Whole Blood Interferon γ Release Is a More Sensitive Marker of Prior Exposure to Coxiella burnetii Than Are Antibody Responses

Abstract

For the zoonotic disease Q fever, serological analysis plays a dominant role in the diagnosis of Coxiella burnetii infection and in pre-screening for past exposure prior to vaccination. A number of studies suggest that assessment of C. burnetii-specific T-cell IFNγ responses may be a more sensitive tool to assess past exposure. In this study, we assessed the performance of a whole blood C. burnetii IFNγ release assay in comparison to serological detection in an area of high Q fever incidence in 2014, up to seven years after initial exposure during the Dutch Q fever outbreak 2007-2010. In a cohort of >1500 individuals from the Dutch outbreak village of Herpen, approximately 60% had mounted IFNγ responses to C. burnetii. This proportion was independent of the Coxiella strain used for stimulation and much higher than the proportion of individuals scored sero-positive using the serological gold standard immunofluorescence assay. Moreover, C. burnetii-specific IFNγ responses were found to be more durable than antibody responses in two sub-groups of individuals known to have sero-converted as of 2007 or previously reported to the municipality as notified Q fever cases. A novel ready-to-use version of the IFNγ release assay assessed in a subgroup of pre-exposed individuals in 2021 (10-14 years post exposure) proved again to be more sensitive than serology in detecting past exposure. These data demonstrate that C. burnetii-induced IFNγ release is indeed a more sensitive and durable marker of exposure to C. burnetii than are serological responses. In combination with a simplified assay version suitable for implementation in routine diagnostic settings, this makes the assessment of IFNγ responses a valuable tool for exposure screening to obtain epidemiological data, and to identify previously exposed individuals in pre-vaccination screens.

Natural Exposure- and Vaccination-Induced Profiles of Ex Vivo Whole Blood Cytokine Responses to Coxiella burnetii

“…Samples from n=98 de-identified adult blood bank donors from the Amsterdam/Rotterdam area (The Netherlands) with unknown prior exposure to C. burnetii were obtained in November 2020 from the Sanquin Blood bank ( Table 1 ) ( 24 ).…”

“…unknown prior exposure to C. burnetii were obtained in November 2020 from the Sanquin Blood bank (Table 1) (24).…”

Recent Advances on the Innate Immune Response to Coxiella burnetii

“…Recently, it has been reported that C. burnetii -specific T-cell IFN-γ release may represent a sensitive and long-lasting marker of past C. burnetii exposure ( Scholzen et al., 2021 ). The evaluation of cell-mediated responses to Coxiella through IFN-γ release assay (IGRA) could be very useful to detect past infections, since cellular response persists also in sero- and skin test-negative individuals ( Schoffelen et al., 2014a ; Schoffelen et al., 2013 ; Scholzen et al., 2021 ).…”

“…Recently, it has been reported that C. burnetii -specific T-cell IFN-γ release may represent a sensitive and long-lasting marker of past C. burnetii exposure ( Scholzen et al., 2021 ). The evaluation of cell-mediated responses to Coxiella through IFN-γ release assay (IGRA) could be very useful to detect past infections, since cellular response persists also in sero- and skin test-negative individuals ( Schoffelen et al., 2014a ; Schoffelen et al., 2013 ; Scholzen et al., 2021 ). It is still unknown which fraction of C. burnetii is responsible for IFN-γ release, but reported data show the existence of some immunodominant-specific peptides from its proteins that are recognized in IGRA-positive when compared with IGRA-negative subjects.…”

“…Some endotoxins can also induce IFN-γ release from T and NK cells, probably mediated by monocytes, activated by Coxiella LPS, endothelial cells, and other cytokines ( Le et al., 1986 ; Tennenberg and Weller, 1996 ; Lauw et al., 2000 ). Among T cells, preliminary data ( Scholzen et al., 2021 ) indicate CD4 + cells as the major source of IFN-γ, followed by CD8 + T cells.…”