Brewer, S. M. | Search bioRxiv

bioRxiv2022

Single-cell profiling identifies ACE+ granuloma macrophages as a non-permissive niche for intracellular bacteria during persistent Salmonella infection

Macrophages mediate key antimicrobial responses against intracellular bacterial pathogens, such as Salmonella enterica. Yet, they can also act as a permissive niche for these pathogens to persist in infected tissues within granulomas, which are immunological structures comprised of macrophages and other immune cells. We apply single-cell transcriptomics to investigate macrophage functional diversity during persistent Salmonella enterica serovar Typhimurium (STm) infection in mice. We identify determinants of macrophage heterogeneity in infected spleens and describe populations of distinct phenotypes, functional programming, and spatial localization. Using a STm mutant with impaired ability to polarize macrophage phenotypes, we find that angiotensin converting enzyme (ACE) defines a granuloma macrophage population that is non-permissive for intracellular bacteria and their abundance anticorrelates with tissue bacterial burden. Disruption of pathogen control by neutralizing TNF preferentially depletes ACE+ macrophages in infected tissues. Thus ACE+ macrophages have differential capacity to serve as cellular niche for intracellular bacteria to establish persistent infection. TeaserThis study shows that ACE+ granuloma macrophages have restricted capacity to act as a cellular niche that enables intracellular bacterial persistence.

immunology↗

bioRxiv2021

Gut regulatory T cells mediate immunological tolerance in Salmonella Typhimurium-infected superspreader hosts by suppressing cytotoxic activity of T cells.

Superspreader hosts carry out most pathogen transmission events and are often disease tolerant since they remain asymptomatic despite high pathogen burdens. Here we describe the superspreader immune state that allows for disease tolerance. In a model of Salmonella infection, superspreader mice develop colitis with robust CD4+ and CD8+ T-cell responses, however, they remain asymptomatic. We found that superspreaders have significantly more regulatory T cells (Tregs) in the distal gut compared to non-superspreader infected hosts. Surprisingly, the depletion of Tregs did not induce pathogen clearance but rather exacerbated weight loss, increased gut inflammation, and compromised epithelial intestinal barrier. This loss of tolerance correlated with dramatic increases in cytotoxic CD4+ and CD8+ T cells. Interestingly, CD4 neutralization in Tregs-depleted superspreaders was sufficient to rescue tolerance. Our results indicate that Tregs play a crucial role in maintaining immunologic tolerance in the guts of superspreader mice by suppressing cytotoxic CD4+ and CD8+ T-cell activities. AUTHOR SUMMARYSuperspreader hosts are the main cause of disease transmission and a very important public health concern. Here, we evaluated the immunological tolerance of the Salmonella infected superspreaders in a mouse model. By manipulating Tregs, we demonstrated the immunological mechanism from the host to maintain health status and high pathogen burden. Tregs depletion in the superspreaders led to severe disease, with damage of the intestinal epithelia, and high morbidity without having any effect on shedding and systemic Salmonella burden. Furthermore, we demonstrated that the damage of the intestinal epithelia was related to cytotoxic activity of T cells. When Tregs were depleted, CD8+ T cells produced high levels of granzyme B and perforin. CD8+ T cells neutralization in Tregs depleted mice led to increased cytotoxic CD4+ T cells. Interestingly, neutralization of CD4+ T cells in the Tregs depleted mice led to a reduction in the CD8+ T cells producing granzyme B and it was sufficient to rescue host tolerance in this model. We demonstrate for the first time that cytotoxic CD4+ T cells damage the epithelial intestinal barrier and contribute to loss of tolerance in the context of a superspreader host. These findings open new perspectives to understand mechanisms of tolerance in the intestine of a superspreader host.

immunology↗