Classical labeling of bacterial pathogens according to their lifestyle in the host: inconsistencies and alternatives

Abstract

An ample understanding of the complex interactions between host and pathogen will improve our ability to develop new prophylactic and therapeutic measures against infection. Precise classification of infectious agents in regards to their infective lifestyles in the host and corresponding pathogenic implications are required because clear concepts are essential to plan fruitful research. Classically, pathogenic bacteria are classified as extracellular, facultative intracellular, and obligate intracellular. In my opinion, this classification is inadequate because, as concluded from data here discussed, it is based on inconsistencies and hyper-valorizes the capacity of the infectious agent replicate in vitro in cell-free media. For a microbial pathogen, what matters is whether intra- or extracellularity is in the context of the in vivo life and in association with pathogenicity. When living as a pathogen in association with its host, what is relevant in microbiological terms is not the ability to grow in artificial cell-free bacteriological media or in environmental niches but whether the intracellular infectious agent, besides the phase of intracellular growth which is behind its label, also is able to live extracellularly in the natural settings of the extracellular territories of their hosts. To eliminate the inconsistencies associated with the classical labeling of bacterial pathogens, I propose that bacterial pathogens be labeled exclusive extracellular, dual intracellular/extracellular and exclusive intracellular based on their infective lifestyle in the host, not in the ability to grow in artificial bacteriological media.

Keywords: dual intra/extracellular pathogens; extracellular pathogens; facultative intracellular pathogens; obligate intracellular pathogens.

Figure 1

The dual lifestyle of intracellular/extracellular bacterial pathogens. (1) Transmission of bacterial pathogens to a new host from infected hosts, (2) from vectors and environment (water, soil, etc.). (3) Intercellular transit in the INTRACELLULAR PHASE (A). (4) Egress of intracellular pathogens to extracellular territories of the host leading to systemic dissemination and extracellular replication [EXTRACELLULAR PHASE (B)]. (C) Switch from the INTRACELLULAR PHASE to the EXTRACELLULAR PHASE, which may be essential for the pathogenesis. (5) Transmission of extracellular bacterial pathogens from infected hosts to vector and environment. (6) Transmission of extracellular pathogens from an infected host to a new host. Red bacteria: bacteria with phenotypes adapted to intracellular life and intercellular transit. Blue bacteria: bacteria with phenotypes adapted to extracellular multiplication in the host.

Figure 2

The three modes of microbial infection. In situation 1 (blue arrows) only the extracellular phase of infection occurs. I label the bacteria following this infectious process “exclusive extracellular pathogens.” In situation 2 (red arrows) extracellular replication occurs after a phase of intracellular multiplication. I label these infectious agents “dual intracellular/extracellular pathogens.” In some infections the extracellular phase may originate new phases of intracellular replication, as is the case of pulmonary tuberculosis (Dannenberg Jr., ; see main text). In situation 3 (green arrows) only the intracellular phase occurs. I label these infectious agents “exclusive intracellular pathogens.” The outcome of the infections will depend on the virulence of the pathogen and on the immune competence of the host.

Figure 3

The group of bacterial pathogens with a dual intracellular/extracellular life style in the host is widespread and expanding. Scheme showing the advanced perspective that the group enclosing intracellular/extracellular bacterial pathogens is continuously enlarging. With advances in the research in the field, traditionally labeled extracellular bacterial pathogens (left) have been transferred to the group of dual intracellular/extracellular pathogens (center) through the demonstration that they use to their advantage the virulence-associated ability to grow intracellularly in the host. On the other hand, traditionally labeled obligate intracellular pathogens (right) have been found to be capable of cell-free replication in vitro although the implications for pathogenicity in vivo of this attribute have not been assessed. Perspectives similar to those in this scheme have previously been hypothesized in relation to the traditionally labeled obligate intracellular or extracellular parasites by Moulder (1985) and Casadevall (2008), respectively. Emerging evidence discussed in this review has strengthened the view of a trend toward the progressive enlargement of the group of intracellular/extracellular bacterial pathogens at the expenses of extracellular and obligate intracellular infectious agents and by discovering new cases of intracellular/extracellular bacteria among facultative intracellular pathogens.