Heme acquisition mechanisms of Porphyromonas gingivalis – strategies used in a polymicrobial community in a heme‐limited host environment

Abstract

Summary Porphyromonas gingivalis, a main etiologic agent and key pathogen responsible for initiation and progression of chronic periodontitis requires heme as a source of iron and protoporphyrin IX for its survival and the ability to establish an infection. Porphyromonas gingivalis is able to accumulate a defensive cell‐surface heme‐containing pigment in the form of μ‐oxo bisheme. The main sources of heme for P. gingivalis in vivo are hemoproteins present in saliva, gingival crevicular fluid, and erythrocytes. To acquire heme, P. gingivalis uses several mechanisms. Among them, the best characterized are those employing hemagglutinins, hemolysins, and gingipains (Kgp, RgpA, RgpB), TonB‐dependent outer‐membrane receptors (HmuR, HusB, IhtA), and hemophore‐like proteins (HmuY, HusA). Proteins involved in intracellular heme transport, storage, and processing are less well characterized (e.g. PgDps). Importantly, P. gingivalis may also use the heme acquisition systems of other bacteria to fulfill its own heme requirements. Porphyromonas gingivalis displays a novel paradigm for heme acquisition from hemoglobin, whereby the Fe(II)‐containing oxyhemoglobin molecule must first be oxidized to methemoglobin to facilitate heme release. This process not only involves P. gingivalis arginine‐ and lysine‐specific gingipains, but other proteases (e.g. interpain A from Prevotella intermedia) or pyocyanin produced by Pseudomonas aeruginosa. Porphyromonas gingivalis is then able to fully proteolyze the more susceptible methemoglobin substrate to release free heme or to wrest heme from it directly through the use of the HmuY hemophore.

Missing pieces of the puzzle to effectively control digital dermatitis

“…Likewise, we must also consider the possibility that regardless of potential interaction between the bacterial species themselves, the presence of these multiple species could impact the immune response of the host, particularly by polyclonal activation of the lymphoid system and induction of immunological dysregulation (Montes, Acosta‐Rodriguez, Merino, Bermejo, & Gruppi, ). Alternatively, expression of virulence factors such as proteases or leukotoxins by some organisms may alter the ecological adaptation and virulence potential of other organisms in the same niche (Castro et al., ; Lohinai et al., ; Smalley & Olczak, ). Although these interactions have the potential to be extremely complex and time‐consuming to study, it is likely that this broader systems approach to the complex pathobiology of DD holds potential for more fully understanding the mechanisms and roles that each of these organisms may play in the disease process.…”

Potential role for Streptococcus gordonii‐derived hydrogen peroxide in heme acquisition by Porphyromonas gingivalis

“…The main source of heme in the human host is hemoglobin and P. gingivalis obtains heme from it with the aid of R‐ and K‐gingipains, and hemophore‐like proteins such as HmuY and HusA . Although R‐gingipain mediates oxidation of oxyHb to metHb for further globin degradation by K‐gingipain and eventual heme extraction by HmuY, here we have shown that the metHb formed by the action of H 2 O 2 produced by S. gordonii represents another potential source from which Fe(III)heme might be gained without the reliance upon R‐gingipain protease at a time when there is insufficient R‐gingipain expression by P. gingivalis .…”

“…Hanioka et al showed that Hb in gingival tissue may be up to 80% O 2 ‐saturated and hence any Hb entering the gingival sulcus or periodontal pocket following tissue bleeding will initially be largely oxygenated. For heme‐requiring organisms like P. gingivalis to use heme in the form of oxyHb they must be reliant upon mechanisms that guarantee the efficient conversion of oxyHb into the metHb form, from which heme may be more easily extracted . In this context, we observed that Hb extracted from S. gordonii zones of α‐hemolysis typically contained > 90% in the metHb form after 16 hours of aerobic growth, demonstrating that the organism can facilitate large‐scale oxidation of oxyHb.…”

“…Heme sources available to P. gingivalis in the gingival sulcus and periodontal pocket also include the serum proteins albumin and hemopexin, which function to sequester free heme especially during inflammation. However, it must be remembered that P. gingivalis may survive during periods in these habitats where there is no host‐derived heme.…”

Porphyromonas gingivalis: the gift of community involvement

“…The asaccharolytic nature of P. gingivalis is facilitated by its proteolytic capacity, which is vital for nutrition. As part of its function, proteolytic enzymes play a role in the acquisition of heme, a required component for growth, survival and virulence in the polymicrobial community of the heme‐limited host environment (reviewed by Smalley and Olczak and available in the accompanying virtual issue). The authors reviewed data that suggested that P. gingivalis uses a novel heme acquisition mechanism from hemoglobin.…”