Hypoxia-related immune subsets induced by Salmonella Typhi infection link early bacterial gut invasion to human infection outcomes

Salmonella Typhi (S. Typhi), the causative agent of typhoid disease, remains a major public health concern. Owing to the human-restricted nature of S. Typhi, current studies of typhoid pathogenesis in animal models are limited to a murine non-typhoidal pathogen. Furthermore, human studies are limited to analyses of peripheral immune responses which are blind to tissue-specific immunity and do not allow perturbations. What is now needed is an integrative approach that will provide mechanistic insights into S. Typhi pathogenesis and immune correlates of infection outcome. Here, we performed an integrated single-cell analysis of immune responses from the human S. Typhi challenge model and mouse model of typhoid disease, to associate biological mechanism with human infection outcome. Most prominent, we revealed immune subsets with a hypoxia-related signature in circulating immune cells from individuals that develop disease in the human challenge model. This signature was also evident in the mouse model in activated macrophages infiltrating into the Peyers patches, but not during infection with a mutant strain impaired for gut invasion. We further identified hypoxia-related signature as a general immune correlate of disease outcome in other infection- and inflammatory-related diseases. Collectively, using integrated analysis of mouse and human infection models, we revealed a hypoxia-related signature that link immune responses during bacterial invasion to increased risk of developing typhoid disease in humans, suggesting a possible causative role during the development of typhoid disease.