Aggregatibacter actinomycetemcomitans: Difference between revisions

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==Classification==
==Classification==
Kingdom: ''Bacteria'' <br>Phylum: ''Proteobacteria'' <br>Class: ''Gammaproteobacteria'' <br>Order: ''Pasteurellales'' <br>Family: ''Pasteurellaceae'' <br>Genus: ''Aggregatibacter'' <br>Species: ''Actinomycetemcomitans''
Kingdom: ''Bacteria'' <br>Phylum: ''Proteobacteria'' <br>Class: ''Gammaproteobacteria'' <br>Order: ''Pasteurellales'' <br>Family: ''Pasteurellaceae'' <br>Genus: ''Aggregatibacter'' <br>Species: ''Actinomycetemcomitans'' <br> [9]


===Species===
===Species===
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====Description====
====Description====
In 1975, scientists Killian and Schiott were the first to demonstrate that Aggie was present in dental plaque and from that point on, more and more important discoveries about Agie have been made. Aggregatibacter actinomycetemcomitans are nonmotile, gram-negative bacteria capable of growing under both aerobic and anaerobic conditions. They also thrive in high concentrations of carbon dioxide. What’s really interesting about this bacterium is its shape. You can see it has an internal star-shape and translucent colonies. Aggie has three main features including fimbriae, vesicles and extracellular amorphous materials. Fimbriae of aggie are small, filamentous cell surface appendages. They are uniformly distributed in bundles and don’t measure more than two micrometers in diameter. Aggie can either have star-positive fimbriated colonies or have a non-fimbriated strain. Non-fimbriated aggie are smooth, leading to poor adherence and poor biofilm forming capacity. The most abundant fimbriae protein is 304-a, a thin protein with a low molecular weight. These fimbriae provide the attachment factor, allowing adhesion. Vesicles, otherwise known as blebs, of Aggie are lipopolysaccharide in nature, which is common for a great majority of gram-negative bacteria. Highly leukotoxic strains of Aggie tend to have more vesicles. These leukotoxins are described as virulence factors that kill leukocytes allowing them to escape from the host immune system. They play a critical role in the survival of Aggie and periodontal disease progression. Aggie’s vesicles also contain endotoxin, which is critical in the role of Aggie. Endotoxin basically links cytokine stimulation and proinflammatory reactions, leading to the decay of dental pulp and periodontal disease. Vesicles also contain a bacteriocin named actinobacillus which is known for adhering to and colonizing the human oral cavity, leading to aggressive periodontitis. Furthermore, these vesicles also exhibit adhesive properties and function to deliver toxic materials. Finally, the extracellular amorphous material exhibits bone-resorbing activity and adhesive properties as well.
[[File:Screenshot_2024-04-07_at_10.19.28_PM.png|left|180px|thumb|Figure 1. Star-positive ''A.actinomycetemcomitans'' demonstrating its star shaped interior [17]]] ''Aggregatibacter actinomycetemcomitans'' are exogenous, nonmotile, gram-negative bacteria found in the oral cavity [9]. They are capable of growing under both aerobic and anaerobic conditions and are classified as capnophilic, meaning they thrive in high concentrations of carbon dioxide. With an internal, opaque, rought-textured star-shape and translucent colonies, ''A. actinomycetemcomitans'' have three main features: fimbriae, vesicles and extracellular amorphous material [9]. Fimbriae of ''A. actinomycetemcomitans'' are small, filamentous cell surface appendages. They are uniformly distributed in bundles and don’t measure more than two micrometers in diameter. ''A. actinomycetemcomitans'' can either form star-positive, fimbriated colonies with a star shaped interior, or form star-negative, non-fimbriated colonies [9]. Non-fimbriated ''A. actinomycetemcomitans'' are smooth, causing characteristics of poor adherence and poor biofilm forming capacity. The most abundant fimbriae protein in this bacterium is 304-a, a thin protein with a low molecular weight. These fimbriae provide the attachment factor, allowing adhesion to hydroxyapatite, a mineral of the tooth. Vesicles, otherwise known as blebs, of ''A. actinomycetemcomitans'' are lipopolysaccharide in nature, which is common for a great majority of gram-negative bacteria. Highly leukotoxic strains of ''A. actinomycetemcomitans'' tend to have more vesicles. These leukotoxins are described as virulence factors which kill leukocytes allowing them to escape from the host immune system. They play a critical role in the survival of ''A. actinomycetemcomitans'' and periodontal disease progression [14]. ''A. actinomycetemcomitans'' vesicles also contain endotoxin, which is critical in the role of this bacteria as it links cytokine stimulation and pro-inflammatory reactions, leading to the decay of dental pulp and the progression of periodontal disease. Furthermore, vesicles also contain a bacteriocin named ''actinobacillus'', known for adhering to and colonizing the human oral cavity, leading to aggressive periodontitis. Additionally, these vesicles also exhibit adhesive properties and function to deliver toxic materials. Finally, the extracellular amorphous material exhibits bone-resorbing activity and adhesive properties [9].


[[File:Screenshot_2024-04-07_at_10.19.28_PM.png|50px]]
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====Significance====
====Significance====
Aggie inhabits the mouths of one-third or more of the population. It is most commonly known as a systemic pathogen, causing the rapid progression of localized aggressive periodontal disease, otherwise known as LAP. As a matter of fact, aggie is present in approximately 90% of patients with LAP. LAP is significant because, as opposed to general periodontitis, it specifically impacts the central incisors (which are your top two teeth and bottom two teeth) and first molars. It is common for LAP patients to have tooth loss and breakdown of supporting tooth structures when this disease is left untreated. Another risk is through blood circulation, there is the risk of swelling of the endocardium, the innermost tissue lining the heart. This actually makes a lot of sense because Aggie thrives in environments of periodontal pockets and blood circulation. This shines light on the importance of maintaining proper oral hygiene because of the significant correlation between oral and cardiovascular health. Referring to the general population, approximately 70,000 adolescents in the United States develop periodontitis disease annually. And individuals of African-American descent have a 10 to 15 fold greater risk of developing periodontal disease than Caucasian Americans.
''A. actinomycetemcomitans'' is prevalent in more than one-third of the population [17]. In the United States, approximately 70,000 adolescents develop periodontitis disease annually. Additionally, individuals of African-American descent have a 10 to 15 fold greater risk of developing periodontal disease than Caucasian Americans [15]. There still is not a concrete answer for this significant difference in risk, however several reports state that a contributing factor is the lack of dental care. [[File:Stages-of-Gum-Disease-Periodontitis.jpg|right|300px|thumb|Figure 2. Progression of periodontitis in a patient's tooth [16]]] ''A. actinomycetemcomitans'' is most commonly known as a systemic pathogen, causing the rapid progression of localized aggressive periodontal disease, otherwise known as LAP. ''A. actinomycetemcomitans'' is present in approximately 90% of patients with LAP [2]. Similarly, 97% of this bacteria is commonly found in LJP (localized juvenile periodontitis) lesions [15]. LAP is significant because, as opposed to general periodontitis, it specifically impacts the central incisors and first molars. It is common for LAP patients to experience tooth loss and breakdown of supporting tooth structures when this disease is left untreated [1]. Patients may also experience the risk of swelling of the endocardium, the innermost tissue lining the heart [9]. ''A. actinomycetemcomitans'' thrives in environments of periodontal pockets and blood circulation, being the reason for the prevalence of these risks. This shines light on the importance of maintaining proper oral hygiene because of the significant correlation between oral and cardiovascular health.


==Genome Structure==
==Genome Structure==
Aggregatibacter actinomycetemcomitans, a bacterium of clinical
The ''A. actinomycetemcomitans'' genome is made of ranges from 2.0 to 2.7Mb, which is very small compared to other bacteria. It is a single circular chromosome, which contains 2206 genes that make up its genomic structure. These genes include 2129 coding sequenced, along with 19 rRNAs and 54 tRNAs that are need in protein synthesis. Also 4 noncoding RNAs regulate the function that are in the bacteria. Based on differences in its genomic composition and transformation capacity, ''A. actinomycetemcomitans'' can be divided into three evolutionary lineages (I, II, and III) [5]. It has also been shown that serotyping, the common approach to categorization, is not useful for providing a complete description of the species since certain serotypes are not restricted to specific lineages. In addition, ''A. actinomycetemcomitans'' distinct lineages exhibit varying degrees of natural competence. This transformative capacity is linked to horizontal gene transfer and could impact the proportion of a strain's genome that is found within the species. Furthermore, ''A. actinomycetemcomitans's'' prior taxonomic classifications were entirely based on serotyping [5].
significance, exhibits a relatively small genome size compared to other bacteria, ranging from 2.0 to 2.7 Mb. Its genome structure is characterized by a single circular chromosome containing 2,206 genes. Among these genes are 2,129 coding sequences, which contribute to various cellular functions, along with 19 rRNAs and 54 tRNAs responsible for protein synthesis. Additionally, the genome harbors 4 noncoding RNAs, which may play regulatory roles within the bacterium. Whole genome sequencing (WGS) studies have revealed that A. actinomycetemcomitans can be divided into three phylogenetic lineages (I, II, and III) based on differences in genomic content and competence for transformation. Furthermore, serotyping, traditionally used for classification, has been shown to be insufficient for accurately characterizing the species, as certain serotypes are not confined to specific lineages.
 
In addition to its genomic diversity, A. actinomycetemcomitans exhibits
variation in competence for transformation, with specific lineages showing
varying degrees of natural competence. This competence for transformation is
linked to horizontal gene transfer and may impact the genome size of strains
within the species. Moreover, WGS studies have challenged traditional
taxonomic classifications of A. actinomycetemcomitans based solely on
serotyping. Certain strains, such as those in the clade e&#39; outgroup, have been found to fall outside the species boundary based on genomic relatedness. Therefore, while serotyping and WGS provide valuable insights into the genetic diversity and phylogenetic relationships of A. actinomycetemcomitans, the latter offers a more comprehensive understanding of its genome structure, lineage diversity, and taxonomic implications.


==Cell Structure, Metabolism and Life Cycle==
==Cell Structure, Metabolism and Life Cycle==


====Cell Structure and Metabolism====
====Cell Structure and Metabolism====
 
''Aggretatibacter actinomycetemcomitans'' has a distinct metabolism and cell structure. It has certain characteristic such as it has rod and facultative anaerobic bacteria that is Gram-negative with specific traits [3].The dimensions of its rod-shaped cell normally range from 0.4 to 0.5 µm in width and 1.0 to 1.5 µm in length. These cells sometimes appear as cocci under microscope as seen in Image A of Figure 3 that is collected from clinical sample. This bacterium exhibits environmental flexibility despite not being motile and lacking flagella. It grows poorly in environment air but thrives in 5% CO2. On chocolate agar, colonies are tiny, rough-textured, and firm, sticking to the agar surfaces with great strength as seen in figure B [6]. [[File:Picture1.png|left|250px|thumb|Figure 3. (A) ''A. actinomycetemcomitans'' strain HK1651 on chocolate agar. (B) Distinctive "star shaped" colony incubated and grown in TSBV agar [6]]] ''A. actinomycetemcomitans'' is also unique in that it can create a number of different enzymes and toxins, such as leukotoxin and cytolethal distending toxin (CDT). This adds to its pathogenicity in periodontal infections. Although this bacteria lacks mobility, its rough texture helps it stick to surfaces. This increases colonization and pathogeneticity. ''A. actinomycetemcomitans'' can produce a variety of toxins that are essential to its pathogenicity through metabolism, which can lead to tissue damage and immune evasion in the host [3].  
Aggregatibacter actinomycetemcomitans, a clinically significant bacterium
associated with periodontal disease, exhibits distinctive cell structure and
metabolism. As a fastidious, facultatively anaerobic, Gram-negative rod, A.
actinomycetemcomitans presents unique characteristics. Microscopically, its cells may appear as cocci in broth and clinical samples, indicating potential
pleomorphism. Despite its non-motile nature and lack of flagella, this bacterium demonstrates adaptability to environmental conditions, thriving well in 5% CO2 but growing poorly in ambient air. Colonies on chocolate agar are notably small, rough-textured, and tenacious, adhering strongly to agar surfaces. Additionally, A. actinomycetemcomitans is distinguished by its capability to produce important toxins, including leukotoxin, cytolethal distending toxin, and various enzymes, contributing to its pathogenicity in periodontal infections.
 
Moreover, at the molecular level, A. actinomycetemcomitans is
characterized by its outer membrane, which encloses a thin layer of
peptidoglycan and an inner cytoplasmic membrane. Its cell shape is rod-shaped, with dimensions typically ranging from 0.4–0.5 µm in width and 1.0–1.5 µm in length. Despite its lack of motility, this bacterium&#39;s ability to adhere to surfaces is facilitated by its rough texture, enhancing its colonization and virulence. Metabolically, A. actinomycetemcomitans is capable of producing various toxins crucial for its pathogenicity, contributing to tissue damage and immune evasion in the host. This intricate interplay between cell structure, metabolism, and virulence factors underscores the pathogenic potential of A. actinomycetemcomitans in periodontal diseases and highlights the importance of understanding its biology for effective diagnosis and treatment strategies.


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====Life Cycle====
====Life Cycle====
The bacterium colonizes the oral mucosa early in life and is inherited by vertical transmission from close relatives. There is a prevalence and gingival localization of Aggie in periodontal lesions of young patients along with intra-tissue bacterial cells and phagocytic cells, which had invaded gingival connective tissue. Aggie utilizes metabolic products from other inhabitants of the biofilm for survival and growth. This bacterium also makes use of lactic acid produced by Streptococcus pyogenes as a nutrient to increase its numbers. More recent studies have demonstrated invasion of Aggie into epithelial cells. Outer membrane protein OmpA1 is associated with the entry of Aggie into gingival epithelial cells caused by the up-regulating F-actin rearrangement via the FAK signaling pathway. Another outer membrane protein, Omp100 promotes adhesion of Aggie, and their invasion of gingival epithelial cells. These outer membrane proteins contribute to pathogenicity which will be discussed later on. Streptococcus pyogenes produce Hydrogen peroxide, protecting Aggie from oxidative damage and allowing it to migrate deeper into the gingival pocket where they are exposed to th host immune response. The image on the top right shows the invasion of Aggie into epithelial cells. Aggie is now protected from mechanical removal, antibiotics, immune cell phagocytosis, and antibody building. Aggie has developed mechanisms to survive in human serum‐rich environments in vivo, including resistance to complement‐mediated cell lysis and phagocytosis regardless of serotypes and leukotoxin production. These features allow it to survive in hostile environments of periodontal pockets and blood circulation, where human serum is the predominant nutrient source for bacterial metabolism. Human serum is basically blood plasma without clotting factors. In the presence of human serum, bacteriophages are induced to undergo a transition from a lysogenic prophage into the lytic cycle, resulting in bacterial lysis. The pyruvate dehydrogenase complex oxidatively decarboxylates pyruvate to acetyl-coA for the TCA cycle. The TCA cycle, otherwise known as cyclic acid cycle, provides large amounts of energy in aerobic conditions. This energy production and delivery system is required for the replication of phage progeny. Under the PDHc catalytic reaction, bacterial lysis occurs and regulates this bacterium.
The bacterium colonizes the oral mucosa early in life and is inherited by vertical transmission. There is a prevalence and gingival localization of ''Aggregatibacter actinomycetemcomitans'' in periodontal lesions of young patients along with intra-tissue bacterial cells and phagocytic cells, which had invaded gingival connective tissue. ''A. actinomycetemcomitans'' utilizes metabolic products from other inhabitants of the biofilm for survival and growth [7]. This bacterium also makes use of lactic acid produced by Streptococcus pyogenes as a nutrient to increase the number of bacteria [4]. More recent studies have demonstrated invasion of ''A. actinomycetemcomitans'' into epithelial cells. Outer membrane protein OmpA1 is associated with the entry of ''A. actinomycetemcomitans'' into gingival epithelial cells caused by the up-regulating F-actin rearrangement via the FAK signaling pathway. Another outer membrane protein, Omp100 promotes adhesion of ''A. actinomycetemcomitans'', and their invasion of gingival epithelial cells. These outer membrane proteins contribute to pathogenicity [4]. Streptococcus pyogenes produce Hydrogen Peroxide, protecting ''A. actinomycetemcomitans'' from oxidative damage and allowing it to migrate deeper into the gingival pocket where they are exposed to the host immune response. Figure 4 shows the invasion of ''A. actinomycetemcomitans'' into epithelial cells. ''A. actinomycetemcomitans'' is now protected from mechanical removal, antibiotics, immune cell phagocytosis, and antibody building. ''A. actinomycetemcomitans'' has developed mechanisms to survive in human serum‐rich environments in vivo, including resistance to complement‐mediated cell lysis and phagocytosis regardless of serotypes and leukotoxin production [8]. [[File:Screenshot_2024-04-24_at_3.38.28_PM.png|right|400px|thumb|Figure 4. Interactions of ''A. actinomycetemcomitans'' in the gingival pocket [8]]]These features allow it to survive in hostile environments of periodontal pockets and blood circulation, where human serum is the predominant nutrient source for bacterial metabolism. In the presence of human serum, bacteriophages are induced to undergo a transition from a lysogenic prophage into the lytic cycle, resulting in bacterial lysis. The pyruvate dehydrogenase complex oxidatively decarboxylates pyruvate to acetyl-coA for the TCA cycle. The TCA cycle, otherwise known as cyclic acid cycle, provides large amounts of energy in aerobic conditions. This energy production and delivery system is required for the replication of phage progeny. Under the PDHc catalytic reaction, bacterial lysis occurs and regulates this bacterium [12].


==Ecology and Pathogenesis==
==Ecology and Pathogenesis==
Aggregatibacter actinomycetemcomitans, a Gram-negative bacterium
[[File: Screenshot 2024-04-25 at 8.16.11 PM.png|left|170px|thumb|Figure 5. Displays the significant impact of periodontitis on a once healthy tooth [2]]] The pathogenic potential and aggressive nature of ''Aggregatibacter actinomycetemcomitans'' are factors that make it important in human disease. The increased understanding of non-oral infectious involvement in periodontitis is due to the fact that it can cause both oral and systemic infections. It is possible to isolate this using an oral as well as a non-oral range of infectious disorders. Among these are UTIs, bacteremia, endocarditis, osteomyelitis, arthritis, skin infections and abscesses. This periodontitis contributes to an imbalanced formation in periodontal microbiota by these bacteria. As a result, the inflammation destroys the tissues around teeth that connect to them. Its complex role in pathogenesis of many diseases is also demonstrated through its capacity to elude host immune system and interact with other microbial species found in oral cavity [11]. Also, ''A. actinomycetemcomitans'' may be connected with some virulence factors including leukotoxin as a potential one which can lead to apoptosis or programmed cell death among epithelial cells resulting into tissue damage hence localized aggressive periodontitis. Moreover, ''A.actinomycetemcomitans'' produces CDTs known as cytolethal distending toxins that affect DNA via interaction with the host cell cycle. Clinical signs of ''A. actinomycetemcomitans'' infections include bone loss leading to pocket formations around the tooth root [1].
found in the oral microbiota, plays a significant role in human disease due to its aggregative nature and pathogenic potential. While initially cultured from non-oral infections, its involvement in periodontitis has gained recognition, highlighting its dual capacity to cause both oral and systemic diseases. A. actinomycetemcomitans can be isolated from various oral and non-oral infectious diseases, including infective endocarditis, arthritis, bacteraemia, osteomyelitis, skin infections, urinary tract infections, and abscesses. Its pathogenicity in infective endocarditis is particularly notable, with the bacterium being a member of the HACEK group associated with a small but significant percentage of cases. In the context of periodontitis, A. actinomycetemcomitans contributes to the dysbiotic changes within the periodontal microbiota, leading to inflammatory destruction of connective tissue and bone around teeth. The bacterium&#39;s ability to
 
evade host immune responses and interact with other microbial species in the
==Treating ''A.actinomycetemcomitans''==
oral cavity underscores its complex role in disease pathogenesis.


Furthermore, A. actinomycetemcomitans is associated with specific
Ways to maintain periodontitis and treat ''Aggregatibacter actinomycetemcomitans'' include utilizing deep cleaning methods (scaling and root planing), blue light, amoxicillin-metronidazole treatment, and systemic ciprofloxacin treatment [2][14]. [[File:Jcm-08-01079-g001.png|200px|thumb|right|Figure 6. Mechanical and chemical ways of treatment and prevention of ''A.actinomycetemcomitans'' [8]]]
virulence factors, notably leukotoxin, which is implicated in localized aggressive periodontitis and can induce apoptosis in epithelial cells, contributing to tissue damage. Additionally, the bacterium produces cytolethal distending toxin (CDT), which disrupts the cell cycle in host cells, leading to DNA damage. Clinical symptoms associated with A. actinomycetemcomitans infections include gingival inflammation, periodontal pocket formation, bone loss, and tooth mobility. The complexity of interactions between A. actinomycetemcomitans, other microbial
species, and the host immune system underscores the multifaceted nature of its ecology and pathogenesis, highlighting the need for comprehensive approaches to understanding and managing diseases associated with this bacterium.


==Reference==
==References==
1) Belibasakis, G. N., Maula, T., Bao, K., Lindholm, M., Bostanci, N., Oscarsson, J., Ihalin, R., & Johansson, A.(2019). Virulence and Pathogenicity Properties of Aggregatibacter actinomycetemcomitans. Pathogens (Basel,  
[1] Belibasakis, G. N., Maula, T., Bao, K., Lindholm, M., Bostanci, N., Oscarsson, J., Ihalin, R., & Johansson, A.(2019). Virulence and Pathogenicity Properties of Aggregatibacter actinomycetemcomitans. Pathogens(Basel, Switzerland), 8(4), 222.
:: Switzerland), 8(4), 222.


2) Flemmig, T. F. (1999). Periodontitis. Annals of periodontology, 4(1), 32-37.
[2] C. C. Medical. (n.d.). Periodontitis (gum disease): Symptoms, stages & treatment. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/16620-periodontitis


3) Kelk, P., Abd, H., Claesson, R., SandstrÃm, G., SjÃstedt, A., & Johansson, A. (2011). Cellular and molecular response of human macrophages exposed to  
[3] Kelk, P., Abd, H., Claesson, R., SandstrÃm, G., SjÃstedt, A., & Johansson, A. (2011). Cellular and molecular response of human macrophages exposed to  
:: Aggregatibacter actinomycetemcomitans leukotoxin. Cell Death & Disease, 2(3), e126–e126.
:: Aggregatibacter actinomycetemcomitans leukotoxin. Cell Death & Disease, 2(3), e126–e126.


4) Lindholm, M., Min Aung, K., Nyunt Wai, S., & Oscarsson, J. (2019). Role of OmpA1 and OmpA2 in Aggregatibacter actinomycetemcomitans and Aggregatibacter  
[4] Lindholm, M., Min Aung, K., Nyunt Wai, S., & Oscarsson, J. (2019). Role of OmpA1 and OmpA2 in Aggregatibacter actinomycetemcomitans and Aggregatibacter  
:: aphrophilus serum resistance. Journal of Oral Microbiology, 11(1), 1536192.
:: aphrophilus serum resistance. Journal of Oral Microbiology, 11(1), 1536192.


5) May, A. C., Ehrlich, R. L., Balashov, S., Ehrlich, G. D., Shanmugam, M., Fine, D. H., ... & Cugini, C. (2016).Complete genome sequence of Aggregatibacter  
[5] May, A. C., Ehrlich, R. L., Balashov, S., Ehrlich, G. D., Shanmugam, M., Fine, D. H., ... & Cugini, C. (2016).Complete genome sequence of Aggregatibacter  
:: actinomycetemcomitans strain IDH781. Genome Announcements, 4(6), 10-1128.
:: actinomycetemcomitans strain IDH781. Genome Announcements, 4(6), 10-1128.


6) Nedergaard, S., Kobel, C. M., Nielsen, M. B., Møller, R. T., Jensen, A. B., & Nørskov-Lauritsen, N. (2019).
[‌6] Nørskov-Lauritsen, N., Claesson, R., Jensen, A. B., Åberg, C. H., & Haubek, D. (2019). Aggregatibacter Actinomycetemcomitans: Clinical Significance of a  
:: Whole Genome Sequencing of Aggregatibacter actinomycetemcomitans Cultured from Blood Stream Infections Reveals Three Major Phylogenetic Groups Including a
:: Novel Lineage Expressing Serotype a Membrane O Polysaccharide. Pathogens, 8(4), 256.
 
‌7) Nørskov-Lauritsen, N., Claesson, R., Jensen, A. B., Åberg, C. H., & Haubek, D. (2019). Aggregatibacter Actinomycetemcomitans: Clinical Significance of a  
:: Pathobiont Subjected to Ample Changes in Classification and Nomenclature. Pathogens, 8(4).  
:: Pathobiont Subjected to Ample Changes in Classification and Nomenclature. Pathogens, 8(4).  


8) Oscarsson, J., Claesson, R., Lindholm, M., Höglund Åberg, C., & Johansson, A. (2019). Tools of Aggregatibacter actinomycetemcomitans to evade the host response. :: Journal of clinical medicine, 8(7), 1079.
[7] Oscarsson, J., Claesson, R., Lindholm, M., Höglund Åberg, C., & Johansson, A. (2019). Tools of Aggregatibacter actinomycetemcomitans to evade the host response. :: Journal of clinical medicine, 8(7), 1079.


9) Ozuna, H., Snider, I., Belibasakis, G. N., Oscarsson, J., Johansson, A., & Uriarte, S. M. (2022). Aggregatibacter actinomycetemcomitans and Filifactor alocis Two exotoxin-producing oral pathogens. Frontiers in oral health,  
[8] Ozuna, H., Snider, I., Belibasakis, G. N., Oscarsson, J., Johansson, A., & Uriarte, S. M. (2022). Aggregatibacter actinomycetemcomitans and Filifactor alocis Two exotoxin-producing oral pathogens. Frontiers in oral health,  
:: 3, 981343.
:: 3, 981343.


10) Raja, M., Ummer, F., & Dhivakar, C. P. (2014). Aggregatibacter actinomycetemcomitans–a tooth killer?. Journal of clinical and diagnostic research: JCDR, 8(8), ZE13.
[9] Raja, M., Ummer, F., & Dhivakar, C. P. (2014). Aggregatibacter actinomycetemcomitans–a tooth killer?. Journal of clinical and diagnostic research: JCDR, 8(8), ZE13.


11) Sampathkumar, V., Velusamy, S. K., Godboley, D., & Fine, D. H. (2017). Increased leukotoxin production: Characterization of 100 base pairs within the 530 base pair leukotoxin promoter region of Aggregatibacter  
[10] Sampathkumar, V., Velusamy, S. K., Godboley, D., & Fine, D. H. (2017). Increased leukotoxin production: Characterization of 100 base pairs within the 530 base pair leukotoxin promoter region of Aggregatibacter  
:: actinomycetemcomitans. Scientific reports, 7(1), 1887.
:: actinomycetemcomitans. Scientific reports, 7(1), 1887.


12) Tang-Siegel, G. G. (2023). Human Serum Mediated Bacteriophage Life Cycle Switch in Aggregatibacter actinomycetemcomitans Is Linked to Pyruvate Dehydrogenase  
[11] Socransky, S. S., & Haffajee, A. D. (2002). Dental biofilms: difficult therapeutic targets. Periodontology 2000, 28(1), 12–55.
 
[12] Tang-Siegel, G. G. (2023). Human Serum Mediated Bacteriophage Life Cycle Switch in A2gregatibacter actinomycetemcomitans Is Linked to Pyruvate Dehydrogenase  
:: Complex. Life, 13(2), 436.
:: Complex. Life, 13(2), 436.


13) Tsai, C. C., Ho, Y. P., Chou, Y. S., Ho, K. Y., Wu, Y. M., & Lin, Y. C. (2018). Aggregatibacter (Actinobacillus) actimycetemcomitans leukotoxin and human  
[13] Tsai, C. C., Ho, Y. P., Chou, Y. S., Ho, K. Y., Wu, Y. M., & Lin, Y. C. (2018). Aggregatibacter (Actinobacillus) actimycetemcomitans leukotoxin and human  
:: periodontitis–A historic review with emphasis on JP2. The Kaohsiung journal of medical sciences, 34(4), 186-193.
:: periodontitis–A historic review with emphasis on JP2. The Kaohsiung journal of medical sciences, 34(4), 186-193.


14) Vega, B. A., Belinka Jr, B. A., & Kachlany, S. C. (2019). Aggregatibacter actinomycetemcomitans leukotoxin (LtxA; Leukothera®): mechanisms of action and  
[14] Vega, B. A., Belinka Jr, B. A., & Kachlany, S. C. (2019). Aggregatibacter actinomycetemcomitans leukotoxin (LtxA; Leukothera®): mechanisms of action and  
:: therapeutic applications. Toxins, 11(9), 489.
:: therapeutic applications. Toxins, 11(9), 489.


15) Yoshida, A., Bouziane, A., Erraji, S., Lakhdar, L., Rhissassi, M., Miyazaki, H., ... & Ennibi, O. (2021). Etiology of aggressive periodontitis in individuals of :: African descent. Japanese Dental Science Review, 57, 20-26.
[15] Yoshida, A., Bouziane, A., Erraji, S., Lakhdar, L., Rhissassi, M., Miyazaki, H., ... & Ennibi, O. (2021). Etiology of aggressive periodontitis in individuals of African descent. Japanese Dental Science Review, 57, 20-26.
 
[16] Periodontitis - gum disease: Symptoms, causes, & treatment. Amazing Smiles. (2023, August 22). https://amazingsmiles.com.au/periodontitis-symptoms-and-treatment-options/
 
[17] Unique exotoxin-producing oral bacterium. (n.d.). https://schaechter.asmblog.org/schaechter/2013/07/aggregatibacter-actinomycetemcomitans-a-unique-exotoxin-producing-oral-bacterium-.html
 
==Authors==
Page authored by Hannah Pedersen and Nirali Patel, students of Professor Jay Lennon at Indiana University.

Latest revision as of 14:21, 26 April 2024

This student page has not been curated.

Classification

Kingdom: Bacteria
Phylum: Proteobacteria
Class: Gammaproteobacteria
Order: Pasteurellales
Family: Pasteurellaceae
Genus: Aggregatibacter
Species: Actinomycetemcomitans
[9]

Species

NCBI: HK1651 Taxonomy

Aggregatibacter Actinomycetemcomitans

Description and Significance

Description

Figure 1. Star-positive A.actinomycetemcomitans demonstrating its star shaped interior [17]

Aggregatibacter actinomycetemcomitans are exogenous, nonmotile, gram-negative bacteria found in the oral cavity [9]. They are capable of growing under both aerobic and anaerobic conditions and are classified as capnophilic, meaning they thrive in high concentrations of carbon dioxide. With an internal, opaque, rought-textured star-shape and translucent colonies, A. actinomycetemcomitans have three main features: fimbriae, vesicles and extracellular amorphous material [9]. Fimbriae of A. actinomycetemcomitans are small, filamentous cell surface appendages. They are uniformly distributed in bundles and don’t measure more than two micrometers in diameter. A. actinomycetemcomitans can either form star-positive, fimbriated colonies with a star shaped interior, or form star-negative, non-fimbriated colonies [9]. Non-fimbriated A. actinomycetemcomitans are smooth, causing characteristics of poor adherence and poor biofilm forming capacity. The most abundant fimbriae protein in this bacterium is 304-a, a thin protein with a low molecular weight. These fimbriae provide the attachment factor, allowing adhesion to hydroxyapatite, a mineral of the tooth. Vesicles, otherwise known as blebs, of A. actinomycetemcomitans are lipopolysaccharide in nature, which is common for a great majority of gram-negative bacteria. Highly leukotoxic strains of A. actinomycetemcomitans tend to have more vesicles. These leukotoxins are described as virulence factors which kill leukocytes allowing them to escape from the host immune system. They play a critical role in the survival of A. actinomycetemcomitans and periodontal disease progression [14]. A. actinomycetemcomitans vesicles also contain endotoxin, which is critical in the role of this bacteria as it links cytokine stimulation and pro-inflammatory reactions, leading to the decay of dental pulp and the progression of periodontal disease. Furthermore, vesicles also contain a bacteriocin named actinobacillus, known for adhering to and colonizing the human oral cavity, leading to aggressive periodontitis. Additionally, these vesicles also exhibit adhesive properties and function to deliver toxic materials. Finally, the extracellular amorphous material exhibits bone-resorbing activity and adhesive properties [9].


Significance

A. actinomycetemcomitans is prevalent in more than one-third of the population [17]. In the United States, approximately 70,000 adolescents develop periodontitis disease annually. Additionally, individuals of African-American descent have a 10 to 15 fold greater risk of developing periodontal disease than Caucasian Americans [15]. There still is not a concrete answer for this significant difference in risk, however several reports state that a contributing factor is the lack of dental care.

Figure 2. Progression of periodontitis in a patient's tooth [16]

A. actinomycetemcomitans is most commonly known as a systemic pathogen, causing the rapid progression of localized aggressive periodontal disease, otherwise known as LAP. A. actinomycetemcomitans is present in approximately 90% of patients with LAP [2]. Similarly, 97% of this bacteria is commonly found in LJP (localized juvenile periodontitis) lesions [15]. LAP is significant because, as opposed to general periodontitis, it specifically impacts the central incisors and first molars. It is common for LAP patients to experience tooth loss and breakdown of supporting tooth structures when this disease is left untreated [1]. Patients may also experience the risk of swelling of the endocardium, the innermost tissue lining the heart [9]. A. actinomycetemcomitans thrives in environments of periodontal pockets and blood circulation, being the reason for the prevalence of these risks. This shines light on the importance of maintaining proper oral hygiene because of the significant correlation between oral and cardiovascular health.

Genome Structure

The A. actinomycetemcomitans genome is made of ranges from 2.0 to 2.7Mb, which is very small compared to other bacteria. It is a single circular chromosome, which contains 2206 genes that make up its genomic structure. These genes include 2129 coding sequenced, along with 19 rRNAs and 54 tRNAs that are need in protein synthesis. Also 4 noncoding RNAs regulate the function that are in the bacteria. Based on differences in its genomic composition and transformation capacity, A. actinomycetemcomitans can be divided into three evolutionary lineages (I, II, and III) [5]. It has also been shown that serotyping, the common approach to categorization, is not useful for providing a complete description of the species since certain serotypes are not restricted to specific lineages. In addition, A. actinomycetemcomitans distinct lineages exhibit varying degrees of natural competence. This transformative capacity is linked to horizontal gene transfer and could impact the proportion of a strain's genome that is found within the species. Furthermore, A. actinomycetemcomitans's prior taxonomic classifications were entirely based on serotyping [5].

Cell Structure, Metabolism and Life Cycle

Cell Structure and Metabolism

Aggretatibacter actinomycetemcomitans has a distinct metabolism and cell structure. It has certain characteristic such as it has rod and facultative anaerobic bacteria that is Gram-negative with specific traits [3].The dimensions of its rod-shaped cell normally range from 0.4 to 0.5 µm in width and 1.0 to 1.5 µm in length. These cells sometimes appear as cocci under microscope as seen in Image A of Figure 3 that is collected from clinical sample. This bacterium exhibits environmental flexibility despite not being motile and lacking flagella. It grows poorly in environment air but thrives in 5% CO2. On chocolate agar, colonies are tiny, rough-textured, and firm, sticking to the agar surfaces with great strength as seen in figure B [6].

Figure 3. (A) A. actinomycetemcomitans strain HK1651 on chocolate agar. (B) Distinctive "star shaped" colony incubated and grown in TSBV agar [6]

A. actinomycetemcomitans is also unique in that it can create a number of different enzymes and toxins, such as leukotoxin and cytolethal distending toxin (CDT). This adds to its pathogenicity in periodontal infections. Although this bacteria lacks mobility, its rough texture helps it stick to surfaces. This increases colonization and pathogeneticity. A. actinomycetemcomitans can produce a variety of toxins that are essential to its pathogenicity through metabolism, which can lead to tissue damage and immune evasion in the host [3].

Life Cycle

The bacterium colonizes the oral mucosa early in life and is inherited by vertical transmission. There is a prevalence and gingival localization of Aggregatibacter actinomycetemcomitans in periodontal lesions of young patients along with intra-tissue bacterial cells and phagocytic cells, which had invaded gingival connective tissue. A. actinomycetemcomitans utilizes metabolic products from other inhabitants of the biofilm for survival and growth [7]. This bacterium also makes use of lactic acid produced by Streptococcus pyogenes as a nutrient to increase the number of bacteria [4]. More recent studies have demonstrated invasion of A. actinomycetemcomitans into epithelial cells. Outer membrane protein OmpA1 is associated with the entry of A. actinomycetemcomitans into gingival epithelial cells caused by the up-regulating F-actin rearrangement via the FAK signaling pathway. Another outer membrane protein, Omp100 promotes adhesion of A. actinomycetemcomitans, and their invasion of gingival epithelial cells. These outer membrane proteins contribute to pathogenicity [4]. Streptococcus pyogenes produce Hydrogen Peroxide, protecting A. actinomycetemcomitans from oxidative damage and allowing it to migrate deeper into the gingival pocket where they are exposed to the host immune response. Figure 4 shows the invasion of A. actinomycetemcomitans into epithelial cells. A. actinomycetemcomitans is now protected from mechanical removal, antibiotics, immune cell phagocytosis, and antibody building. A. actinomycetemcomitans has developed mechanisms to survive in human serum‐rich environments in vivo, including resistance to complement‐mediated cell lysis and phagocytosis regardless of serotypes and leukotoxin production [8].

Figure 4. Interactions of A. actinomycetemcomitans in the gingival pocket [8]

These features allow it to survive in hostile environments of periodontal pockets and blood circulation, where human serum is the predominant nutrient source for bacterial metabolism. In the presence of human serum, bacteriophages are induced to undergo a transition from a lysogenic prophage into the lytic cycle, resulting in bacterial lysis. The pyruvate dehydrogenase complex oxidatively decarboxylates pyruvate to acetyl-coA for the TCA cycle. The TCA cycle, otherwise known as cyclic acid cycle, provides large amounts of energy in aerobic conditions. This energy production and delivery system is required for the replication of phage progeny. Under the PDHc catalytic reaction, bacterial lysis occurs and regulates this bacterium [12].

Ecology and Pathogenesis

Figure 5. Displays the significant impact of periodontitis on a once healthy tooth [2]

The pathogenic potential and aggressive nature of Aggregatibacter actinomycetemcomitans are factors that make it important in human disease. The increased understanding of non-oral infectious involvement in periodontitis is due to the fact that it can cause both oral and systemic infections. It is possible to isolate this using an oral as well as a non-oral range of infectious disorders. Among these are UTIs, bacteremia, endocarditis, osteomyelitis, arthritis, skin infections and abscesses. This periodontitis contributes to an imbalanced formation in periodontal microbiota by these bacteria. As a result, the inflammation destroys the tissues around teeth that connect to them. Its complex role in pathogenesis of many diseases is also demonstrated through its capacity to elude host immune system and interact with other microbial species found in oral cavity [11]. Also, A. actinomycetemcomitans may be connected with some virulence factors including leukotoxin as a potential one which can lead to apoptosis or programmed cell death among epithelial cells resulting into tissue damage hence localized aggressive periodontitis. Moreover, A.actinomycetemcomitans produces CDTs known as cytolethal distending toxins that affect DNA via interaction with the host cell cycle. Clinical signs of A. actinomycetemcomitans infections include bone loss leading to pocket formations around the tooth root [1].

Treating A.actinomycetemcomitans

Ways to maintain periodontitis and treat Aggregatibacter actinomycetemcomitans include utilizing deep cleaning methods (scaling and root planing), blue light, amoxicillin-metronidazole treatment, and systemic ciprofloxacin treatment [2][14].

Figure 6. Mechanical and chemical ways of treatment and prevention of A.actinomycetemcomitans [8]

References

[1] Belibasakis, G. N., Maula, T., Bao, K., Lindholm, M., Bostanci, N., Oscarsson, J., Ihalin, R., & Johansson, A.(2019). Virulence and Pathogenicity Properties of Aggregatibacter actinomycetemcomitans. Pathogens(Basel, Switzerland), 8(4), 222.

[2] C. C. Medical. (n.d.). Periodontitis (gum disease): Symptoms, stages & treatment. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/16620-periodontitis

[3] Kelk, P., Abd, H., Claesson, R., SandstrÃm, G., SjÃstedt, A., & Johansson, A. (2011). Cellular and molecular response of human macrophages exposed to

Aggregatibacter actinomycetemcomitans leukotoxin. Cell Death & Disease, 2(3), e126–e126.

[4] Lindholm, M., Min Aung, K., Nyunt Wai, S., & Oscarsson, J. (2019). Role of OmpA1 and OmpA2 in Aggregatibacter actinomycetemcomitans and Aggregatibacter

aphrophilus serum resistance. Journal of Oral Microbiology, 11(1), 1536192.

[5] May, A. C., Ehrlich, R. L., Balashov, S., Ehrlich, G. D., Shanmugam, M., Fine, D. H., ... & Cugini, C. (2016).Complete genome sequence of Aggregatibacter

actinomycetemcomitans strain IDH781. Genome Announcements, 4(6), 10-1128.

[‌6] Nørskov-Lauritsen, N., Claesson, R., Jensen, A. B., Åberg, C. H., & Haubek, D. (2019). Aggregatibacter Actinomycetemcomitans: Clinical Significance of a

Pathobiont Subjected to Ample Changes in Classification and Nomenclature. Pathogens, 8(4).

[7] Oscarsson, J., Claesson, R., Lindholm, M., Höglund Åberg, C., & Johansson, A. (2019). Tools of Aggregatibacter actinomycetemcomitans to evade the host response. :: Journal of clinical medicine, 8(7), 1079.

[8] Ozuna, H., Snider, I., Belibasakis, G. N., Oscarsson, J., Johansson, A., & Uriarte, S. M. (2022). Aggregatibacter actinomycetemcomitans and Filifactor alocis Two exotoxin-producing oral pathogens. Frontiers in oral health,

3, 981343.

[9] Raja, M., Ummer, F., & Dhivakar, C. P. (2014). Aggregatibacter actinomycetemcomitans–a tooth killer?. Journal of clinical and diagnostic research: JCDR, 8(8), ZE13.

[10] Sampathkumar, V., Velusamy, S. K., Godboley, D., & Fine, D. H. (2017). Increased leukotoxin production: Characterization of 100 base pairs within the 530 base pair leukotoxin promoter region of Aggregatibacter

actinomycetemcomitans. Scientific reports, 7(1), 1887.

[11] Socransky, S. S., & Haffajee, A. D. (2002). Dental biofilms: difficult therapeutic targets. Periodontology 2000, 28(1), 12–55.

[12] Tang-Siegel, G. G. (2023). Human Serum Mediated Bacteriophage Life Cycle Switch in A2gregatibacter actinomycetemcomitans Is Linked to Pyruvate Dehydrogenase

Complex. Life, 13(2), 436.

[13] Tsai, C. C., Ho, Y. P., Chou, Y. S., Ho, K. Y., Wu, Y. M., & Lin, Y. C. (2018). Aggregatibacter (Actinobacillus) actimycetemcomitans leukotoxin and human

periodontitis–A historic review with emphasis on JP2. The Kaohsiung journal of medical sciences, 34(4), 186-193.

[14] Vega, B. A., Belinka Jr, B. A., & Kachlany, S. C. (2019). Aggregatibacter actinomycetemcomitans leukotoxin (LtxA; Leukothera®): mechanisms of action and

therapeutic applications. Toxins, 11(9), 489.

[15] Yoshida, A., Bouziane, A., Erraji, S., Lakhdar, L., Rhissassi, M., Miyazaki, H., ... & Ennibi, O. (2021). Etiology of aggressive periodontitis in individuals of African descent. Japanese Dental Science Review, 57, 20-26.

[16] Periodontitis - gum disease: Symptoms, causes, & treatment. Amazing Smiles. (2023, August 22). https://amazingsmiles.com.au/periodontitis-symptoms-and-treatment-options/

[17] Unique exotoxin-producing oral bacterium. (n.d.). https://schaechter.asmblog.org/schaechter/2013/07/aggregatibacter-actinomycetemcomitans-a-unique-exotoxin-producing-oral-bacterium-.html

Authors

Page authored by Hannah Pedersen and Nirali Patel, students of Professor Jay Lennon at Indiana University.

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