Metal uptake in host-pathogen interactions: Role of iron in Porphyromonas gingivalis interactions with host organisms

Iron is a nutrient that is indispensable for growth of almost all living organisms. The virulence of pathogenic organisms in the mammalian host is related to the availability of iron, therefore, microbial iron acquisition mechanisms are an important determinant of infection potential. Indeed, iron levels regulate 10–20% of all genes present on microbial genomes, including iron acquisition mechanism and virulence factor encoding genes. The association between iron and microbial virulence is well established (121,158). Many infectious diseases, such as gonorrhea, malaria, tuberculosis, and diarrheal infections, depend on the expression of microbial acquisition mechanisms capable of competing with the host’s iron scavenging mechanisms. The availability of iron in the mammalian host is extremely low, therefore, successful pathogens evolved strategies to overcome this limitation. Some pathogens produce high affinity metal chelators capable of competing with the host’s scavenging mechanisms, while others degrade and release mammalian proteins such as transferrin or hemoglobin that bind iron or hemin. Iron overload in the host from genetic predispositions, therapeutic intervention, or nutritional status can also increase the risk of infection by many pathogens, such as Plasmodium falciparum and Mycobacterium tuberculosis (121). Treating the host by administering iron chelators that capture free iron and compete with the acquisition system can limit microbial iron acquisition. However, this treatment also limits the availability of iron for the host, which can also have a damaging effect. Another way to alter iron availability is to interfere with the microbial iron acquisition mechanisms required by the pathogen to survive at specific stages of infection. Therefore, understanding the role of the iron acquisition mechanisms at various stages of bacterial infection may lead to the development of additional interventional strategies. The oral cavity harbors at least 700 different species of bacteria (1,19,104,105,139). The contribution of many of those species to onset and progression of oral diseases is still to be established. However, several bacterial species are strongly implicated as aetiological agents of periodontal diseases. Among them are members of the Bacteroidetes phylum: Porphyromonas gingivalis, Prevotella intermedia, and Tannerella forsythia ((18,40,105). Of these, P. gingivalis is the most intensively investigated oral bacterium, and significant progress has been made in recent years regarding its iron uptake mechanisms. Because of this, we chose P. gingivalis as a model to describe the role of iron in host-pathogen interactions in the oral cavity. P. gingivalis is a black pigmented, anaerobic, gram-negative bacterium that is implicated as a prime aetiological agent of initiation and progression of periodontal disease (40,46). As periodontal disease is also associated with increased risk of systemic conditions, such as coronary heart disease and preterm delivery of low birthweight infants (43,50,93,107,119,120,148), the burden of infection caused by P. gingivalis may be higher than previously estimated. The periodontal status of patients was significantly improved following elimination of the bacterium (reviewed in (40,113), however, current therapies still allow for recurrent infections (3,17,125). Currently, the standard therapeutic approach includes mechanical removal of the organism followed by antibiotic treatment. But rapidly increasing resistance to antibiotics and the potential for recurrent infection suggests more targeted and longer-lasting approaches are needed to reduce the levels of P. gingivalis in the oral cavity. To achieve this goal, a thorough knowledge of the biology of P. gingivalis is needed. Periodontal diseases are triggered by microorganisms and manifest themselves in inflammation, bleeding, and destruction of soft and tooth tissues. P. gingivalis is found in healthy sites such as the buccal mucosa, tongue, tonsils, palate and supragingival dental plaque on the tooth enamel surface (86), but its numbers are significantly elevated in the subgingival environment and especially in diseased areas (92), suggesting the bacterium is well adapted and benefits from the hostile inflammatory state of the host. To survive in the diseased periodontal pocket the pathogen must be able to escape host defenses and acquire sufficient nutrients that will sustain its growth. One such nutrient required for growth of P. gingivalis is iron, and its presence has a profound effect on the bacterium’s virulence. Using a mouse abscess model, the Ebersole group demonstrated that bacteria grown under hemin-limitation were less virulent than their counterparts grown in hemin-excess (64,83,87). In this review, we discuss the mechanisms of iron acquisition by P. gingivalis. We also describe regulatory mechanisms, because excess iron reacts with peroxide to generate hydroxyl radicals that are detrimental to the bacterial cell. P. gingivalis is distantly related to bacteria in which iron acquisition and homeostasis mechanisms are well known, so this review provides novel supportive information with regard to iron acquisition mechanisms in bacteria.