Virus-Like Particle-Induced Protection Against MRSA Pneumonia Is Dependent on IL-13 and Enhancement of Phagocyte Function

Abstract

The importance of the priming of the lung environment by past infections is being increasingly recognized. Exposure to any given antigen can either improve or worsen the outcome of subsequent lung infections, depending on the immunological history of the host. Thus, an ability to impart transient alterations in the lung environment in anticipation of future insult could provide an important novel therapy for emerging infectious diseases. In this study, we show that nasal administration of virus-like particles (VLPs) before, or immediately after, lethal challenge with methicillin-resistant Staphylococcus aureus (MRSA) of mice i) ensures complete recovery from lung infection and near absolute clearance of bacteria within 12 hours of challenge, ii) reduces host response-induced lung tissue damage, iii) promotes recruitment and efficient bacterial clearance by neutrophils and CD11c(+) cells, and iv) protects macrophages from MRSA-induced necrosis. VLP-mediated protection against MRSA relied on innate immunity. Complete recovery occurred in VLP-dosed mice with severe combined immunodeficiency, but not in wild-type mice depleted of either Ly6G(+) or CD11c(+) cells. Early IL-13 production associated with VLP-induced CD11c(+) cells was essential for VLP-induced protection. These results indicate that VLP-induced alteration of the lung environment protects the host from lethal MRSA pneumonia by enhancing phagocyte recruitment and killing and by reducing inflammation-induced tissue damage via IL-13-dependent mechanisms.

Biomimetic Antigenic Nanoparticles Elicit Controlled Protective Immune Response to Influenza

“…Because the P22 itself elicits a protective immune response 44 we administered 100 (PR8) and 50 (X-31) times the lethal doses to mice in order to determine whether protection was associated with the encapsulated NP. Mice treated with NP 163 -SP P22 showed protection against both challenges of influenza, with 80% survival over the course of the experiment (after both challenges), whereas mice treated with P22 or control groups given buffer solution (PBS) did not survive the first challenge (Figure 3a).…”

Novel protective mechanism for interleukin-33 at the mucosal barrier during influenza-associated bacterial superinfection

“…IL-13 has shown to be protective early in the course of influenza and MRSA super-infection, although the cellular source of IL-13 has not been shown. By day seven post-influenza infection, IL-13 levels are decreased in part due to the soluble IL-13 decoy receptor and mice are more susceptible to secondary MRSA pneumonia 26,27 . In a post-influenza pneumococcal pneumonia model, ST2−/− mice have been compared to wild-type mice and showed increased bacterial burden in the lung at 48 hours post-bacterial challenge when receiving S. pneumoniae at day 14 of influenza infection 28 .…”

Influenza and Bacterial Superinfection: Illuminating the Immunologic Mechanisms of Disease

“…These data suggest that enhanced neutrophil-mediated responses, perhaps mediated by an IL-13-dependent mechanism, may contribute to improved resolution of superinfection early after influenza virus infection (day 3) (20)(21)(22). As in prior experiments with pneumococcal pneumonia, depletion of neutrophils (with anti-Ly6G antibodies) in mice infected with influenza virus for 3 days significantly increased their susceptibility to S. aureus superinfection compared to mice infected only with bacteria (A. Rynda-Apple, unpublished observation).…”