A soluble host signal drives rapid, brain-predominant capsular thickening in <i>Streptococcus pneumoniae</i> via a putative sodium-dependent transporter (SPD_0642) and capsular prepromoter sequence

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1. Institute of Anatomy, University of Bern, Bern, Switzerland
2. Institute for Infectious Diseases, Faculty of Medicine, University of Bern, Bern, Switzerland
3. Graduate School for Cellular and Biomedical Sciences, Faculty of Medicine, University of Bern, Bern, Switzerland
4. Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa
5. Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA 02115, USA
6. Department of Clinical Microbiology and Infectious Diseases (CMID), School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
7. Multidisciplinary Center for Infectious Diseases, University of Bern, Bern, Switzerland
8. Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland

Abstract

The Streptococcus pneumoniae capsule is a major determinant of virulence, yet whether bacteria actively remodel it during infection remains unclear. Studying Swiss and South African clinical isolates (serotypes 1, 6B, 8, 12F, 19F, and 35B), we identified a rapid, tissue-specific response: capsule thickness increased within hours upon co-exposure to host cells and tissues. Only two 12F strains failed to thicken. Thickening was greatest in brain tissue, moderate in serum, and absent on the epithelium. This adaptation occurred independently of cod locus phase variation and nutritional factors, and was instead driven by a soluble, thermostable host signal (<3 kDa). Thickening correlated with neuroinflammation but did not require it, as it also occurred in contact with resting brain immune cells. It exacerbated meningitis in mice and enhanced bacteremia. Once induced, capsule thickening dampened inflammatory responses, coinciding with downregulation of pneumolysin, a major pro-inflammatory toxin. Genetic analysis of the non-thickening 12F isolates, together with targeted mutagenesis, identified two independent determinants of capsule-thickness modulation: a specific promoter-proximal element and SPD_0642, a conserved putative transporter encoded outside the capsule operon. Both contributed to the host-induced thickening phenotype. Pneumococci therefore rapidly remodel their surface in response to tissue-specific cues within the host, in a manner distinct from stochastic phase variation outside it.

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Accession numbers for the presented sequences: D39 (accession number GCF_023635025.1), 106.66 (accession number PRJNA554545), 50943, 51060, 807.13, 51113, 51114, 48294, and 50793 (available upon publication). All experimental data will be made publicly available upon publication.

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Tomov, N., Hupp, S., Müller, A., Baronti, D., Lux, J., Trillo, I., Lekhuleni, C., van Opijnen, T., Rosconi, F., von Gottberg, A., Hathaway, L. J., & Iliev, A. I. (2026). A soluble host signal drives rapid, brain-predominant capsular thickening in <i>Streptococcus pneumoniae</i> via a putative sodium-dependent transporter (SPD_0642) and capsular prepromoter sequence. bioRxiv (preprint). https://doi.org/10.64898/2026.03.28.714961

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