How bacterial pathogens colonize their hosts and invade deeper tissues

Bacterial pathogens have evolved a wide range of strategies to colonize and invade 33 human organs, despite the presence of multiple host defense mechanisms. In this review, we 34 will describe how pathogenic bacteria can adhere and multiply at the surface of host cells, 35 how some bacteria can enter and proliferate inside these cells, and finally how pathogens may 36 cross epithelial or endothelial host barriers and get access to internal tissues, leading to severe 37 diseases in humans. 38 39 40 41 42 43 46 47


53
The human body harbours a large number of bacteria but their localisation in healthy 54 individuals is normally restricted to certain body areas such as the skin, the mucosae of buccal 55 and nasal cavities, vagina and, most importantly, the gastrointestinal tract [1], [ The internal tissues are normally sterile. In some circumstances, however, some opportunistic 57 pathogens are able to enter the host by taking advantage of injuries or breaches in one of the 58 different host barriers. In addition, bona fide pathogens have evolved mechanisms to cross 59 host barriers and reach deeper organs where they proliferate and lead to severe disease for 60 their host. 61 In this review, we will describe the diversity of mechanisms used by bacterial 62 pathogens to colonize and invade human organs. We will first focus on the capacity of these 63 bacteria to adhere and to proliferate at the surface of host cells and tissues, despite a wide-64 range of defense mechanisms used by the host. We will then present how some bacteria are prevent bacterial adhesion to epithelial surface, as reported in the case of gastric mucus 103 colonized by the pathogenic bacterium Helicobacter pylori [15]. Interestingly, some bacterial 104 pathogens have evolved mechanisms to go through this mucus layer in order to reach 105 epithelial cells. They either produce proteases and directly target host mucins, locomote via 106 flagella-based motility or resist to antimicrobial products [16], [17], [18], [19], [20], [21] (Fig. 2). 107 Interactions between pathogenic bacteria and host mucus thus constitute a challenging issue 108 during host infection. can be considered as a mechanism used by pathogens to alter the microbiota composition, 125 thereby allowing them to outcompete luminal commensals [26]. Inflammation of the gut is 126 characterized by an increase in the quantity of mucosal antimicrobial peptides to which 127 pathogens may exhibit higher resistance compared to commensals [20], [21], [22]. Mucosal 128 inflammation also leads to the production of specific compounds that can be used by 129 pathogens such as particular glycosylated proteins or tetrathionate [27], [28]. This last molecule 130 is indeed used by the murine enteric bacterial pathogen Salmonella Typhimurium, which uses 131 it as a terminal electron acceptor during anaerobic respiration, giving to this pathogen a 132 growth advantage over fermenting commensal bacteria in this inflamed environment [28] (Fig.   133 2). Together, the overall crosstalks and interactions between commensal bacteria, enteric  The base of these structures, initially discovered in gram-negative bacteria, is anchored to the 161 bacterial outer membrane, whereas the tip is usually an adherence factor conferring the 162 binding specificity of these structures. For example, UPEC, which are uropathogenic strains 163 of E. coli colonizing the urinary tract and involved in kidney infections, display 164 pyelonephritis-associated (P) pili at their surface. The tip of these pili is constituted by an 165 adhesion factor called PapG, that binds to glycosphingolipids of the kidney epithelium [32].

166
Some UPEC strains also possess Type I pili at their surface, which have binding specificity to

197
In the last decade, pili structures have also been observed in gram-positive bacteria.

198
Two types of pili have been described so far in these species. The first class consists in 199 "sortase-assembled pili", in which successive pilin subunits are linked by isopeptide bonds     (Fig. 4). 303 In the case of the trigger mechanism, bacteria activate signalling pathways leading to

431
Of note, this mechanism of epithelium traversal has also been reported for S. Typhimurium  The diversity of niches that may be colonized by pathogenic bacteria in the human 472 body is huge. Bacteria have evolved various mechanisms to adhere to the surface of organs in 473 contact with the external milieu, such as the intestine. In addition, some bacteria can adopt an 474 intracellular lifestyle and get internalized inside various host cells types to replicate away 475 from the humoral host immune defenses. In this case, there is again a wide-range of strategies 476 adopted by pathogenic bacteria, which can be illustrated by the different cellular locations 477 they are able to use for replication. Finally, pathogenic bacteria can get access to deeper 478 tissues using various mechanisms to cross mucosal barriers, and access the bloodstream, 479 which is an entry portal for potentially all host organs, and is often associated to severe 480 clinical symptoms.

481
In addition to mucosal surfaces, the skin also corresponds to a preferential site of 482 contact with pathogens. As for mucosal barriers, the production of antimicrobial molecules  The frontier between commensals and pathogens is also not as straightforward as  Finally, in addition to genetic-driven host susceptibility, it is now well-established that 527 the microbiota is playing a critical role to limit colonization and invasion by enteric