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Research Article

Role of disease-associated tolerance in infectious superspreaders

Smita Gopinath, Joshua S. Lichtman, Donna M. Bouley, Joshua E. Elias, and Denise M. Monack
  1. Departments of aMicrobiology and Immunology,
  2. bChemical and Systems Biology,
  3. cComparative Medicine, Stanford University School of Medicine, Stanford, CA 94305

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PNAS November 4, 2014 111 (44) 15780-15785; first published October 20, 2014; https://doi.org/10.1073/pnas.1409968111
Smita Gopinath
Departments of aMicrobiology and Immunology,
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Joshua S. Lichtman
bChemical and Systems Biology,
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Donna M. Bouley
cComparative Medicine, Stanford University School of Medicine, Stanford, CA 94305
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Joshua E. Elias
bChemical and Systems Biology,
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Denise M. Monack
Departments of aMicrobiology and Immunology,
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  • For correspondence: dmonack@stanford.edu
  1. Edited by Ruslan Medzhitov, Yale University School of Medicine, New Haven, CT, and approved September 15, 2014 (received for review May 30, 2014)

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Significance

A minority of infected hosts is thought to be responsible for the majority of pathogen transmission events. Surprisingly little is known about what distinguishes superspreader hosts from the rest of the infected population. Using a mouse model of Salmonella infection, we show that levels of Salmonella are equivalent between antibiotic-treated superspreader and nonsuperspreader hosts; however, superspreader hosts are uniquely able to tolerate antibiotic treatment, unlike nonsuperspreader hosts. We find that nonsuperspreaders have a hyperinflammatory response to antibiotic treatment, resulting in increased inflammatory myeloid cells that contribute to the morbidity observed. Superspreaders display neither an increased frequency of inflammatory myeloid cells nor morbidity upon antibiotic treatment. Our data describe tolerance mechanisms unique to superspreader hosts that enable sustained pathogen transmission.

Abstract

Natural populations show striking heterogeneity in their ability to transmit disease. For example, a minority of infected individuals known as superspreaders carries out the majority of pathogen transmission events. In a mouse model of Salmonella infection, a subset of infected hosts becomes superspreaders, shedding high levels of bacteria (>108 cfu per g of feces) but remain asymptomatic with a dampened systemic immune state. Here we show that superspreader hosts remain asymptomatic when they are treated with oral antibiotics. In contrast, nonsuperspreader Salmonella-infected hosts that are treated with oral antibiotics rapidly shed superspreader levels of the pathogen but display signs of morbidity. This morbidity is linked to an increase in inflammatory myeloid cells in the spleen followed by increased production of acute-phase proteins and proinflammatory cytokines. The degree of colonic inflammation is similar in antibiotic-treated superspreader and nonsuperspreader hosts, indicating that the superspreader hosts are tolerant of antibiotic-mediated perturbations in the intestinal tract. Importantly, neutralization of acute-phase proinflammatory cytokines in antibiotic-induced superspreaders suppresses the expansion of inflammatory myeloid cells and reduces morbidity. We describe a unique disease-associated tolerance to oral antibiotics in superspreaders that facilitates continued transmission of the pathogen.

  • host-to-host transmission
  • carriers
  • pathogenesis
  • acute phase response

Footnotes

  • ↵1To whom correspondence should be addressed. Email: dmonack{at}stanford.edu.
  • Author contributions: S.G. and D.M.M. designed research; S.G. performed research; J.S.L. and J.E.E. contributed new reagents/analytic tools; S.G., J.S.L., and D.M.B. analyzed data; and S.G. and D.M.M. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1409968111/-/DCSupplemental.

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Disease-associated tolerance in transmitters
Smita Gopinath, Joshua S. Lichtman, Donna M. Bouley, Joshua E. Elias, Denise M. Monack
Proceedings of the National Academy of Sciences Nov 2014, 111 (44) 15780-15785; DOI: 10.1073/pnas.1409968111

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Disease-associated tolerance in transmitters
Smita Gopinath, Joshua S. Lichtman, Donna M. Bouley, Joshua E. Elias, Denise M. Monack
Proceedings of the National Academy of Sciences Nov 2014, 111 (44) 15780-15785; DOI: 10.1073/pnas.1409968111
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  • Biological Sciences
  • Immunology and Inflammation
Proceedings of the National Academy of Sciences: 111 (44)
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