Intramacrophage Survival for Extracellular Bacterial Pathogens: MgtC As a Key Adaptive Factor

Classically, pathogenic bacteria are classified as intracellular or extracellular pathogens. Intracellular bacterial pathogens, as Mycobacterium tuberculosis, Salmonella enterica, Brucella suis, or Listeria monocytogenes, can replicate within host cells. After entering the target host cell (professional or non-professional phagocyte), the intracellular pathogen follows vacuolar or cytosolic pathways to replicate. In contrast, extracellular pathogens, as Staphylococcus aureus, Pseudomonas aeruginosa or streptococci, avoid phagocytosis, thus promoting extracellular multiplication. However, the situation appears more complex with a dual lifestyle of intracellular/extracellular bacterial pathogens (Silva, 2012). Indeed, diverse bacterial intracellular pathogens have the ability to produce extracellular infections as a second phase after the initial intracellular stage. Conversely, several extracellular pathogens can enter host cells in vivo, resulting in a phase of intracellular residence, which can be of importance prior the typical extracellular infection. During infection, macrophage lineage cells eliminate infiltrating pathogens through a battery of antimicrobial responses that include oxidative and acid stresses, toxic metal cations, and antimicrobial peptides. Bacterial pathogens have developed strategies to escape the innate immune system and counteract the microbicidal action of macrophages (reviewed by Sarantis and Grinstein, 2012). Whereas some pathogens inhibit phagocytosis (extracellular pathogens), others use virulence factors to subvert the macrophage antimicrobial role and manipulate the host-cell to establish a replication niche. Hence, intracellular pathogens overcome macrophage defenses and use these immune cells as residence and dissemination strategies. Even if it accounts for a transitory initial event, so-called extracellular pathogens can also encounter an intramacrophage stage and have therefore to escape the killing by these immune cells. Intracellular bacteria use a broad range of molecular pathogenicity determinants to manipulate host cell processes and adapt to the intracellular environment. Recent data, described below, reveal that so-called extracellular pathogens have also acquired similar pathogenicity determinants to improve intramacrophage survival.