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One major challenge to studying human microbiome and its associated diseases is the lack of effective tools to achieve targeted modulation of individual species and study its ecological function within multispecies communities. Here, we show that C16G2, a specifically targeted antimicrobial peptide, was able to selectively kill cariogenic pathogen Streptococcus mutans with high efficacy within a human saliva-derived in vitro oral multispecies community. Importantly, a significant shift in the overall microbial structure of the C16G2-treated community was revealed after a 24-h recovery period: several bacterial species with metabolic dependency or physical interactions with S. mutans suffered drastic reduction in their abundance, whereas S. mutans' natural competitors, including health-associated Streptococci, became dominant. This study demonstrates the use of targeted antimicrobials to modulate the microbiome structure allowing insights into the key community role of specific bacterial species and also indicates the therapeutic potential of C16G2 to achieve a healthy oral microbiome.

The myeloid-specific transcription factor, CCAAT/enhancer-binding protein ζ(C/EBPζ) is a critical mediator of myelopoiesis. Mutation of this gene is responsible for neutrophil-specific granule deficiency in humans, a condition that confers susceptibility to Staphylococcus aureus infection. We found that C/EBP ζ-deficient mice are severely affected by infection with S. aureus, and C/EBP ζ deficiency in neutrophils contributes to the infectious phenotype. Conversely, exposure to the epigenetic modulator nicotinamide (vitamin B3) increased expression of C/EBPζin WT myeloid cells. Further, nicotinamide increased the activity of C/EBPζand select downstream antimicrobial targets, particularly in neutrophils. In a systemic murine infection model as well as in murine and human peripheral blood, nicotinamide enhanced killing of S. aureus by up to 1,000 fold but no effect when administered to either C/EBP ζ-deficient mice or mice depleted of neutrophils. Nicotinamide was efficacious in both prophylactic and therapeutic settings. Our findings suggest that C/EBP ζis an important target to boost killing of bacteria by the innate immune system., Introduction Staphylococcus aureus in community and health care settings commonly causes serious and potentially life-threatening infections (1-3). Widespread use of antibiotics is responsible for the emergence and rapid spread of [...]

Research reveals that the phase variation associated growth characteristics are not connected to the loss of pilation in Bartonella henselae. However, they may be related to the variation in outer membrane protein expression and genotype. B. henselae characteristically form biofilms and exhibit putative type IV pili.

One major challenge to studying human microbiome and its associated diseases is the lack of effective tools to achieve targeted modulation of individual species and study its ecological function within multispecies communities. Here, we show that C16G2, a specifically targeted antimicrobial peptide, was able to selectively kill cariogenic pathogen Streptococcus mutans with high efficacy within a human saliva-derived in vitro oral multispecies community. Importantly, a significant shift in the overall microbial structure of the C16G2-treated community was revealed after a 24-h recovery period: several bacterial species with metabolic dependency or physical interactions with S. mutans suffered drastic reduction in their abundance, whereas S. mutans' natural competitors, including health-associated Streptococci, became dominant. This study demonstrates the use of targeted antimicrobials to modulate the microbiome structure allowing insights into the key community role of specific bacterial species and also indicates the therapeutic potential of C16G2 to achieve a healthy oral microbiome. [ABSTRACT FROM AUTHOR]

Bartonella henselaecauses the vasculoproliferative disorders bacillary angiomatosis and peliosis probably resulting from the release of vasculoendothelial growth factor (VEGF) from infected epithelial or monocytic host cells. Here we demonstrate thatB. henselaein addition to VEGF induction was also capable of inhibiting the endogenous sucide programme of monocytic host cells. Our results show thatB. henselaeinhibits pyrrolidine dithiocarbamate (PDTC)-induced apoptosis in Mono Mac 6 cells.B. henselaewas observed to be present in a vacuolic compartment of Mono Mac 6 cells. Direct contact ofB. henselaewith Mono Mac 6 cells was crucial for inhibition of apoptosis as shown by the use of a two-chamber model. Inhibition of apoptosis was paralleled by diminished caspase-3 activity which was significantly reduced in PDTC-stimulated andB. henselae-infected cells. The anti-apoptotic effect ofB. henselaewas accompanied by (i) the activation of the transcription factor NF-κB and (ii) the induction of cellular inhibitor of apoptosis proteins-1 and -2 (cIAP-1, -2). Our results suggest a new synergistic mechanism inB. henselaepathogenicity by (i) inhibition of host cell apoptosis via activation of NF-κB and (ii) induction of host cell VEGF secretion. [ABSTRACT FROM AUTHOR]

Bartonella henselae causes the vasculoproliferative disorders bacillary angiomatosis and peliosis probably resulting from the release of vasculoendothelial growth factor (VEGF) from infected epithelial or monocytic host cells. Here we demonstrate that B. henselae in addition to VEGF induction was also capable of inhibiting the endogenous sucide programme of monocytic host cells. Our results show that B. henselae inhibits pyrrolidine dithiocarbamate (PDTC)-induced apoptosis in Mono Mac 6 cells. B. henselae was observed to be present in a vacuolic compartment of Mono Mac 6 cells. Direct contact of B. henselae with Mono Mac 6 cells was crucial for inhibition of apoptosis as shown by the use of a two-chamber model. Inhibition of apoptosis was paralleled by diminished caspase-3 activity which was significantly reduced in PDTC-stimulated and B. henselae-infected cells. The anti-apoptotic effect of B. henselae was accompanied by (i) the activation of the transcription factor NF-kappaB and (ii) the induction of cellular inhibitor of apoptosis proteins-1 and -2 (cIAP-1, -2). Our results suggest a new synergistic mechanism in B. henselae pathogenicity by (i) inhibition of host cell apoptosis via activation of NF-kappaB and (ii) induction of host cell VEGF secretion.