Aggregatibacter actinomycetemcomitans Colonization and Persistence in a Primate Model

Proc Natl Acad Sci U S A. 2019 Oct 29;116(44):22307-22313. doi: 10.1073/pnas.1905238116. Epub 2019 Oct 14.


Aggregatibacter actinomycetemcomitans is associated with aggressive periodontitis resulting in premature tooth loss in adolescents. Tooth adherence and biofilm persistence are prerequisites for survival in the oral domain. Here, using a rhesus monkey model, 16S rRNA sequencing, and weighted network analysis, we assessed colonization of A. actinomycetemcomitans variants and ascertained microbial interactions in biofilm communities. Variants in A. actinomycetemcomitans leukotoxin (ltx) were created, labeled, inoculated, and compared with their progenitor strain for in vivo colonization. Samples of tooth-related plaque were assessed for colonization at baseline and after debridement and inoculation of labeled strains. Null, minimal, and hyper-Ltx-producing strains were created and assessed for hydroxyapatite binding and biofilm formation in vitro. Ltx-hyperproducing strains colonized with greater prevalence and at higher levels than wild type or ltx mutants (P = 0.05). Indigenous and inoculated A. actinomycetemcomitans strains that attached were associated with lactate-producing species (i.e., Leptotrichia, Abiotrophia, and Streptoccocci). A. actinomycetemcomitans was found at 0.13% of the total flora at baseline and at 0.05% 4 wk after inoculation. In vivo data were supported by in vitro results. We conclude that hyper-Ltx production affords these strains with an attachment advantage providing a foothold for competition with members of the indigenous microbiota. Increased attachment can be linked to ltx gene expression and up-regulation of adherence-associated genes. Growth of attached A. actinomycetemcomitans in vivo was enhanced by lactate availability due to consorting species. These associations provide A. actinomycetemcomitans with the constituents required for its colonization and survival in the complex and competitive oral environment.

Keywords: Aggregatibacter actinomycetemcomitans; l-lactate; leukotoxin; microbiome; rhesus monkey.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aggregatibacter actinomycetemcomitans / genetics
  • Aggregatibacter actinomycetemcomitans / metabolism
  • Aggregatibacter actinomycetemcomitans / pathogenicity*
  • Aggregatibacter actinomycetemcomitans / physiology
  • Animals
  • Bacterial Adhesion / drug effects
  • Biofilms
  • Durapatite / pharmacology
  • Exotoxins / genetics
  • Exotoxins / metabolism
  • Lactic Acid / metabolism
  • Macaca mulatta
  • Male
  • Microbiota
  • Mouth / microbiology*
  • Periodontitis / microbiology*


  • Exotoxins
  • leukotoxin
  • Lactic Acid
  • Durapatite