1. Borrelia peptidoglycan interacting Protein (BpiP) contributes to the fitness of Borrelia burgdorferi against host-derived factors and influences virulence in mouse models of Lyme disease
- Author
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Taylor MacMackin Ingle, Floyd L. Wormley, Karen L. Wozniak, Janakiram Seshu, Trever C. Smith, Sean M. Vargas, Sai Lakshmi Rajasekhar Karna, and Yue Chen
- Subjects
Bacterial Diseases ,Life Cycles ,Mutant ,Mice, SCID ,Pathology and Laboratory Medicine ,Mice ,chemistry.chemical_compound ,Medical Conditions ,Medicine and Health Sciences ,Biology (General) ,Cells, Cultured ,Lyme Disease ,Mice, Inbred BALB C ,Mice, Inbred C3H ,Virulence ,Spirochetes ,biology ,Animal Models ,Bacterial Pathogens ,Immunoblot Analysis ,Infectious Diseases ,Experimental Organism Systems ,Medical Microbiology ,Host-Pathogen Interactions ,Pathogens ,Cell envelope ,Research Article ,Borrelia Burgdorferi ,QH301-705.5 ,Immunology ,Molecular Probe Techniques ,Mouse Models ,Peptidoglycan ,Research and Analysis Methods ,Microbiology ,Cell wall ,Model Organisms ,Bacterial Proteins ,Antigen ,Virology ,Borrelia ,Genetics ,Animals ,Immunologic Factors ,Borrelia burgdorferi ,Molecular Biology Techniques ,Microbial Pathogens ,Molecular Biology ,Bacteria ,Organisms ,Biology and Life Sciences ,RC581-607 ,biology.organism_classification ,Borrelia Infection ,Nymphs ,Mice, Inbred C57BL ,Disease Models, Animal ,chemistry ,Animal Studies ,Parasitology ,Genetic Fitness ,Immunologic diseases. Allergy ,Developmental Biology - Abstract
The Peptidoglycan (PG) cell wall of the Lyme disease (LD) spirochete, Borrelia burgdorferi (Bb), contributes to structural and morphological integrity of Bb; is a persistent antigen in LD patients; and has a unique pentapeptide with L-Ornithine as the third amino acid that cross-links its glycan polymers. A borrelial homolog (BB_0167) interacted specifically with borrelilal PG via its peptidoglycan interacting motif (MHELSEKRARAIGNYL); was localized to the protoplasmic cylinder of Bb; and was designated as Borrelia peptidoglycan interacting Protein (BpiP). A bpiP mutant displayed no defect under in vitro growth conditions with similar levels of several virulence-related proteins. However, the burden of bpiP mutant in C3H/HeN mice at day 14, 28 and 62 post-infection was significantly lower compared to control strains. No viable bpiP mutant was re-isolated from any tissues at day 62 post-infection although bpiP mutant was able to colonize immunodeficient SCID at day 28 post-infection. Acquisition or transmission of bpiP mutant by Ixodes scapularis larvae or nymphs respectively, from and to mice, was significantly lower compared to control strains. Further analysis of bpiP mutant revealed increased sensitivity to vancomycin, osmotic stress, lysosomal extracts, human antimicrobial peptide cathelicidin-LL37, complement-dependent killing in the presence of day 14 post-infection mouse serum and increased internalization of CFSC-labeled bpiP mutant by macrophages and dendritic cells compared to control strains. These studies demonstrate the importance of accessory protein/s involved in sustaining integrity of PG and cell envelope during different phases of Bb infection., Author summary Borrelia burgdorferi (Bb), the agent of Lyme disease, is capable of survival in widely divergent hosts such as the tick vector and numerous vertebrates. Peptidoglycan (PG) cell wall contributes to structural integrity of Bb, remodeling of its cell envelope in response to environmental signals and in modulation of antimicrobial responses in different hosts during the infectious cycle. The glycan polymers of PG are cross-linked via a unique pentapeptide with L-Ornithine as the third amino acid. Here, we demonstrate the role of a borrelial protein, designated as Borrelia peptidoglycan interacting Protein (BpiP), in the patho-physiology of Bb. Deletion of bpiP results in attenuation of infection in immunocompetent C3H/HeN or BALB/c mice unlike in immunodeficient SCID mice. The bpiP mutant is more susceptible to effects of vancomycin, osmotic stress, lysosomal extracts, antimicrobial peptides, complement-dependent killing and increased phagocytosis by macrophages and dendritic cells. These observations demonstrated that cellular and soluble factors of the host immune response limit the colonization of bpiP mutant in immunocompetent hosts. Understanding the role of cell wall components and its accessory factors in the survival of Bb during tick and mammalian phases of infection is anticipated to advance strategies to reduce the incidence of Lyme disease.
- Published
- 2021