Mucin promotes pneumococcal colonization via autolysis suppression and tryptophan-mediated immune modulation
- 1St Jude Children's Research Hospital
Abstract
Streptococcus pneumoniae is a leading human respiratory pathogen, yet its success depends not on disease but on its ability to persist as an asymptomatic colonizer of the nasopharynx. The nasopharyngeal mucosa is lined with mucus, whose heavily O-glycosylated mucin proteins are the most abundant macromolecules in the pneumococcal natural niche. While mucus is canonically viewed as a host defense barrier, we found that mucin actively reprograms pneumococcal physiology to promote colonization through two distinct mechanisms. First, mucin suppresses pneumococcal autolysis by specifically inhibiting the enzymatic activity of the major autolysin LytA, prolonging bacterial survival and restricting release of the cholesterol-dependent cytotoxin pneumolysin, thereby reducing host cell damage. Second, mucin induces de novo biosynthesis and extracellular release of tryptophan, an essential amino acid that humans cannot synthesize and that serves as a substrate for host immunomodulatory pathways. Tryptophan biosynthesis was critical for pneumococcal survival against macrophage killing, and its disruption abolished both colonization and invasive disease. Transcriptomic analysis revealed that tryptophan biosynthesis enables the pneumococcus to survive a bactericidal macrophage state while preventing macrophage transition to proliferative tissue repair. Together, these findings reveal that mucin is not merely a barrier but an active signal that reprograms the pneumococcus toward a persistent, host-tolerant state, identifying a distinctive repertoire of colonization mechanisms that allow a virulent respiratory pathogen to sustain long-term asymptomatic carriage in its human reservoir.
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BibTeX
@misc{johnson2026mucin,
title = {{Mucin promotes pneumococcal colonization via autolysis suppression and tryptophan-mediated immune modulation}},
author = {C. N. Johnson and J. Rosch and M. W. Frank and Y. Laguna-Terai and W. MacCain and T. S. Simmons and S. Zamakhaeva and N. Korotkova and C. Aherne and E. Tuomanen and C. Evans and K. Ribbeck},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.06.764952},
url = {https://www.biorxiv.org/content/10.64898/2026.11.06.764952v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Mucin promotes pneumococcal colonization via autolysis suppression and tryptophan-mediated immune modulation
AU - C. N. Johnson
AU - J. Rosch
AU - M. W. Frank
AU - Y. Laguna-Terai
AU - W. MacCain
AU - T. S. Simmons
AU - S. Zamakhaeva
AU - N. Korotkova
AU - C. Aherne
AU - E. Tuomanen
AU - C. Evans
AU - K. Ribbeck
PY - 2026
DA - 2026/11/06
PB - bioRxiv
DO - 10.64898/2026.11.06.764952
UR - https://www.biorxiv.org/content/10.64898/2026.11.06.764952v1
AB - Streptococcus pneumoniae is a leading human respiratory pathogen, yet its success depends not on disease but on its ability to persist as an asymptomatic colonizer of the nasopharynx. The nasopharyngeal mucosa is lined with mucus, whose heavily O-glycosylated mucin proteins are the most abundant macromolecules in the pneumococcal natural niche. While mucus is canonically viewed as a host defense barrier, we found that mucin actively reprograms pneumococcal physiology to promote colonization through two distinct mechanisms. First, mucin suppresses pneumococcal autolysis by specifically inhibiting the enzymatic activity of the major autolysin LytA, prolonging bacterial survival and restricting release of the cholesterol-dependent cytotoxin pneumolysin, thereby reducing host cell damage. Second, mucin induces de novo biosynthesis and extracellular release of tryptophan, an essential amino acid that humans cannot synthesize and that serves as a substrate for host immunomodulatory pathways. Tryptophan biosynthesis was critical for pneumococcal survival against macrophage killing, and its disruption abolished both colonization and invasive disease. Transcriptomic analysis revealed that tryptophan biosynthesis enables the pneumococcus to survive a bactericidal macrophage state while preventing macrophage transition to proliferative tissue repair. Together, these findings reveal that mucin is not merely a barrier but an active signal that reprograms the pneumococcus toward a persistent, host-tolerant state, identifying a distinctive repertoire of colonization mechanisms that allow a virulent respiratory pathogen to sustain long-term asymptomatic carriage in its human reservoir.
ER -