Streptococcus pneumoniae Senses a Human-like Sialic Acid Profile via the Response Regulator CiaR.
Streptococcus pneumoniae is a human-adapted pathogen that encounters terminally sialylated glycoconjugates and free sialic acid (Sia) in the airways. Upon scavenging by the bacterial sialidase NanA, Sias serve as carbon sources for the bacteria. Unlike most animals in which cytidine-monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) converts Sia N-acetylneuraminic acid (Neu5Ac) into N-glycolylneuraminic acid (Neu5Gc), humans have an inactive CMAH, causing an absence of Neu5Gc and excess Neu5Ac. We find that pneumococcal challenge in Cmah(-/-) mice leads to heightened bacterial loads, virulence, and NanA expression. In vitro, NanA is upregulated in response to Neu5Ac compared with Neu5Gc, a process controlled by the two-component response regulator CiaR and requiring Sia uptake by the transporter SatABC. Additionally, compared with Neu5Gc, Neu5Ac increases pneumococcal resistance to antimicrobial reactive oxygen species in a CiaR-dependent manner. Thus, S. pneumoniae senses and responds to Neu5Ac, leading to CiaR activation and increased virulence and potentially explaining the greater susceptibility in humans.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Clinical Microbiology, Karolinska University Hospital, 171 76 Stockholm, Sweden.
Karina
K
Hentrich
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
Jonas
J
Löfling
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Clinical Microbiology, Karolinska University Hospital, 171 76 Stockholm, Sweden.
Anuj
A
Pathak
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093, USA.
Victor
V
Nizet
Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Cellular and Molecular Medicine; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093, USA.
Ajit
A
Varki
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Clinical Microbiology, Karolinska University Hospital, 171 76 Stockholm, Sweden. Electronic address: birgitta.henriques@ki.se.
Birgitta
B
Henriques-Normark
D000818:Animals; D058491:Bacterial Load; D001426:Bacterial Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D015964:Gene Expression Regulation, Bacterial; D051379:Mice; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000172:deficiency; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D011018:Pneumonia, Pneumococcal / Q000382:microbiology; D011494:Protein Kinases / Q000378:metabolism*; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000502:physiology*; D037521:Virulence Factors / Q000096:biosynthesis*
D001426:Bacterial Proteins; D037521:Virulence Factors; D006899:Mixed Function Oxygenases; C074383:CMPacetylneuraminate monooxygenase; D011494:Protein Kinases; C088910:CiaR protein, Streptococcus pneumoniae; D019158:N-Acetylneuraminic Acid