Innate Imprinting by the Modified Heat-Labile Toxin of Escherichia coli (LTK63) Provides Generic Protection against Lung Infectious Disease

Abstract

In a healthy individual, the lung contains few lymphoid cells. However, amplified immune responses, as exemplified during lung infection, can cause extensive tissue damage. We have previously demonstrated that one lung infection modulates the immunopathological outcome to a subsequent unrelated pathogen. Mimicking heterologous immunity may provide a means of enhancing both innate and acquired immunity. We now show that prior lung administration of a modified heat-labile toxin from Escherichia coli (LTK63) enhances immunity to respiratory syncytial virus, influenza virus, and the fungus Cryptococcus neoformans. Treatment with LTK63 decreased lung inflammation and tissue damage and improved the ability to resolve the infection. APCs expressing the activation markers MHC class II, CD80, and CD40 increased in number in the lung. LTK63 treatment increased the pathogen-specific IgA response in the nasal mucosa and simultaneously decreased inflammatory cytokine production (IFN-γ and TNF-α) after infection. The number of activated CD8+CD44+ T cells and the respiratory syncytial virus- or influenza-specific CD8-proliferative responses increased, although the total inflammatory infiltrate was reduced. LTK63 treatment matured lung APCs (LTK63 prevented efficient presentation of whole OVA to DO11.10 cells, whereas OVA peptide presentation was unaffected), enhanced immunity in both a Th1 and Th2 environment, was long lasting, and was not pathogen or host strain specific; the protective effects were partially independent of T and B cells. Innate imprinting by toxin-based immunotherapeutics may provide generic protection against infectious disease in the lung, without the need for coadministered pathogen-specific Ag.

The Acquired Immune Response to the Mucosal Adjuvant LTK63 Imprints the Mouse Lung with a Protective Signature

“…In agreement with a previous report and with the data originated from the BAL, we found that LTK63 administration triggered the recruitment at 6 -8 days of CD4 ϩ T cells, CD8 ϩ T cells, NK cells (Fig. 5, A-C), and B cells (data not shown) (21). We extended the analysis of lung single cell suspension by monitoring the activation status of T and NK cells.…”

“…It has been shown that the pulmonary administration of LTK63 affects the composition of lung cellularity, indicating a recruitment of several blood cell types (21). The B cell and T cell gene clusters identified by hierarchical clustering analysis (Fig.…”

“…In these infection models the net effect of LTK63 pretreatment is characterized by enhanced adaptive responses to the infectious agent, reduced inflammation and tissue damage, and more efficient clearance of the pathogen. In particular, in the case of influenza infection mice pretreated with LTK63 display reduced lung viral burden, negligible weight loss, and improved flu-specific CD4 ϩ and CD8 ϩ T cell response (21). Despite the great potential of LTK63 as vaccine adjuvant and immune therapeutic, little is known about its mechanism of action in vivo.…”

Viral–bacterial interactions in the respiratory tract

“…In a similar approach, activation of TLR2/6 and TLR9 by pre-treatment with synthetic agonists reduced parainfluenza virus titres in guinea pigs; however, this regimen was not able to prevent virus-induced airway hyperreactivity (Drake et al, 2013). Similar to the immunostimulatory effect of individual TLR agonists, innate immune imprinting by local application of modified heat-labile Escherichia coli toxins has been shown to confer protection against respiratory viral infection in murine models (Norton et al, 2010;Williams et al, 2004). The need for local application might even be circumvented by dietary intake of probiotics, specifically those bacterial strains that trigger type I IFN production by plasmacytoid DCs (Jounai et al, 2015).…”

Desenvolvimento de uma estratégia vacinal dose-reforço heterológo baseada em linhagens recombinantes de <i>Bacillus subitilis</i> para o controle de <i>Spreptococcus mutans</i>.

“…A cárie é uma doença oral de caráter crônico e infeccioso, definida pela Organização Mundial de Saúde (OMS) como um dos principais problemas de saúde pública no mundo (PETERSEN, 2003;WORSLEY et al, 2016). Essa doença atinge países subdesenvolvidos ou mesmo aqueles mais desenvolvidos, sendo as populações mais desfavorecidas as mais afetadas.…”