Editors' ChoiceHost-Pathogen Interactions

A uniquely human susceptibility to bacterial infection

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Science Signaling  04 Oct 2016:
Vol. 9, Issue 448, pp. ec228
DOI: 10.1126/scisignal.aal1244

Streptococcus pneumoniae is found in the upper respiratory tracts of many mammals, yet humans are particularly susceptible to this bacterium, which causes pneumonia and meningitis. The mucus lining the respiratory tract is rich in glycoproteins, many of which incorporate sialic acids. The sialidase NanA and the multisubunit sialic acid transporter SatABC enable S. pneumoniae to liberate sialic acids from glycoproteins and bring them into the bacterium, where they are metabolized to support growth. In most mammals, cytidine-monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) converts some of the N-acetylneuraminic acid (Neu5Ac) into N-glycolylneuraminic acid (Neu5Gc), leading to the presence of both of these sialic acids in the tissues of most mammals. However, human CMAH is catalyically inactive, leading to a greater abundance of Neu5Ac in human mucus relative to the mucus of other mammals. Hentrich et al. found that Cmah–/– mice were more susceptible to S. pneumoniae infection than were wild-type mice and that nanA transcription was induced in S. pneumoniae isolated from the nasopharynx of these mice a few hours after infection. Culturing S. pneumoniae in the presence of Neu5Ac induced the transcription of nanA and SatA. CiaR, the response regulator of the CiaRH two-component system, was required for Neu5Ac-stimulated expression of nanA and for bacterial growth on Neu5Ac. Wild-type S. pneumoniae exhibited increased colonization of the lungs of Cmah–/–- mice compared with wild-type mice, and infection with wild-type S. pneumoniae caused sepsis in Cmah–/– mice but not in wild-type mice. In contrast, S. pneumoniae mutants lacking satABC or ciaR colonized the lungs of wild-type and Cmah–/– mice at similar rates and did not induce sepsis in Cmah–/– mice. These findings indicate that the CiaHK two-component system is important for stimulating S. pneumoniae virulence in response to Neu5Ac and offer a potential explanation for why humans are more susceptible than other mammals to S. pneumoniae infection.

K. Hentrich, J. Löfling, A. Pathak, V. Nizet, A. Varki, B. Henriques-Normark, Streptococcus pneumoniae senses a human-like sialic acid profile via the response regulator CiaR. Cell Host Microbe 20, 307–317 (2016). [PubMed]

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