The in vivo extracellular life of facultative intracellular bacterial parasites: Role in pathogenesis

Classically labeled facultative intracellular pathogens are characterized by the ability to have an intracellular phase in the host, which is required for pathogenicity, while capable of extracellular growth in vitro. The ability of these bacteria to replicate in cell-free conditions is usually assessed by culture in artificial bacteriological media. However, the extracellular growth ability of these pathogens may also be expressed by a phase of extracellular infection in the natural setting of the host with pathologic consequences, an ability that adds to the pathogenic potential of the infectious agent. This infective capability to grow in the extracellular sites of the host represents an additional virulence attribute of those pathogens which may lead to severe outcomes. Here we discuss examples of infectious diseases where the in vivo infective extracellular life is well documented, including infections by Francisella tularensis, Yersinia pestis, Burkholderia pseudomallei, Burkholderia cenocepacia, Salmonella enterica serovar Typhimurium and Edwardsiella tarda. The occurrence of a phase of systemic dissemination with extracellular multiplication during progressive infections by facultative intracellular bacterial pathogens has been underappreciated, with most studies exclusively centered on the intracellular phase of the infections. The investigation of the occurrence of a dual lifestyle in the host among bacterial pathogens in general should be extended and likely will reveal more cases of infectious diseases with a dual infective intracellular/extracellular pattern.