{Reference Type}: Clinical Trial, Phase II
{Title}: TGF-β/IFN-γ Antagonism in Subversion and Self-Defense of Phase II Coxiella burnetii-Infected Dendritic Cells.
{Author}: Matthiesen S;Christiansen B;Jahnke R;Zaeck LM;Karger A;Finke S;Franzke K;Knittler MR;
{Journal}: Infect Immun
{Volume}: 91
{Issue}: 2
{Year}: 02 2023 16
{Factor}: 3.609
{DOI}: 10.1128/iai.00323-22
{Abstract}: Dendritic cells (DCs) belong to the first line of innate defense and come into early contact with invading pathogens, including the zoonotic bacterium Coxiella burnetii, the causative agent of Q fever. However, the pathogen-host cell interactions in C. burnetii-infected DCs, particularly the role of mechanisms of immune subversion beyond virulent phase I lipopolysaccharide (LPS), as well as the contribution of cellular self-defense strategies, are not understood. Using phase II Coxiella-infected DCs, we show that impairment of DC maturation and MHC I downregulation is caused by autocrine release and action of immunosuppressive transforming growth factor-β (TGF-β). Our study demonstrates that IFN-γ reverses TGF-β impairment of maturation/MHC I presentation in infected DCs and activates bacterial elimination, predominantly by inducing iNOS/NO. Induced NO synthesis strongly affects bacterial growth and infectivity. Moreover, our studies hint that Coxiella-infected DCs might be able to protect themselves from mitotoxic NO by switching from oxidative phosphorylation to glycolysis, thus ensuring survival in self-defense against C. burnetii. Our results provide new insights into DC subversion by Coxiella and the IFN-γ-mediated targeting of C. burnetii during early steps in the innate immune response.