# Chaperone-Mediated Secretion of Borrelia Lipoproteins

> **NIH NIH R21** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2020 · $187,341

## Abstract

Abstract
Bacterial protein secretion is a fundamental physiological process that generates the cell envelope and maintains
its integrity throughout the bacterial life cycle. In bacterial pathogens, a variety of protein secretion systems have
been shown to deploy important virulence factors to the bacterial surface, into the milieu, or even directly into
eukaryotic cells or other bacteria. Borrelia spirochetes, the causative agents of tick-borne Lyme disease and
relapsing fever, have a unique double-membrane envelope with periplasmic flagella. The Borrelia surface lacks
lipopolysaccharide and is instead covered by abundant, immunodominant and serotype-defining surface
lipoproteins that serve as linchpins for transmission and pathogenesis. A recent study has shown that two thirds
of the about 130 lipoproteins expressed by the Lyme disease bacterium Borrelia burgdorferi localize to the
surface. Therefore, B. burgdorferi is a perfect model organism for investigations into the secretion of bacterial
surface lipoproteins.
 Several seminal studies have demonstrated that (i) Borrelia surface lipoprotein secretion determinants
commonly localize to N-terminal disordered tether regions of the mature lipoproteins, (ii) translocation through
the outer membrane can initiate at a lipoprotein's C terminus and requires an at least partially unfolded
conformation, and (iii) Borrelia surface lipoproteins are ultimately anchored in the surface leaflet of the outer
membrane bilayer. These data support the hypothesis that the Borrelia surface lipoprotein secretion pathway
includes a periplasmic mechanism that prevents premature folding of surface lipoprotein and an outer membrane
translocon complex that allows for the flipping of lipoproteins from the periplasm to the surface.
 This proposal will test the above hypothesis by identifying and mechanistically defining the components
of the B. burgdorferi surface lipoprotein secretion pathway. Aim 1 will focus on defining periplasmic events, taking
a high-resolution structure-guided approach to detail the function of the B. burgdorferi LolA homolog via dominant
negative screens, conditional knockouts, quantitative proteomics and X-ray crystallography. Aim 2 will focus on
outer membrane events and identify and characterize the proteins and mechanisms facilitating the translocation
of lipoproteins from the periplasm to the surface, using a novel tunable CRISPR interference knockdown system
in addition to the techniques described for aim 1. Together, these experiments will use novel approaches to
further elucidate how emerging pathogens of global importance generate their interface with the host. This will
ultimately yield better tools for diagnostics and improved strategies for prevention and treatment.

## Key facts

- **NIH application ID:** 9936311
- **Project number:** 5R21AI144624-02
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** WOLFRAM R ZUECKERT
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $187,341
- **Award type:** 5
- **Project period:** 2019-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936311

## Citation

> US National Institutes of Health, RePORTER application 9936311, Chaperone-Mediated Secretion of Borrelia Lipoproteins (5R21AI144624-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9936311. Licensed CC0.

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