A new host cell internalisation pathway for SadA‐expressing staphylococci triggered by excreted neurochemicals

Abstract

Staphylococcus aureus is a facultative intracellular pathogen that invades a wide range of professional and nonprofessional phagocytes by triggering internalisation by interaction of surface‐bound adhesins with corresponding host cell receptors. Here, we identified a new concept of host cell internalisation in animal‐pathogenic staphylococcal species. This new mechanism exemplified by Staphylococcus pseudintermedius ED99 is not based on surface‐bound adhesins but is due to excreted small neurochemical compounds, such as trace amines (TAs), dopamine (DOP), and serotonin (SER), that render host cells competent for bacterial internalisation. The neurochemicals are produced by only one enzyme, the staphylococcal aromatic amino acid decarboxylase (SadA). Here, we unravelled the mechanism of how neurochemicals trigger internalisation into the human colon cell line HT‐29. We found that TAs and DOP are agonists of the α2‐adrenergic receptor, which, when activated, induces a cascade of reactions involving a decrease in the cytoplasmic cAMP level and an increase in F‐actin formation. The signalling cascade of SER follows a different pathway. SER interacts with 5HT receptors that trigger F‐actin formation without decreasing the cytoplasmic cAMP level. The neurochemical‐induced internalisation in host cells is independent of the fibronectin‐binding protein pathway and has an additive effect. In a sadA deletion mutant, ED99ΔsadA, internalisation was decreased approximately threefold compared with that of the parent strain, and treating S. aureus USA300 with TAs increased internalisation by approximately threefold.

The Neuromodulator-Encoding sadA Gene Is Widely Distributed in the Human Skin Microbiome

“…Moreover, a sadA deletion mutant of the animal pathogen Staphylococcus pseudintermedius showed a lower internalization rate than the parent strain in the presence of aromatic amino acids (AAAs). This may reinforce the hypothesis that the excreted TA interfere with host communication to improve the survival and colonization of the bacteria (Luqman et al, 2018(Luqman et al, , 2019. More recently it has been shown that TA-producing Staphylococcus epidermidis strains expressing SadA are predominant on human skin and that TA accelerate wound healing by antagonizing the β2-adrenergic receptor (β2-AR) in keratinocytes (Luqman et al, 2020b).…”

“…We show that the intestinal (Luqman et al, 2018) and skin microbiota is quite capable of increasing the concentration of TA, and that the increased TA concentration causes new activities and interactions with receptors. It has been shown already that TA interact with α2and β-AR and the biological consequences (Luqman et al, 2018(Luqman et al, , 2019(Luqman et al, , 2020b. But these are probably not the only receptors with which TA interact.…”

“…It also decarboxylates dihydroxy phenylalanine (L-DOPA) and 5-hydroxytryptophan (5-HTP) to the neurotransmitters DOP and serotonin (Luqman et al, 2018). TA producing staphylococci triggered the internalization into human colon adenocarcinoma cells by activation of the α2adrenergic receptor (α2-AR) (Luqman et al, 2018(Luqman et al, , 2019.…”

“…It decarboxylates all AAAs to TAs, and also dihydroxylated phenylalanine and 5-HTP to the neurotransmitters DOP and serotonin (Luqman et al, 2018). SadA producing staphylococci are prevalent in the gut and the human skin (Luqman et al, 2018(Luqman et al, , 2019(Luqman et al, , 2020b.…”

The Ambivalent Role of Skin Microbiota and Adrenaline in Wound Healing and the Interplay between Them

“…TAs can interact with various ARs. They act as agonists of α2-AR [ 91 , 92 ] and as antagonists of β-AR [ 44 , 93 ] and of α1-AR [ 94 ]. Some studies used antagonists to block β-AR, which resulted in an increase in ERK phosphorylation, keratinocyte migration, and re-epithelialization and conclusively accelerated wound healing [ 72 , 95 ].…”