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Innate immune responses yield tissue-specific bottlenecks that scale with pathogen dose.

ABSTRACT: To cause infection, pathogens must overcome bottlenecks imposed by the host immune system. These bottlenecks restrict the inoculum and largely determine whether pathogen exposure results in disease. Infection bottlenecks therefore quantify the effectiveness of immune barriers. Here, using a model of Escherichia coli systemic infection, we identify bottlenecks that tighten or widen with higher inoculum sizes, revealing that the efficacy of innate immune responses can increase or decrease with pathogen dose. We term this concept "dose scaling". During E. coli systemic infection, dose scaling is tissue specific, dependent on the lipopolysaccharide (LPS) receptor TLR4, and can be recapitulated by mimicking high doses with killed bacteria. Scaling therefore depends on sensing of pathogen molecules rather than interactions between the host and live bacteria. We propose that dose scaling quantitatively links innate immunity with infection bottlenecks and is a valuable framework for understanding how the inoculum size governs the outcome of pathogen exposure.

SUBMITTER: Hullahalli K

PROVIDER: S-EPMC10500177 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Innate immune responses yield tissue-specific bottlenecks that scale with pathogen dose.

Hullahalli Karthik K Dailey Katherine G KG Waldor Matthew K MK

Proceedings of the National Academy of Sciences of the United States of America 20230905 37

To cause infection, pathogens must overcome bottlenecks imposed by the host immune system. These bottlenecks restrict the inoculum and largely determine whether pathogen exposure results in disease. Infection bottlenecks therefore quantify the effectiveness of immune barriers. Here, using a model of <i>Escherichia coli</i> systemic infection, we identify bottlenecks that tighten or widen with higher inoculum sizes, revealing that the efficacy of innate immune responses can increase or decrease w ...[more]

PMID: 37669395

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Innate immune responses yield tissue-specific bottlenecks that scale with pathogen dose.

Publications

Innate immune responses yield tissue-specific bottlenecks that scale with pathogen dose.

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