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Reduction of tumor necrosis factor alpha-inducing capacity of recombinant Lactobacillus casei via expression of Salmonella OmpC.

ABSTRACT: The insertion of a heterologous gene into commensal bacteria is a common technique to develop a delivery agent for vaccination and therapies, but the pleiotropic effects of genetic modifications need to be investigated before its use in practical applications. Although supplemental properties provided by the expression of heterologous antigens have been reported, the negative or side effects on the immune-modulating properties caused by recombination are barely understood. In the present study, we fortuitously found that the secretion of tumor necrosis factor alpha (TNF-alpha) from murine macrophages was reduced by recombinant Lactobacillus casei expressing Salmonella OmpC compared to the stimulation of TNF-alpha secretion by nonexpressing L. casei. This reduction could not be attributed to OmpC as a purified protein. The main component of the OmpC-expressing strain included in the attenuation of TNF-alpha release seemed to be the cell wall, which exhibited higher sensitivity against N-acetylmuramidase than that of nonexpressing strains. These results suggest that the recombinant strain expressing a specific heterologous antigen might be digested rapidly in macrophages and lose immune-stimulating capability at an early time point.

SUBMITTER: Kajikawa A

PROVIDER: S-EPMC2681715 | biostudies-other | 2009 May

REPOSITORIES: biostudies-other

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Project description:Reactive arthritis is the development of sterile joint inflammation as a sequel to a remote infection, often in the gut. We have previously shown that a low dose of S. enteritidis inoculated to streptomycin-pretreated mice generates a self-limiting enterocolitis suitable for studying reactive arthritis. Here we show that consumption of Lactobacillus casei prior to infection abolishes intestinal and joint inflammation triggered by Salmonella. BALB/c mice were sacrificed after infection; intestinal and joint samples were analyzed for histological changes and expression of cytokines. TNF-α was measured by ELISA and the expression of IL-1β, IL-6, IL-10, IL-17, IL-23 and TGF-β was assessed by qPCR. L. casei consumption prevented Salmonella-induced synovitis, the increment of TNF-α in knees and the increase of IL-17 expression in popliteal and inguinal lymph nodes. At intestinal level consumption of L. casei drastically diminished S. enteritidis invasiveness and shortened splenic persistence of the pathogen. Bacterial loads recovered at days 2 and 5 from Peyer's patches were 10-fold lower in mice fed with L. casei. In accordance, we found that the augment in gut permeability induced during enterocolitis was decreased in those animals. Consumption of L. casei prior to infection failed to increase anti- inflammatory molecules such as IL-10 and TGF-β in the intestine. On the other hand, consumption of L. casei abrogated the expression of TNF-α, IL-17, IL-23, IL-1β and IL-6 in cecum and mesenteric lymph nodes. These cytokines are needed for differentiation of immune cells involved in the development of reactive arthritis such as Th17 and γδ T cells. Trafficking of these inflammatory cells from the gut to the joints has been proposed as a mechanism of generation of reactive arthritis. Our results suggest that L. casei consumption prevents Salmonella-induced synovitis by altering the intestinal milieu necessary for differentiation of cells involved in the generation of joint inflammation.

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Reduction of tumor necrosis factor alpha-inducing capacity of recombinant Lactobacillus casei via expression of Salmonella OmpC.

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