Coordinate actions of innate immune responses oppose those of the adaptive immune system during Salmonella infection of mice

Multiparametric analysis of immune cell signaling, cytokines, and bacteria identifies connections that balance innate and adaptive immune responses to infection. Assembling the immune system jigsaw Analysis of individual components of the immune response to infection solves only small parts of the immune system puzzle. Hotson et al. analyzed the variable immune responses of Salmonella-infected mice over time by measuring the numbers and signaling states of multiple immune cell types and combining these data with measurements of serum cytokine concentrations, antibody responses, and bacterial burden. Mathematical analysis of this multiparametric data set revealed response elements that clustered together into patterns that showed how different components of the immune system interacted with each other. For example, neutrophils inhibited the functions of B cells during the course of infection. Thus, this systems biology approach enables the assembly of interconnected sections of the immune system puzzle. The immune system enacts a coordinated response when faced with complex environmental and pathogenic perturbations. We used the heterogeneous responses of mice to persistent Salmonella infection to model system-wide coordination of the immune response to bacterial burden. We hypothesized that the variability in outcomes of bacterial growth and immune response across genetically identical mice could be used to identify immune elements that serve as integrators enabling co-regulation and interconnectedness of the innate and adaptive immune systems. Correlation analysis of immune response variation to Salmonella infection linked bacterial load with at least four discrete, interacting functional immune response “cassettes.” One of these, the innate cassette, in the chronically infected mice included features of the innate immune system, systemic neutrophilia, and high serum concentrations of the proinflammatory cytokine interleukin-6. Compared with mice with a moderate bacterial load, mice with the highest bacterial burden exhibited high activity of this innate cassette, which was associated with a dampened activity of the adaptive T cell cassette—with fewer plasma cells and CD4+ T helper 1 cells and increased numbers of regulatory T cells—and with a dampened activity of the cytokine signaling cassette. System-wide manipulation of neutrophil numbers revealed that neutrophils regulated signal transducer and activator of transcription (STAT) signaling in B cells during infection. Thus, a network-level approach demonstrated unappreciated interconnections that balanced innate and adaptive immune responses during the dynamic course of disease and identified signals associated with pathogen transmission status, as well as a regulatory role for neutrophils in cytokine signaling.