# PlrSR-dependent Signal Transduction in Bordetella Virulence

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $498,220

## Abstract

Summary/Abstract:
Pertussis (aka whooping cough) is a serious reemerging public health problem with incidence estimated
at 20 million cases annually and deaths (mostly in infants) at ~200,000 annually. Recent rises in
pertussis in countries with high vaccine coverage, such as the United States, correlate with a switch from
whole cell (wP) to acellular (aP) pertussis vaccines and are attributed to a larger reservoir of infected
individuals composed of adolescents and young adults who were vaccinated (rather than infected) as
children. It is now apparent that immunity induced by aP vaccination is not as durable as vaccination by
wP vaccination, which is not as durable as immunity induced by infection with Bordetella pertussis, the
primary causal agent of pertussis. Moreover, while immunization with wP and aP vaccines provides
protection against disease (at least initially), it does not protect against colonization. New vaccines that
provide sterilizing, long-lasting immunity are needed. We have discovered a previously uncharacterized
signal transduction system (PlrSR) that is required for B. pertussis and the closely-related broad host
range pathogen Bordetella bronchiseptica to colonize and persist in the lower respiratory tract (LRT). Our
preliminary data support a model in which PlrSR functions as a kinase in response to increased CO2 and
low oxygen conditions (reflective of the LRT), resulting in high levels of PlrR-phosphate (PlrR~P) that
activate expression of genes including those encoding high-affinity cytochrome oxidases. Our model
states that under aerobic conditions, PlrS functions primarily as a phosphatase, and that low levels of
PlrR~P are essential for cell viability. We will use genetic, molecular biological, and genome-wide
approaches to identify PlrSR-regulated genes, especially those induced only in the LRT, and will
determine the roles of PlrSR-dependent gene regulation and of the factors encoded by the regulated
genes in virulence. Using genetic approaches, we will determine the role of the PlrS PDC and PAS
domains, as well as the predicted kinase and phosphatase activities of PlrS, in the ability of the bacteria
to grow in vitro and in the LRT. Using biochemical approaches, we will determine if PlrS is a redox-
sensitive heme-containing protein that functions as a kinase under low oxygen conditions and a
phosphatase in ambient air, and we will identify DNA sequences to which PlrR~P binds. Our results will
be significant because previously unknown PlrSR-dependent virulence factors, and the PlrSR system
itself, will be excellent candidates for the development of new component vaccines and targets for the
development of new therapeutics. Our results will also advance our understanding NtrYX family proteins
(of which PlrSR is a member and which control virulence in other pathogens) function and they will
provide insight into how respiratory pathogens, in general, grow in the LRT.

## Key facts

- **NIH application ID:** 9856967
- **Project number:** 5R01AI129541-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Peggy A Cotter
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $498,220
- **Award type:** 5
- **Project period:** 2017-03-06 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856967

## Citation

> US National Institutes of Health, RePORTER application 9856967, PlrSR-dependent Signal Transduction in Bordetella Virulence (5R01AI129541-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856967. Licensed CC0.

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