# Role of Borrelia Lpt Homologs in Surface Lipoprotein Secretion

> **NIH NIH R21** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2024 · $193,750

## 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 build on recent CRISPRi gene silencing
data and employ site-directed mutagenesis and quantitative proteomics to begin determining the structure-
function relationships of a B. burgdorferi outer membrane protein shown to facilitate translocation of lipoproteins
from the periplasm to the surface. Fluorescent tags will be used to further define the sequestration of the B.
burgdorferi lipoproteome in space and time. Aim 2 will use the same approaches as well as X-ray crystallography
to characterize periplasmic proteins that are hypothesized to release surface lipoproteins from the inner
membrane and deliver them to the outer membrane.
 Together, these experiments will use novel approaches to further elucidate how emerging pathogens of
global importance generate and maintain 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:** 10874563
- **Project number:** 5R21AI173835-02
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** WOLFRAM R ZUECKERT
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $193,750
- **Award type:** 5
- **Project period:** 2023-06-23 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874563

## Citation

> US National Institutes of Health, RePORTER application 10874563, Role of Borrelia Lpt Homologs in Surface Lipoprotein Secretion (5R21AI173835-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10874563. Licensed CC0.

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