Group A Streptococcus interactions with the host across time and space

Abstract

Group A Streptococcus (GAS) has a fantastically wide tissue tropism in humans, manifesting as different diseases depending on the strain's virulence factor repertoire and the tissue involved. Activation of immune cells and pro-inflammatory signaling has historically been considered an exclusively host-protective response that a pathogen would seek to avoid. However, recent advances in human and animal models suggest that in some tissues, GAS will activate and manipulate specific pro-inflammatory pathways to promote growth, nutrient acquisition, persistence, recurrent infection, competition with other microbial species, dissemination, and transmission. This review discusses molecular interactions between the host and pathogen to summarize how infection varies across tissue and stages of inflammation. A need for inflammation for GAS survival during common, mild infections may drive selection for mechanisms that cause pathological and excess inflammation severe diseases such as toxic shock syndrome, necrotizing fasciitis, and rheumatic heart disease.

Figure 1:

Interplay between inflammation-induced cathelicidin/LL-37 and reactive oxygen species (ROS) and bacterial virulence. Concentrations of LL-37 range from undetectable in healthy skin, 50–300 nM in saliva, which can induce CovRS signaling. Many GAS are resistant to 10 μM or higher concentrations. Concentrations of the ROS hydrogen peroxide range from low μM levels in the phagosome concentrations with GAS resistant to 500 μM or higher concentrations. Inflammation increases LL-37 and ROS concentrations in phagocytes, phagosomes, and neutrophil extracellular traps, and when released, are proinflammatory themselves.

Figure 2:

Host-pathogen interactions are divergent between body sites. GAS infects the skin and upper respiratory tract, secreting exotoxins that trigger a host inflammation. The GAS exotoxin SpeB activates IL-1ß and pyroptosis via the cell death effector Gasdermin A, both of which recruit neutrophils to the infection site. GAS superantigens activate T lymphocytes, resulting in IFNγ, IL-6, and TNFα production. While the molecular mechanisms of these interactions are similar in the upper respiratory and skin, the consequence of this inflammation is tissue-dependent.