Synergic effect of combined intervention with clindamycin and PPARγ agonist in an HLA-II mouse model of Group A Streptococcal Necrotizing Fasciitis

Abstract

Abstract Group A Streptococcus (GAS, Streptococcus pyogenes) is an important human pathogen that can cause a broad spectrum of diseases ranging from self-limiting pharyngitis and impetigo to deeper, life-threatening invasive infections such as streptococcal toxic shock syndrome and necrotizing fasciitis (NF). An overarching pro-inflammatory cytokine storm and a rapidly progressive tissue destruction lead to significant morbidity and lethal outcomes of GAS NF. Transcriptome profiling of uninfected and GAS infected skin from HLA-II transgenic mouse models of GAS NF revealed strong activation of inflammatory signaling and inhibition of peroxisome proliferator-activated receptor (PPAR) signaling pathways. Specifically, PPARgamma (PPARγ), a lipid ligand-activated transcription factor driving adipogenic and anti-inflammatory effects, was a significantly inhibited upstream regulator and this inhibition was reflected in downregulation of PPARγ-dependent genes. So far, there are no reports on the role of PPARγ in GAS infections. Here, we explored the potential use of the PPARγ selective synthetic agonist, pioglitazone (PZ), in combination with clindamycin (CLN), as a combined therapeutic approach in vivo in an HLA-II mouse model of GAS NF. Although the mechanism of synergy is not understood, our data demonstrate that combined CLN PZ intervention offers significant advantages over treatment with CLN alone, and uncover a new role for PPARγ in attenuating skin lesions, GAS burden, IL-6 and IFN-γ levels, and weight loss during GAS NF. To our knowledge, this is the first report to demonstrate the benefits of a combined host- and pathogen-directed treatment approach to ameliorate severity and inflammation during GAS NF.