Novel multiparameter correlates of Coxiella burnetii infection and vaccination identified by longitudinal deep immune profiling

P M Reeves,S Raju Paul,A Garritsen,A E Sluder,T Brauns,R Bowen,D Sobell,M C Poznansky,A Scholzen,J Hess,Y Yi,L Baeten,S E Korek,L Moise,A S De Groot

doi:10.1038/s41598-020-69327-x

Abstract

Q-fever is a flu-like illness caused by Coxiella burnetii (Cb), a highly infectious intracellular bacterium. There is an unmet need for a safe and effective vaccine for Q-fever. Correlates of immune protection to Cb infection are limited. We proposed that analysis by longitudinal high dimensional immune (HDI) profiling using mass cytometry combined with other measures of vaccination and protection could be used to identify novel correlates of effective vaccination and control of Cb infection. Using a vaccine-challenge model in HLA-DR transgenic mice, we demonstrated significant alterations in circulating T-cell and innate immune populations that distinguished vaccinated from naïve mice within 10 days, and persisted until at least 35 days post-vaccination. Following challenge, vaccinated mice exhibited reduced bacterial burden and splenomegaly, along with distinct effector T-cell and monocyte profiles. Correlation of HDI data to serological and pathological measurements was performed. Our data indicate a Th1-biased response to Cb, consistent with previous reports, and identify Ly6C, CD73, and T-bet expression in T-cell, NK-cell, and monocytic populations as distinguishing features between vaccinated and naïve mice. This study refines the understanding of the integrated immune response to Cb vaccine and challenge, which can inform the assessment of candidate vaccines for Cb.

Highlights

Q-fever is a flu-like illness caused by Coxiella burnetii (Cb), a highly infectious intracellular bacterium
Subunit vaccines containing Cb epitopes to elicit protective T-cell responses are a proposed strategy to bypass concerns related to LPS-induced reactogenicity[17,18,19,20], while pre-clinical evaluation of candidate vaccines bearing computationally identified human-specific epitopes can be accomplished in mice expressing human MHC a lleles[21,22,23]
We identified novel correlates of Cb vaccination and infection characterized by expression of Ly6C, CD73, and T-bet, among other key markers across distinct T-cell, B-cell, and innate populations, and observed that key features of this response are detected in vaccinated mice

Summary

Introduction

Q-fever is a flu-like illness caused by Coxiella burnetii (Cb), a highly infectious intracellular bacterium. We proposed that analysis by longitudinal high dimensional immune (HDI) profiling using mass cytometry combined with other measures of vaccination and protection could be used to identify novel correlates of effective vaccination and control of Cb infection. This study refines the understanding of the integrated immune response to Cb vaccine and challenge, which can inform the assessment of candidate vaccines for Cb. Development of a safe, non-reactogenic and effective vaccine for Q-fever, a zoonotic disease found worldwide caused by the obligate intracellular bacteria Coxiella burnetii (Cb), represents a current unmet need. The objective of this study was to generate immune profiling data using mass cytometry, along with serological and pathological assessments, to identify novel correlates of effective vaccination and control of Cb infection that could inform the development of a safe and effective vaccine for Q-fever. Our results reveal the dynamic and broad immune response to Cb to support the development of subunit-based vaccines for Cb and inform future investigations into immune pathogenesis of this and other intracellular pathogens

Objectives

Methods

Results

Conclusion