Low-oxygen tensions found inSalmonella-infected gut tissue boostSalmonellareplication in macrophages by impairing antimicrobial activity and augmentingSalmonellavirulence

Abstract

In Salmonella infection, the Salmonella pathogenicity island-2 (SPI-2)-encoded type three secretion system (T3SS2) is of key importance for systemic disease and survival in host cells. For instance, in the streptomycin-pretreated mouse model SPI-2-dependent Salmonella replication in lamina propria CD11c(-)CXCR1(-) monocytic phagocytes/macrophages (MΦ) is required for the development of colitis. In addition, containment of intracellular Salmonella in the gut critically depends on the antimicrobial effects of the phagocyte NADPH oxidase (PHOX), and possibly type 2 nitric oxide synthase (NOS2). For both antimicrobial enzyme complexes, oxygen is an essential substrate. However, the amount of available oxygen upon enteroinvasive Salmonella infection in the gut tissue and its impact on Salmonella-MΦ interactions was unknown. Therefore, we measured the gut tissue oxygen levels in a model of Salmonella enterocolitis using luminescence two-dimensional in vivo oxygen imaging. We found that gut tissue oxygen levels dropped from ∼78 Torr (∼11% O2) to values of ∼16 Torr (∼2% O2) during infection. Because in vivo virulence of Salmonella depends on the Salmonella survival in MΦ, Salmonella-MΦ interaction was analysed under such low oxygen values. These experiments revealed an increased intracellular replication and survival of wild-type and t3ss2 non-expressing Salmonella. These findings were paralleled by blunted nitric oxide and reactive oxygen species (ROS) production and reduced Salmonella ROS perception. In addition, hypoxia enhanced SPI-2 transcription and translocation of SPI-2-encoded virulence protein. Neither pharmacological blockade of PHOX and NOS2 nor impairment of T3SS2 virulence function alone mimicked the effect of hypoxia on Salmonella replication under normoxic conditions. However, if t3ss2 non-expressing Salmonella were used, hypoxia did not further enhance Salmonella recovery in a PHOX and NOS2-deficient situation. Hence, these data suggest that hypoxia-induced impairment of antimicrobial activity and Salmonella virulence cooperate to allow for enhanced Salmonella replication in MΦ.

Oxygen metabolism and barrier regulation in the intestinal mucosa

“…Mucosa-associated microbiota are likely also prominent modulators of potential hypoxia-elicited autophagic responses (see Figure 2). Both commensal and pathogenic species have been shown to influence mucosal pO 2 and/or enterocyte HIF signaling (95,121,122), and ablation of epithelial HIF-1 increases susceptibility to pathogen infection in a number of studies (95,121). Reciprocally, intestinal oxygenation directly shapes the composition of gut microbial communities, and oxidative changes in intestinal inflammation may underlie the dysbiosis characteristic of IBD (5).…”

Mechanisms of inflammation-driven bacterial dysbiosis in the gut

“…For instance, a recent study demonstrated a significant reduction in gut tissue oxygen levels in mice infected orally with Salmonella . 68 Higher blood flow and hemoglobulin within the luminal environment in an inflamed intestine is thought to result in a more aerobic microenvironment in the lumen that favors the bloom of facultative anaerobes such as Enterobacteriaceae. 59 However, it remains challenging to measure luminal oxygen levels.…”

The iron-sulfur cluster sensor IscR is a negative regulator of Spi1 type III secretion system in Salmonella enterica

“…They also reflect an adaptive mechanism used by Salmonella to favor its infectivity in the gut lumen and tissues, where oxygen is rare and iron available to the bacterium (Kortman, Raffatellu, Swinkels, & Tjalsma, ; Jennewein et al . , ).…”

“…, ; Jennewein et al . , ). In contrast, iron is present in sufficient amounts to sustain bacterial replication in the gut, although the production of siderophores by enteric pathogens suggests a limited availability (Kortman et al .…”