Deciphering the immune subsets in Salmonella Typhi human infection which underly disease outcome

Management of bacterial infections is becoming increasingly difficult due to rapidly evolving pathogens with increased virulence and drug resistance. Promising alternatives to targeting pathogens, novel anti-infective approaches, harness the host’s own response to infection. To use these alternatives, a comprehensive understanding of the complex interaction between different immune cells, and how they translate into infection outcome is required. Currently, our understanding of human infection is limited to studies performed at disease stages, when symptoms already evident. We believe that early stages of infection are critical in determining infection outcome. To bridge this gap, models of human disease are required, in order to characterize early immune responses which correlate with infection outcome. For this, we used samples from the human challenge model, in which healthy volunteers are infected with Salmonella Typhi (S.ty). We performed single-cell RNA-seq on PBMCs samples from 6 individuals before and in different time-points post-infection. Three individuals developed disease and three did not. We functionally characterized the immune subsets and found (1) immune subsets that are shared across all individuals and represent global response to S.ty infection; and (2) immune subset that exhibit inter-individual variability which was connected to infection outcome. Interestingly, some of these states were already evident before challenge, suggesting protective effects to S.ty infection; other states were evident as early as 12 hours post challenge. These immune subsets can be used to predict the risk to develop disease, and suggest new opportunities to direct the course of infection towards a favorable outcome to the host.