Omp19 Enables Brucella abortus to Evade the Antimicrobial Activity From Host's Proteolytic Defense System.

Karina A Pasquevich,Marianela V Carabajal,Lorena M Coria,Laura Bruno,Juliana Cassataro,Francisco F Guaimas,Diego A Rey Serrantes,Mara S Roset,Diego J Comerci

doi:10.3389/fimmu.2019.01436

Abstract

Pathogenic microorganisms confront several proteolytic events in the molecular interplay with their host, highlighting that proteolysis and its regulation play an important role during infection. Microbial inhibitors, along with their target endogenous/exogenous enzymes, may directly affect the host's defense mechanisms and promote infection. Omp19 is a Brucella spp. conserved lipoprotein anchored by the lipid portion in the Brucella outer membrane. Previous work demonstrated that purified unlipidated Omp19 (U-Omp19) has protease inhibitor activity against gastrointestinal and lysosomal proteases. In this work, we found that a Brucella omp19 deletion mutant is highly attenuated in mice when infecting by the oral route. This attenuation can be explained by bacterial increased susceptibility to host proteases met by the bacteria during establishment of infection. Omp19 deletion mutant has a cell division defect when exposed to pancreatic proteases that is linked to cell-cycle arrest in G1-phase, Omp25 degradation on the cell envelope and CtrA accumulation. Moreover, Omp19 deletion mutant is more susceptible to killing by macrophage derived microsomes than wt strain. Preincubation with gastrointestinal proteases led to an increased susceptibility of Omp19 deletion mutant to macrophage intracellular killing. Thus, in this work, we describe for the first time a physiological function of B. abortus Omp19. This activity enables Brucella to better thrive in the harsh gastrointestinal tract, where protection from proteolytic degradation can be a matter of life or death, and afterwards invade the host and bypass intracellular proteases to establish the chronic infection.

Highlights

The intestinal mucosa is the largest interface between the external environment and the tissues of the human body
We studied if Omp19 enables Brucella to better thrive in the harsh gastrointestinal tract, where protection from proteolytic degradation can be a matter of life or death, and promoting host invasion and intracellular infection
Twenty days post-infection B. abortus were isolated from spleens and cervical lymph nodes (CLNs) from wt infected mice, whereas almost no CFUs were found in these organs of omp19 infected mice (p < 0.05 and p < 0.01 vs. wt, respectively) (Figures 1C,D)

Summary

Introduction

The intestinal mucosa is the largest interface between the external environment and the tissues of the human body. The first line of defense in the gastrointestinal tract is in the lumen, where microorganisms are degraded in a non-specific fashion by pH and gastric, pancreatic and biliary secretions. Pathogenic microorganisms confront several proteolytic events in the molecular interplay with their host, proteolysis and its regulation play an important role during infection. Microbes synthetize protease inhibitors to control endogenous proteases. Some inhibitors can interact with exogenous peptidases produced by other species and may directly affect host’s defense mechanisms [1]. Few works in the literature show the importance of bacterial protease inhibitors activity against host-proteases [2,3,4]. Our hypothesis is that pathogenic bacteria synthesize protease inhibitors to evade the antimicrobial activity from host’s proteases

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Conclusion