An Ecological View of Intracellular Life

Pathogens lack malice; they are just trying to survive.

Arno Karen, in Biography of a Germ, 2000.

We have argued that bacteria developed ways to escape or survive the attack of predatory amoeba in the early ponds of evolution. However, successful intracellular survivors did not only gain the benefit of not being digested but also were rewarded with protection from environmental conditions and the possibility of accessing novel food sources. Exploiting the newly inhabited intracellular niche for survival and growth was a profitable result of novel adaptations to avoid or resist phagocyte digestion (Figure 1.3). The intracellular niche can provide microbes with nutrients, including essential micronutrients they otherwise have to compete for with fellow microbes in the extracellular environment and/or have to capture or synthesize by themselves:

Rickettsiae graze on the host cell's energy sources including ATP [51]. Mycobacteria inhibit phagosome maturation in macrophages and thus inhabit early phagosomes where they can scavenge iron from transferrin because this compartment intersects with the iron import pathway of the host cells (i.e., the transferrin-transferrin receptor uptake system into early endosomes) [52]. Coxiella burnetti and Leishmania amastigotes exploit the harsh lysosomal environment for growth and probably feast on hydrolytic degradation products such as amino acids [53-55]. L. mexicana amastigotes probably exploit autophagolysosomes to access purines [56]. Leishmania species are purine auxotrophs and require host cell-derived purine sources such as autophagosomes. Certain C. trachomatis strains are unable to synthesize the amino acid tryptophan.

Nutrient limitation - the bacteria's Achilles heel - is targeted by the host response in an interferon g (IFNg)-induced manner. Activated macrophages express the gene for indoleamine 2,3-dioxygenase (IDO), which depletes tryptophan by degradation to kynurein [57]. Sequestration of C. trachomatis from tryptophan drives the bacteria to differentiate into the nongrowing residual body form and causes latent infection. The genome of C. psittaci contains a more complete tryptophan synthesis machinery and resistance to IDO of this Chlamydia species is due to efficient recycling of the amino acid [57].

Genome reduction is a common consequence of colonization for pathogens or symbionts which became highly adapted to the intracellular lifestyle and entirely dependent on their host cells. This is seen in diverse obligate intracellular microbes such as the insect symbionts of the Buchnera genus, or M. leprae, Rickettsia or Chlamydia species, as well as in extracellular Mycoplasma species. The host provides a pretty constant environment as well as nutrients and metabolic resources. As a consequence of this close relationship, obligate intracellular microbes lost their ability to survive and proliferate outside of the host cell and become metabolically dependent. This often leads to loss of genes required for the synthesis of organic molecules such as amino acids and, ultimately, to the inability to generate ATP.

In an ecological view of interspecies relationships, interactions between two partners also determine interactions beyond this partnership. Thus, simple coevo-lution is unlikely, because the broad ecological context with its entire range of interacting factors, including food competition and predator-prey interactions, also influence host-parasite/symbiont interactions [58]. Intracellular microbes probably also influence each other. In the broader ecological context it can be hypothesized that intracellular symbionts such as Rhizobium or Wolbachia species enhance the fitness of legumes or parasitic nematodes, respectively. Studies on the evolution of virulence have found that the more virulent parasites are, the higher their transmission rates and the less they are controlled by immunity. It has been shown that immune pressure selects for more virulent parasites [59, 60]. These studies, however, never took into account that hosts with higher parasite loads may be an easier prey for predators and are therefore removed more quickly from the population [58]. This would increase the resistance to the parasite within the host population and would eventually lead to an equilibrium in an individual host-pathogen relationship (i.e., between defense and virulence). It may become disturbed, however, when the predator is removed, for example, or a new pathogen is introduced that affects herd immunity. A good example is the increased tuberculosis rate as boosted by the HIV pandemic.

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