Dysregulation of Serum Gamma Interferon Levels in Vascular Chronic Q Fever Patients Provides Insights into Disease Pathogenesis

Abstract

f A large community outbreak of Q fever occurred in the Netherlands in the period 2007 to 2010. Some of the infected patients developed chronic Q fever, which typically includes pathogen dissemination to predisposed cardiovascular sites, with potentially fatal consequences. To identify the immune mechanisms responsible for ineffective clearance of Coxiella burnetii in patients who developed chronic Q fever, we compared serum concentrations of 47 inflammation-associated markers among patients with acute Q fever, vascular chronic Q fever, and past resolved Q fever. Serum levels of gamma interferon were strongly increased in acute but not in vascular chronic Q fever patients, compared to past resolved Q fever patients. Interleukin-18 levels showed a comparable increase in acute as well as vascular chronic Q fever patients. Additionally, vascular chronic Q fever patients had lower serum levels of gamma interferon-inducible protein 10 (IP-10) and transforming growth factor ␤ (TGF-␤) than did acute Q fever patients. Serum responses for these and other markers indicate that type I immune responses to C. burnetii are affected in chronic Q fever patients. This may be attributed to an affected immune system in cardiovascular patients, which enables local C. burnetii replication at affected cardiovascular sites.

Adjuvanting Coxevac® with QuilA® skews Coxiella burnetii-induced inflammatory responses towards a sustained Th1-CD8+-mediated activation and increases protection in an experimental goat model

“…During C. burnetii infection, IP10 is strongly induced by IFNγ and its expression is increased in infected mice, as a model of acute Q Fever [70][71][72] . By contrast, in patients with chronic Q Fever, IP10 expression is downregulated 73,74 . In our study, IP10 was part of the transcriptional cluster which included genes more expressed in the spleen or in bronchial lymph-nodes of the QuilA®-Coxevac® group.…”

QuilA® adjuvanted Coxevac® sustains Th1-CD8+-type immunity and increases protection in Coxiella burnetii-challenged goats

“…During C. burnetii infection, IP10 is strongly induced by IFNγ and its expression is increased in infected mice, as a model of acute Q fever 65 – 67 . By contrast, in patients with chronic Q fever, IP10 expression is downregulated 68 , 69 . The co-clustering of IP10, TBX21 and TRGC2 genes suggests the involvement of IFNγ-producing γδ T cells after challenge in this group.…”

Natural genetic variation inDrosophila melanogasterreveals genes associated withCoxiella burnetiiinfection

“…We found that multiple genes within the decapentaplegic (DPP) pathway, which is homologous to the TGF-β pathway in mammals ( Gelbart 1989 ) were associated with susceptibility to infection. Similarly, we identified Rho GEFs and TGF-β, which are associated with the development of the Coxiella -containing vacuole and pathogenesis in humans, respectively ( Benoit et al 2008a , 2008b ; Aguilera et al 2009 ; Pennings et al 2015 ; Salinas et al 2015 ; Weber et al 2016 ). Importantly, all the candidate genes identified here have mammalian orthologs or highly conserved functions that allow for extrapolation to mammalian systems.…”