Background

Salmonella enterica is a highly iron-dependent siderophilic intracellular Gram-negative pathogen, which can cause local intestinal disease, or severe systemic infection and septicemia. Hence, it was included in the WHO list of the most serious infectious disease threats to human health (Keestra-Gounder et al., 2015; Bumann and Schothorst, 2017). Salmonella invades and multiplies within mononuclear phagocytic cells in the liver, spleen, lymph nodes, and Peyer’s patches, in so-called Salmonella-containing vacuoles (SCV) (Steele-Mortimer, 2008). However, Salmonella exhibits different mechanisms to evade antimicrobial activities, for example by inhibiting phagolysosomal fusion (Baumler and Fang, 2013; Bhutta et al., 2018).

Several immune cells are important in the defense against bacterial infections. While some act as the first barrier, by taking up and killing bacteria, others are responsible for long-term immunity or for coordinating efficient anti-microbial immune responses. Macrophages, dendritic cells (DCs), and neutrophils represent one of the first lines of defense against invading pathogens like Salmonella, by recognizing specific pathogen-associated molecular patterns (PAMPs), and danger-associated-molecular patterns (DAMPs) (de Jong et al., 2012). Recognition of Gram-negative bacteria in macrophages involves the binding of LPS to a receptor complex, leading to the secretion of pro- and anti-inflammatory cytokines (Nagai et al., 2002; Bode et al., 2012). Macrophages can polarize dependending on local factors within the microenvironment, microbial stimuli, and cytokines secreted by other cells. Pro-inflammatory macrophages are essential components of anti-microbial host defense mechanisms, and can be characterized by the synthesis of inducible nitric oxide synthase (iNOS). Anti-inflammatory macrophages dampen the inflammatory state, by producing anti-inflammatory cytokines and Arginase-1 (ARG1). ARG1 cleaves L-arginine, the substrate of iNOS, and thereby impairs the control of various intracellular pathogens (Mosser and Edwards, 2008; Murray, 2017).

Several studies have shown that Salmonella is also phagocytosed by dendritic cells, which serve as an important link between innate and adaptive immunity (Steinman and Hemmi, 2006). Upon phagocytic internalization of bacteria, DCs mature and migrate to defined lymphoid tissues. Thereby, they increase the expression of the major histocompatibility complex II (MHCII) to present specific antigens to T cells, initiating adaptive immune response.

Due to the widespread development of multidrug resistances against antibiotics, current antibiotic treatments of invasive salmonellosis is often not successful. In addition, it is uncertain whether standard antibiotics can penetrate into the Salmonella-containing vacuole. Thus, it is necessary to better understand the host-pathogen interplay in salmonellosis, to develop novel effective antimicrobial therapies targeting intracellular pathogens (Lahiri et al., 2010; Navarre et al., 2010; Mastroeni and Grant, 2011).