<em>Listeria monocytogenes </em>Infection of the Brain

Listeria monocytogenes is an intracellular bacterial pathogen that is frequently associated with food-borne infection. The ability of&#160;L. ...

Harvard Medical School

Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) causes Johne's disease, a chronic enteric infection in ruminants with severe economic impact on the dairy industry in the USA and worldwide. Currently, available vaccines have limited protective efficacy against disease progression and does not prevent spread of the infection among animals. Because of their ability to elicit wide-spectrum immune responses, we adopted a live-attenuated vaccine approach based on a sigH knock-out strain of M. paratuberculosis (ΔsigH). Earlier analysis of the ΔsigH mutant in mice indicated their inadequate ability to colonize host tissues, unlike the isogenic wild-type strain, validating the role of this sigma factor in M. paratuberculosis virulence. In the present study, we evaluated the performance of the ΔsigH mutant compared to inactivated vaccine constructs in a vaccine/challenge model of murine paratuberculosis. The presented analysis indicated that ΔsigH mutant with or without QuilA adjuvant is capable of eliciting strong immune responses (such as interferon gamma-γ, IFN-γ) suggesting their immunogenicity and ability to potentially initiate effective vaccine-induced immunity. Following a challenge with virulent strains of M. paratuberculosis, ΔsigH conferred protective immunity as indicated by the reduced bacterial burden accompanied with reduced lesions in main body organs (liver, spleen and intestine) usually infected with M. paratuberculosis. More importantly, our data indicated better ability of the ΔsigH vaccine to confer protection compared to the inactivated vaccine constructs even with the presence of oil-adjuvant. Overall, our approach provides a rational basis for using live-attenuated mutant strains to develop improved vaccines that elicit robust immunity against this chronic infection. 

Superior protection elicited by live-attenuated vaccines in the murine model of paratuberculosis.

 is a Gram-positive intracellular pathogen that causes a severe invasive disease. Upon infecting a host cell,  upregulates the transcription of numerous factors necessary for productive infection. VirR is the response regulator component of a two-component regulatory system in  In this report, we have identified the putative ABC transporter encoded by genes  as necessary for VirR function. We have designated  We constructed an in-frame deletion of  and determined that the Δ mutant exhibited reduced transcription of VirR-regulated genes. The Δ mutant also showed defects in  plaque formation and  virulence that were similar to those of a Δ deletion mutant. Since VirR is important for innate resistance to antimicrobial agents, we determined the MICs of nisin and bacitracin for Δ bacteria. We found that VirAB expression was necessary for nisin resistance but was dispensable for resistance to bacitracin. This result suggested a VirAB-independent mechanism of VirR regulation in response to bacitracin. Lastly, we found that the Δ and Δ mutants had no deficiency in growth in broth culture, intracellular replication, or production of the ActA surface protein, which facilitates actin-based motility and cell-to-cell spread. However, the Δ and Δ mutants produced shorter actin tails during intracellular infection, which suggested that these mutants have a reduced ability to move and spread via actin-based motility. These findings have demonstrated that  VirAB functions in a pathway with VirR to regulate the expression of genes necessary for virulence and resistance to antimicrobial agents.

The VirAB ABC Transporter Is Required for VirR Regulation of Listeria monocytogenes Virulence and Resistance to Nisin.

 is a facultative intracellular bacterial pathogen that is frequently associated with food-borne infection. Of particular concern is the ability of  to breach the blood-brain barrier, leading to life-threatening meningitis and encephalitis. The mechanisms used by bacterial pathogens to infect the brain are not fully understood. Here we show that  is able to utilize vimentin for invasion of host cells. Vimentin is a type III intermediate filament protein within the cytosol but is also expressed on the host cell surface. We found that  interaction with surface-localized vimentin promoted bacterial uptake. Furthermore, in the absence of vimentin,  colonization of the brain was severely compromised in mice. The  virulence factor InlF was found to bind vimentin and was necessary for optimal bacterial colonization of the brain. These studies reveal a novel receptor-ligand interaction that enhances infection of the brain by  and highlights the importance of surface vimentin in host-pathogen interactions. is an intracellular bacterial pathogen that is capable of invading numerous host cells during infection.  can cross the blood-brain barrier, leading to life-threatening meningitis. Here we show that an  surface protein, InlF, is necessary for optimal colonization of the brain in mice. Furthermore, in the absence of vimentin, a cytosolic intermediate filament protein that is also present on the surface of brain endothelial cells, colonization of the brain was significantly impaired. We further show that InlF binds vimentin to mediate invasion of host cells. This work identifies InlF as a bacterial surface protein with specific relevance for infection of the brain and underscores the significance of host cell surface vimentin interactions in microbial pathogenesis.

Pallab Ghosh

Department of Microbiology and Immunobiology

Harvard Medical School

Listeria monocytogenes Infection of the Brain

Pallab Ghosh

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Microbiology and Immunobiology

Harvard Medical School

Listeria monocytogenes Infection of the Brain

Department of Microbiology and Immunobiology