An extracellular bacterial pathogen modulates host metabolism to regulate its own sensing and proliferation.
Successful infection depends on the ability of the pathogen to gain nutrients from the host. The extracellular pathogenic bacterium group A Streptococcus (GAS) causes a vast array of human diseases. By using the quorum-sensing sil system as a reporter, we found that, during adherence to host cells, GAS delivers streptolysin toxins, creating endoplasmic reticulum stress. This, in turn, increases asparagine (ASN) synthetase expression and the production of ASN. The released ASN is sensed by the bacteria, altering the expression of ∼17% of GAS genes of which about one-third are dependent on the two-component system TrxSR. The expression of the streptolysin toxins is strongly upregulated, whereas genes linked to proliferation are downregulated in ASN absence. Asparaginase, a widely used chemotherapeutic agent, arrests GAS growth in human blood and blocks GAS proliferation in a mouse model of human bacteremia. These results delineate a pathogenic pathway and propose a therapeutic strategy against GAS infections.
Department of Microbiology and Molecular Genetics, The Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem 91120, Israel.
Moshe
M
Baruch
Department of Microbiology and Molecular Genetics, The Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem 91120, Israel.
Ilia
I
Belotserkovsky
Department of Microbiology and Molecular Genetics, The Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem 91120, Israel.
Baruch B
BB
Hertzog
Department of Microbiology and Molecular Genetics, The Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem 91120, Israel.
Miriam
M
Ravins
Department of Microbiology and Molecular Genetics, The Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem 91120, Israel.
Eran
E
Dov
Department of Cell Biology & Molecular Genetics and Maryland Pathogen Research Institut, University of Maryland, College Park, MD 20742, USA.
Kevin S
KS
McIver
Department of Cell Biology & Molecular Genetics and Maryland Pathogen Research Institut, University of Maryland, College Park, MD 20742, USA.
Yoann S
YS
Le Breton
Mechanism of Inflammation Program, Center for Research Excellence & Technological Enterprise (CREATE), National University of Singapore and The Hebrew University of Jerusalem (HUJI), Singapore 138602, Singapore.
Yiting
Y
Zhou
Mechanism of Inflammation Program, Center for Research Excellence & Technological Enterprise (CREATE), National University of Singapore and The Hebrew University of Jerusalem (HUJI), Singapore 138602, Singapore.
Catherine Youting
CY
Cheng
Catherine Youting
CY
Chen
Department of Microbiology and Molecular Genetics, The Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem 91120, Israel; Mechanism of Inflammation Program, Center for Research Excellence & Technological Enterprise (CREATE), National University of Singapore and The Hebrew University of Jerusalem (HUJI), Singapore 138602, Singapore. Electronic address: emanuelh@ekmd.huji.ac.il.
Emanuel
E
Hanski
D000818:Animals; D001216:Asparagine / Q000378:metabolism; D001217:Aspartate-Ammonia Ligase / Q000235:genetics / Q000378:metabolism; D016470:Bacteremia / Q000382:microbiology; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053038:Quorum Sensing; D013290:Streptococcal Infections / Q000382:microbiology*; D013291:Streptococcus / Q000166:cytology / Q000378:metabolism* / Q000472:pathogenicity; D014158:Transcription, Genetic; D037521:Virulence Factors / Q000235:genetics
D037521:Virulence Factors; D001216:Asparagine; D001217:Aspartate-Ammonia Ligase