<i>Staphylococcus aureus</i>skin colonization is mediated by SasG lectin variation

Mills, Krista B.; Maciag, Joseph J.; Wang, Can; Crawford, John A.; Enroth, Timothy J.; Keim, Klara C.; Dufrêne, Yves F.; Robinson, D. Ashley; Fey, Paul D.; Herr, Andrew B.; Horswill, Alexander R.

doi:10.1101/2023.11.20.567970

Cited by 1 publication

(3 citation statements)

References 63 publications

(136 reference statements)

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“…We also included strains that expressed a truncated form of SasG such as those of USA300 strain LAC and USA100 strain N315. Together, these strains represent different subtypes of SasG that have been recently described ( 49 ). Finally, we included strains lacking a copy of the sasG gene altogether, such as USA200 strains MN8 and MRSA252, as controls for comparison.…”

Section: Resultsmentioning

confidence: 90%

“…We also found that there is significant variation in sasG expression and molecular characteristics among strains. It was recently reported that most S. aureus strains have a full-length copy of SasG ( 49 ), but not all express SasG at detectable levels ( 57 ) and some strains have truncated copies of SasG. USA400 MW2 and 502a encode full-length, surface-attached copies of SasG with 5 B-repeats which aggregate with high efficiency.…”

Section: Discussionmentioning

confidence: 99%

“…SasG is constitutively expressed by some clinical isolates ( 39 ), and the presence of anti-SasG human antibodies demonstrates its expression during infection ( 47 , 48 ). While the majority of S. aureus strains encode sasG ( 49 ), some do not express it under laboratory conditions ( 39 , 50 ). Recently, it has become apparent that this lack of SasG expression might be due to its repression by an ArlRS-MgrA regulatory cascade under in vitro conditions ( 48 , 51 ).…”

Section: Introductionmentioning

confidence: 99%

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Host-derived protease promotes aggregation of Staphylococcus aureus by cleaving the surface protein SasG

Crosby,

Keim,

Kwiecinski

et al. 2024

mBio

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Staphylococcus aureus is one of the leading causes of hospital-acquired infections, many of which begin following attachment and accumulation on indwelling medical devices or diseased tissue. These infections are often linked to the establishment of biofilms, but another often overlooked key characteristic allowing S. aureus to establish persistent infection is the formation of planktonic aggregates. Such aggregates are physiologically similar to biofilms and protect pathogens from innate immune clearance and increase antibiotic tolerance. The cell-wall-associated protein SasG has been implicated in biofilm formation via mechanisms of intercellular aggregation but the mechanism in the context of disease is largely unknown. We have previously shown that the expression of cell-wall-anchored proteins involved in biofilm formation is controlled by the ArlRS-MgrA regulatory cascade. In this work, we demonstrate that the ArlRS two-component system controls aggregation, by repressing the expression of sasG by activation of the global regulator MgrA. We also demonstrate that SasG must be proteolytically processed by a non-staphylococcal protease to induce aggregation and that strains expressing functional full-length sasG aggregate significantly upon proteolysis by a mucosal-derived host protease found in human saliva. We used fractionation and N-terminal sequencing to demonstrate that human trypsin within saliva cleaves within the A domain of SasG to expose the B domain and induce aggregation. Finally, we demonstrated that SasG is involved in virulence during mouse lung infection. Together, our data point to SasG, its processing by host proteases, and SasG-driven aggregation as important elements of S. aureus adaptation to the host environment. IMPORTANCE Here, we demonstrate that the Staphylococcus aureus surface protein SasG is important for cell-cell aggregation in the presence of host proteases. We show that the ArlRS two-component regulatory system controls SasG levels through the cytoplasmic regulator MgrA. We identified human trypsin as the dominant protease triggering SasG-dependent aggregation and demonstrated that SasG is important for S. aureus lung infection. The discovery that host proteases can induce S. aureus aggregation contributes to our understanding of how this pathogen establishes persistent infections. The observations in this study demonstrate the need to strengthen our knowledge of S. aureus surface adhesin function and processing, regulation of adhesin expression, and the mechanisms that promote biofilm formation to develop strategies for preventing chronic infections.

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Section: Resultsmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%