期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：44
页码：15780-15785
DOI：10.1073/pnas.1409968111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceA 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. 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.
