host recycling endosomes for vacuolar expansion and potentially uncovers novel host cell factors essential forCoxiellapathogenesis.

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Section: Introductionmentioning

confidence: 99%

Coxiella burnetii-containing vacuoles interact with host recycling-endosomal proteins Rab11a and Rab35 for vacuolar expansion

Hall,

Senior,

Ocampo

et al. 2024

Preprint

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“…The treatment plan for chronic Q fever involves an 18-month-long combined antibiotic therapy and currently, there is no Q fever vaccine licensed in the U.S., presenting challenges in both treating and preventing the disease. Q fever has emerged as a significant public health concern worldwide ( Lyytikainen et al., 1998 ; Amitai et al., 2010 ; Porter et al., 2011 ; Nett et al., 2013 ; White et al., 2013 ; Angelakis et al., 2014 ; Bjork et al., 2014 ; Eldin et al., 2014 ; Alonso et al., 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Coxiella burnetii-containing vacuoles interact with host recycling endosomal proteins Rab11a and Rab35 for vacuolar expansion and bacterial growth

Hall,

Senior,

Ocampo

et al. 2024

Front. Cell. Infect. Microbiol.

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IntroductionCoxiella burnetii is a gram-negative obligate intracellular bacterium and a zoonotic pathogen that causes human Q fever. The lack of effective antibiotics and a licensed vaccine for Coxiella in the U.S. warrants further research into Coxiella pathogenesis. Within the host cells, Coxiella replicates in an acidic phagolysosome-like vacuole termed Coxiella-containing vacuole (CCV). Previously, we have shown that the CCV pH is critical for Coxiella survival and that the Coxiella Type 4B secretion system regulates CCV pH by inhibiting the host endosomal maturation pathway. However, the trafficking pattern of the ‘immature’ endosomes in Coxiella- infected cells remained unclear.MethodsWe transfected HeLa cells with GFP-tagged Rab proteins and subsequently infected them with mCherry-Coxiella to visualize Rab protein localization. Infected cells were immunostained with anti-Rab antibodies to confirm the Rab localization to the CCV, to quantitate Rab11a and Rab35- positive CCVs, and to quantitate total recycling endosome content of infected cells. A dual-hit siRNA mediated knockdown combined with either immunofluorescent assay or an agarose-based colony-forming unit assay were used to measure the effects of Rab11a and Rab35 knockdown on CCV area and Coxiella intracellular growth.ResultsThe CCV localization screen with host Rab proteins revealed that recycling endosome-associated proteins Rab11a and Rab35 localize to the CCV during infection, suggesting that CCV interacts with host recycling endosomes during maturation. Interestingly, only a subset of CCVs were Rab11a or Rab35-positive at any given time point. Quantitation of Rab11a/Rab35-positive CCVs revealed that while Rab11a interacts with the CCV more at 3 dpi, Rab35 is significantly more prevalent at CCVs at 6 dpi, suggesting that the CCV preferentially interacts with Rab11a and Rab35 depending on the stage of infection. Furthermore, we observed a significant increase in Rab11a and Rab35 fluorescent intensity in Coxiella-infected cells compared to mock, suggesting that Coxiella increases the recycling endosome content in infected cells. Finally, siRNA-mediated knockdown of Rab11a and Rab35 resulted in significantly smaller CCVs and reduced Coxiella intracellular growth, suggesting that recycling endosomal Rab proteins are essential for CCV expansion and bacterial multiplication.DiscussionOur data, for the first time, show that the CCV dynamically interacts with host recycling endosomes for Coxiella intracellular survival and potentially uncovers novel host cell factors essential for Coxiella pathogenesis.

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“…Further, the only vaccine available for humans is licensed exclusively in Australia due to reactivity issues [10]. Between 2007 and 2010, the Netherlands experienced a large Q fever outbreak with more than 40,000 individuals infected [11], with smaller outbreaks occurring in the US [12][13][14], Spain [15], Australia [15], Japan [16] and Israel [17]. These outbreaks exemplify how expansive C. burnetii is globally, but the scarcity of prevention and treatment options is due to our lack of understanding of C. burnetii pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Coxiella burnetiiactively blocks IL-17-induced oxidative stress in macrophages

Clemente

Augusto

Angara

et al. 2023

Preprint

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Coxiella burnetii is a highly infectious pathogen that causes Q fever, a leading cause of culture-negative endocarditis. Coxiella first targets alveolar macrophages and forms a phagolysosome-like compartment called the Coxiella-Containing Vacuole (CCV). Successful host cell infection requires the Type 4B Secretion System (T4BSS), which translocates bacterial effector proteins across the CCV membrane into the host cytoplasm, where they manipulate numerous cell processes. Our prior transcriptional studies revealed that Coxiella T4BSS blocks IL-17 signaling in macrophages. Given that IL-17 is known to protect against pulmonary pathogens, we hypothesize that C. burnetii T4BSS downregulates intracellular IL-17 signaling to evade the host immune response and promote bacterial pathogenesis. Using a stable IL-17 promoter reporter cell line, we confirmed that Coxiella T4BSS blocks IL-17 transcription activation. Assessment of the phosphorylation state of NF-κB, MAPK, and JNK revealed that Coxiella downregulates IL-17 activation of these proteins. Using ACT1 knockdown and IL-17RA or TRAF6 knockout cells, we next determined that IL17RA-ACT1-TRAF6 pathway is essential for the IL-17 bactericidal effect in macrophages. In addition, macrophages stimulated with IL-17 generate higher levels of reactive oxygen species, which is likely connected to the bactericidal effect of IL-17. However, C. burnetii T4SS effector proteins block the IL-17-mediated oxidative stress, suggesting that Coxiella blocks IL-17 signaling to avoid direct killing by the macrophages.

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Clinician Assessment forCoxiella burnetiiInfection in Hospitalized Patients with Potentially Compatible Illnesses During Q Fever Outbreaks and Following a Health Alert, Montana, 2011

Abstract: Clinicians should assess for Q fever risk factors and consider the diagnosis in patients hospitalized with Q fever-compatible illnesses when the etiology of illness is unknown. Work is warranted to evaluate the effectiveness of current healthcare alert practices for zoonotic diseases.

Cited by 4 publications

References 9 publications

Coxiella burnetii-containing vacuoles interact with host recycling-endosomal proteins Rab11a and Rab35 for vacuolar expansion

Coxiella burnetii-containing vacuoles interact with host recycling-endosomal proteins Rab11a and Rab35 for vacuolar expansion

Coxiella burnetii-containing vacuoles interact with host recycling endosomal proteins Rab11a and Rab35 for vacuolar expansion and bacterial growth

Coxiella burnetiiactively blocks IL-17-induced oxidative stress in macrophages

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