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

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.

Proteomics of Brucella

“…Surprisingly, the functional aspects of proteases in Brucellae have not been investigated with proteomics so far. This is in sharp contrast to the proven importance of proteases for a great many functions such as host infection and persistence [89][90][91][92], stress response [92][93][94][95][96], morphology [97], communication and signaling [98][99][100], to name the most prominent.…”

RNA-Seq Analysis Reveals the Role of Omp16 in Brucella-Infected RAW264.7 Cells

“…At present, some experiments have shown that Omp10, Omp19, Omp25, and Omp31 are involved in Brucella virulence (11)(12)(13). The Brucella Omp19, Omp25, and Omp31 mutant were attenuated in cellular models and in mice, indicating that Omp19 and Omp25 were important for bacterial survival in vitro and in vivo (11,(14)(15)(16)(17). Furthermore, Omp25 and Omp31 disrupt the immune response by regulating the secretion of tumor necrosis factor alpha (TNF-α) expression and apoptosis in porcine and murine macrophages infected models (18,19).…”

Screening of potential vaccine candidates against pathogenic Brucella spp. using compositive reverse vaccinology

“…Omp19 is a surface-exposed lipoprotein broadly expressed within the Brucella genus, which plays an active role in bacterial cell adhesion, cell invasion, colonization, immune modulation, and intracellular survival (Figure 5 A) [ 48 ]. It has demonstrated that Omp19 is a possible vaccine candidate and has adjuvant activity as protease inhibitor, which can be used as positive control [ 49 , 50 ]. VirB8 from Brucella is a bitopic inner membrane protein, which undergoes several protein–protein interactions that have an impact on both the functionality and assembly of the T4SS complex, suggesting a key role in the T4S system (Figure 5 B) [ 51 , 52 ].…”