Role of disease-associated tolerance in infectious superspreaders

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.A growing body of work has demonstrated that a minority of infected hosts is responsible for the majority of new infections within the population. Woolhouse et al. first formulated the 80/20 rule of host–pathogen interactions, wherein 20% of the infected hosts (“superspreaders”) are responsible for 80% of the infections (1). For example, analysis of cattle herds infected with Escherichia coli O157:H7 has demonstrated that high-shedding individuals (8–20% of the infected herd) are responsible for the majority of the pathogen transmission to uninfected members of the herd (2–5). The identification of these superspreaders is of key importance for disease treatment and clearance (1, 6–8). However, comparatively little is known about the host immune response that contributes to the superspreader state.An infected host can fight pathogenic infection by two distinct processes—resistance and tolerance. Resistance encompasses a diverse set of mechanisms used by the host to control pathogen invasion and replication. Tolerance, conversely, employs different mechanisms that help the host organism tolerate the damage caused by both the pathogenic infection and the resulting immune response, thereby maintaining host health (9–11). Although very little is known about the full spectrum of tolerance mechanisms, the few studies in animals suggest that, because pathogens and immunopathology can potentially affect almost any physiological process, tolerance is not restricted to a single protective pathway (9, 12, 13). Unlike resistance mechanisms, tolerance strategies do not have direct negative consequences for the pathogen and therefore should place no selective pressures upon the pathogen (12, 14, 15). For these reasons, tolerance mechanisms have been hypothesized to play a role in the maintenance of the asymptomatic superspreader state (11, 12, 15). However, an experimental link between tolerance and transmission has not been demonstrated.Upon oral infection with Salmonella enterica serovar Typhimurium, in our mouse model of Salmonella transmission, 30% of infected hosts shed the pathogen at high levels (>10⁸ Salmonella per gram of feces). These superspreader hosts are able to efficiently infect naive cagemates (16) and possess a distinct immune phenotype compared with the majority of the infected hosts which shed the pathogen at lower levels and are nonsuperspreaders (17)]. Importantly, both superspreader and nonsuperspreader hosts carry identical pathogen burdens across all tissues except the intestinal tract. The host microbiota plays an important role in protecting the host from acute Salmonella infection (18, 19) and in the establishment of the superspreader state (16). Frequent subtherapeutic antibiotic use is common among livestock animals, and the resulting disruption of host gut flora or dysbiosis has long-lasting effects on the health of the host (20). Here, we demonstrate that superspreader hosts are uniquely able to tolerate antibiotic treatment and importantly, this tolerance is not maintained in nonsuperspreader hosts.