ObjectivesWe determined the interactions between efficacy of antibiotic treatment, pathogen growth rates and between-organ spread during systemic Salmonella infections.MethodsWe infected mice with isogenic molecularly tagged subpopulations of either a fast-growing WT or a slow-growing ΔaroC Salmonella strain. We monitored viable bacterial numbers and fluctuations in the proportions of each bacterial subpopulation in spleen, liver, blood and mesenteric lymph nodes (MLNs) before, during and after the cessation of treatment with ampicillin and ciprofloxacin.ResultsBoth antimicrobials induced a reduction in viable bacterial numbers in the spleen, liver and blood. This reduction was biphasic in infections with fast-growing bacteria, with a rapid initial reduction followed by a phase of lower effect. Conversely, a slow and gradual reduction of the bacterial load was seen in infections with the slow-growing strain, indicating a positive correlation between bacterial net growth rates and the efficacy of ampicillin and ciprofloxacin. The viable numbers of either bacterial strain remained constant in MLNs throughout the treatment with a relapse of the infection with WT bacteria occurring after cessation of the treatment. The frequency of each tagged bacterial subpopulation was similar in the spleen and liver, but different from that of the MLNs before, during and after treatment.ConclusionsIn Salmonella infections, bacterial growth rates correlate with treatment efficacy. MLNs are a site with a bacterial population structure different to those of the spleen and liver and where the total viable bacterial load remains largely unaffected by antimicrobials, but can resume growth after cessation of treatment.
Invasive non-typhoidal Salmonella (iNTS) infections cause a high burden of lethal sepsis in young children and HIV patients, often associated with malaria, anaemia, malnutrition and sickle-cell disease. Vaccines against iNTS are urgently needed but none are licensed yet. Areas covered: This review illustrates how immunology, epidemiology and within-host pathogen behaviour affect invasive Salmonella infections and highlights how this knowledge can assist the improvement and choice of vaccines. Expert Commentary: Control of iNTS disease requires approaches that reduce transmission and improve diagnosis and treatment. These are often difficult to implement due to the fragile ecology and economies in endemic countries. Vaccines will be key tools in the fight against iNTS disease. To optimise vaccine design, we need to better define protective antigens and mechanisms of resistance to disease in susceptible populations even in those individuals where innate immunity may be impaired by widespread comorbidities.
SummaryVaccines can serve as essential tools to prevent bacterial diseases via the induction of long‐lasting IgG responses. The efficacy of such vaccines depends on the effector mechanisms triggered by IgG. The complement system and Fc‐gamma receptors (FcγRs) can potentially play a crucial role in IgG‐mediated immunity against bacterial diseases. However, their relative importance in vivo is unclear, and has been the object of controversy and debate. In this brief study, we have used gene‐targeted mice lacking either Fcγ RI, II, II and IV or the C3 complement component as well as a novel mouse strain lacking both C3 and FcγRs to conclusively show the essential role of complement in antibody‐mediated host resistance to Salmonella enterica systemic infection. By comparing the effect of IgG2a antibodies against Salmonella O‐antigen in gene‐targeted mice, we demonstrate that the complement system is essential for the IgG‐mediated reduction of bacterial numbers in the tissues.
During the last two decades our understanding of the complex in vivo host-pathogen interactions has increased due to technical improvements and new research tools. The rapid advancement of molecular biology, flow cytometry and microscopy techniques, combined with mathematical modelling, have empowered in-depth studies of systemic bacterial infections across scales from single molecules, to cells, to organs and systems to reach the whole organism level. By tracking subpopulations of bacteria in vivo using molecular or fluorescent tags, it has been possible to reconstruct the spread of infection within and between organs, allowing unprecedented quantification of the effects of antimicrobial treatment and vaccination. This review illustrates recent advances in the study of heterogeneous traits of the infection process and illustrate approaches to investigate the reciprocal interactions between antimicrobial treatments, bacterial growth/death as well as inter-and intra-organ spread. We also discuss how vaccines impact the in vivo behaviour of bacteria and how these findings can guide vaccine design and rational antimicrobial treatment. cessation of antimicrobial treatments, and to guide vaccine treatment.
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