Vaccination with Klebsiella pneumoniae-derived extracellular vesicles protects against bacteria-induced lethality via both humoral and cellular immunity

Abstract

The emergence of multidrug-resistant Klebsiella pneumoniae highlights the need to develop preventive measures to ameliorate Klebsiella infections. Bacteria-derived extracellular vesicles (EVs) are spherical nanometer-sized proteolipids enriched with outer membrane proteins. Gram-negative bacteria-derived EVs have gained interest for use as nonliving complex vaccines. In the present study, we evaluated whether K. pneumoniae-derived EVs confer protection against bacteria-induced lethality. K. pneumoniae-derived EVs isolated from in vitro bacterial culture supernatants induced innate immunity, including the upregulation of co-stimulatory molecule expression and proinflammatory mediator production. EV vaccination via the intraperitoneal route elicited EV-reactive antibodies and interferon-gamma-producing T-cell responses. Three vaccinations with the EVs prevented bacteria-induced lethality. As verified by sera and splenocytes adoptive transfer, the protective effect of EV vaccination was dependent on both humoral and cellular immunity. Taken together, these findings suggest that K. pneumoniae-derived EVs are a novel vaccine candidate against K. pneumoniae infections.

Porin Loss Impacts the Host Inflammatory Response to Outer Membrane Vesicles of Klebsiella pneumoniae

“…The macrophage responses to these OMVs were distinctly more potent than to purified outer membrane and demonstrate that porin composition is a key determinant of the intensity of inflammatory cytokine production. It has recently been demonstrated that vaccination with OMVs from Klebsiella pneumoniae is capable of generating an effective protective response (61). However, this new study does not consider the impact of alterations to OMV composition such as those exhibited with porin loss.…”

Intradermal Immunization of BALB/C Mice with Heat Killed Klebsiella pneumoniae ATCC BAA1706 Leads to the Production of both IgG1 and IgG2a

“…However, when analyzing the proliferation of the bacteria in the scenario of absence of Factor B, the lack of activation of the classical pathway of the complement system seemed to support the bacterial proliferation almost exponentially, this result as also observed in a C5 depletion setup (Nypaver et al, 2010). Additionally, the intraperitoneal adoptive transference of the sera of mice immunized with extracellular vesicles of K. pneumoniae, led to protection from the lethality induced by the intraperitoneal challenge of a high dose of K. pneumoniae (Lee et al, 2015). Taken together, these results suggests that even though some strains of K. pneumoniae possesses resistant mechanisms against the complement system, it activation plays a major role in K. pneumoniae infection control.…”

“…We did not assess the differentiation of naïve lymphocytes in Th17 cells. However, other studies have shown that there are ways to achieve protection against K. pneumoniae in a non-IL17 dependent manner (Tsao et al, 2015;Lee et al, 2015). The activation of the complement system pathways lead to the fragmentation of C5, thus the production of the fragment C5a, a potent neutrophil chemoattractant (Mayadas, Cullere et Lowell, 2014).…”

“…However, the use of protein subunits to construct vaccines often requires the incorporation of inflammatory adjuvants for greater effectiveness of the memory (Lee et al, 2015;Lundberg et al, 2013;Kurupati and Poh, 2011;Jain et al, 2015). The use of the whole bacteria for the construction of a vaccine provides a more ample supply of candidates for vaccination (Ahmad et al, 2012), provides a more suitable inflammatory stimulus for the establishment of an immune response and ensures a more complete understanding of the immunological processes related to a natural contact with the pathogen.…”

Nanovesicles: Diagnostic and Therapeutic Tools in Nanoscale Medicine

“…Above indicates that parts of NVs from tumor cells or pathogens are able to provide protective capability against immunity-requiring diseases [32]. Thus, vesicle-based vaccines are promising way to cope with diseases derived from vesicle-generating-cells.…”