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Longitudinal TprK profiling of in vivo and in vitro-propagated Treponema pallidum subsp. pallidum reveals accumulation of antigenic variants in absence of immune pressure
- Source :
- PLoS Neglected Tropical Diseases, PLoS Neglected Tropical Diseases, Vol 15, Iss 9, p e0009753 (2021)
- Publication Year :
- 2021
- Publisher :
- Public Library of Science, 2021.
-
Abstract
- Immune evasion by Treponema pallidum subspecies pallidum (T. pallidum) has been attributed to antigenic variation of its putative outer-membrane protein TprK. In TprK, amino acid diversity is confined to seven variable (V) regions, and generation of sequence diversity within the V regions occurs via a non-reciprocal segmental gene conversion mechanism where donor cassettes recombine into the tprK expression site. Although previous studies have shown the significant role of immune selection in driving accumulation of TprK variants, the contribution of baseline gene conversion activity to variant diversity is less clear. Here, combining longitudinal tprK deep sequencing of near clonal Chicago C from immunocompetent and immunosuppressed rabbits along with the newly developed in vitro cultivation system for T. pallidum, we directly characterized TprK alleles in the presence and absence of immune selection. Our data confirm significantly greater sequence diversity over time within the V6 region during syphilis infection in immunocompetent rabbits compared to immunosuppressed rabbits, consistent with previous studies on the role of TprK in evasion of the host immune response. Compared to strains grown in immunocompetent rabbits, strains passaged in vitro displayed low level changes in allele frequencies of TprK variable region sequences similar to that of strains passaged in immunosuppressed rabbits. Notably, we found significantly increased rates of V6 allele generation relative to other variable regions in in vitro cultivated T, pallidum strains, illustrating that the diversity within these hypervariable regions occurs in the complete absence of immune selection. Together, our results demonstrate antigenic variation in T. pallidum can be studied in vitro and occurs even in the complete absence of immune pressure, allowing the T. pallidum population to continuously evade the immune system of the infected host.<br />Author summary Syphilis continues to be a disease of global and public health concern, even though the infection can be easily diagnosed and effectively treated with penicillin. Although infected individuals often develop a strong immunity to the pathogen, repeated infection with the syphilis agent, Treponema pallidum subspecies pallidum (T. pallidum), is possible. Several studies point at antigenic variation of the T. pallidum TprK protein as the mechanism responsible for evasion of the immunity that develops during infection, pathogen persistence, and re-infection. Past studies have highlighted the importance of immune clearance of dominant variants that, in turn, allows less represented variants to emerge. The contribution of an immunity-independent baseline generation of variability in the tprK gene is less clear. Here, we used deep sequencing to profile tprK variants using a laboratory-isolated T. pallidum strain nearly isogenic for tprK that was propagated over time in vitro, where no immune pressure is exerted on the pathogen, as well as in samples obtained from immunosuppressed and immunocompetent rabbits infected with the same strain. We confirmed that tprK accumulates significantly more diversity under immune pressure, and demonstrated a low but discernible basal rate of gene conversion in complete absence of immune pressure.
- Subjects :
- Bacterial Diseases
Physiology
Biopsy
RC955-962
Artificial Gene Amplification and Extension
Pathology and Laboratory Medicine
Biochemistry
Polymerase Chain Reaction
Treponematoses
law.invention
Medical Conditions
law
Arctic medicine. Tropical medicine
Immune Physiology
Medicine and Health Sciences
Treponema Pallidum
Polymerase chain reaction
Mammals
education.field_of_study
Treponema
Immune System Proteins
biology
Eukaryota
Animal Models
Antigenic Variation
Bacterial Pathogens
Nucleic acids
Infectious Diseases
Experimental Organism Systems
Medical Microbiology
Vertebrates
Leporids
Rabbits
Public aspects of medicine
RA1-1270
Pathogens
Research Article
Neglected Tropical Diseases
Bacterial Outer Membrane Proteins
DNA recombination
Urology
Population
Immunology
Gene Conversion
Sexually Transmitted Diseases
Porins
Surgical and Invasive Medical Procedures
Research and Analysis Methods
Microbiology
Immunocompromised Host
Immune system
Antigen
Bacterial Proteins
Antigenic variation
Genetics
Animals
Gene conversion
Syphilis
Amino Acid Sequence
Antigens
education
Molecular Biology Techniques
Microbial Pathogens
Molecular Biology
Alleles
Immune Evasion
Antigens, Bacterial
Genitourinary Infections
Public Health, Environmental and Occupational Health
Organisms
Biology and Life Sciences
Proteins
Genetic Variation
DNA
Gene Expression Regulation, Bacterial
biology.organism_classification
Tropical Diseases
Virology
Hypervariable region
Amniotes
Animal Studies
Transcriptome
Zoology
Subjects
Details
- Language :
- English
- ISSN :
- 19352735 and 19352727
- Volume :
- 15
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- PLoS Neglected Tropical Diseases
- Accession number :
- edsair.doi.dedup.....82d63da55eb279ac4b439753efc9f6fa