M1 Protein-Dependent Intracellular Trafficking Promotes Persistence and Replication of <i>Streptococcus pyogenes</i> in Macrophages

Abstract

Streptococcus pyogenes is an important human pathogen that causes a variety of diseases including life-threatening invasive diseases, such as toxic shock and deep tissue infections. Although S. pyogenes are classically considered extracellular pathogens, a clinical significance of an intracellular source has been emphasized. In patients with deep tissue infections, an intracellular reservoir of S. pyogenes within macrophages was shown to contribute to prolonged bacterial persistence. Here we demonstrate that intracellular survival of S. pyogenes in macrophages is associated with an M1 protein-dependent intracellular trafficking in the phagosomal-lysosomal pathway, which results in impaired fusion with lysosomes. The phagocytic vacuoles harbouring M1 protein-expressing bacteria not only served as a safe haven for the bacteria, but also as a replicating niche. An M1 protein-dependent modulation of macrophages was further supported by differences in NF-ĸB signalling between cells infected with either the wild-type or M1 protein-deficient strains, thereby indicating a suppressed inflammatory response when M1 protein was involved. Evidence of egress of bacteria out of their host cell and subsequent re-infection of new cells emphasize the importance of intracellular bacteria as a reservoir for dissemination of infection and continued tissue injury.

Identification of Cell-Penetrating Peptides That Are Bactericidal to Neisseria meningitidis and Prevent Inflammatory Responses upon Infection

“…Isolation of monocytes was performed essentially as previously described (31,32). In brief, CD14 ϩ monocytes were isolated from buffy coats by negative selection using RosetteSep human monocyte enrichment cocktail (0.5 ml/10 ml blood; StemCell Technologies, Vancouver, Canada) and separated on Ficoll-Paque Plus.…”

Necrotizing fasciitis after Caesarean section. Can this complication be avoided?

“…Co gorsze, bakterie mają-ce na swojej powierzchni ekspresję białka M1 wykazują zdolność do unikania połączeń z lizozymami wewnątrz makrofagów. Powoduje to stan, w którym makrofagi stanowią nie tylko bezpieczny rezerwuar pozwalający przetrwać paciorkowcom, ale dochodzi w nich wręcz do replikacji bakterii [15]. Jest to szczególnie niebezpieczne zjawisko będące podstawą patogenności i zdolności wywołania wstrząsu septycznego.…”

The M1 Protein of <b><i>Streptococcus pyogenes</i></b> Triggers an Innate Uptake Mechanism into Polarized Human Endothelial Cells

“…Although S. pyogenes has been considered as an extracellular pathogen, various reports have shown that it invades different cell types in vitro including epithelial cells [4,5,6], neutrophils [7,8] and macrophages [9,10]. Internalization of S. pyogenes into eukaryotic cells is considered to be one successful mechanism for evading host immune responses and penicillin treatment, and it may thus promote transmission and dissemination from the primary side of infection.…”