Microbial exposure early in life regulates airway inflammation in mice after infection with Streptococcus pneumoniae with enhancement of local resistance

Abstract

The immunological explanation for the "hygiene hypothesis" has been proposed to be induction of T helper 1 (Th1) responses by microbial products. However, the protective results of hygiene hypothesis-linked microbial exposures are currently shown to be unlikely to result from a Th1-skewed response. Until now, effect of microbial exposure early in life on airway innate resistance remained unclear. We examined the role of early life exposure to microbes in airway innate resistance to a respiratory pathogen. Specific pathogen-free weanling mice were nasally exposed to the mixture of microbial extracts or PBS (control) every other day for 28 days and intratracheally infected with Streptococcus pneumoniae 10 days after the last exposure. Exposure to microbial extracts facilitated colonization of aerobic gram-positive bacteria, anaerobic microorganisms, and Lactobacillus in the airway, compared with control exposure. In pneumococcal pneumonia, the exposure prolonged mouse survival days by suppressing bacterial growth and by retarding pneumococcal blood invasion, despite significantly low levels of leukocyte recruitment in the lung. Enhancement of airway resistance was associated with a significant decrease in production of leukocyte chemokine (KC) and TNFalpha, and suppression of matrix metalloproteinase (MMP-9) expression/activation with enhancement of tissue inhibitor of MMP (TIMP-3) activation. The exposure increased production of IFN-gamma, IL-4, and monocyte chemoattractant-1 following infection. Furthermore, expression of Toll-like receptor 2, 4, and 9 was promoted by the exposure but no longer upregulated upon pneumococcal infection. Thus, we suggest that hygiene hypothesis is more important in regulating the PMN-dominant inflammatory response than in inducing a Th1-dominant response.

Lung dendritic cells facilitate extrapulmonary bacterial dissemination during pneumococcal pneumonia

“…Thus, it is tempting to speculate that the increased production of MMP-9 by DCs during pneumococcal pneumonia and the resulting breakdown of extracellular matrix and basal membranes on their way to the regional lymph nodes can open tissue barriers and thereby facilitate the extrapulmonary dissemination of S. pneumoniae . In agreement with our results, Yasuda et al (2010) reported enhanced airway resistance to S. pneumoniae associated with suppression of MMP-9 expression/activation in mice. Furthermore, studies performed in a rat model of pneumococcal meningitis documented induction of MMPs in brain parenchymal tissue and significantly reduced brain injury after MMP chemical inhibition (Leib et al, 2000, 2001).…”

Early Innate Immunity to Bacterial Infection in the Lung Is Regulated Systemically by the Commensal Microbiota via Nod-Like Receptor Ligands

“…Outside the intestine, it has also been shown that skin commensals regulate local T-cell-mediated immunity to cutaneous Leishmania major infection via IL-1 signaling (11), and upper airway commensals regulate immunity to viral infection in the lower airway (42). Furthermore, studies have also shown that repeated intranasal administration of a combination of both bacterial and fungal ligands to mice colonized by commensal bacteria provides additional local stimulation that enhances survival during bacterial lung infection (64). In the current study, defects in bacterial clearance from the lung due to microbiota depletion could be rescued only by NLR ligands originating from the intestine and not the upper airway.…”

The hygiene hypothesis in allergy and asthma

“…In a murine model of Streptococcus pneumoniae infection, early-life exposure to microbial components was associated with airway colonization by nonpathogenic bacteria (such as lactobacilli), increased airway expression of TLR2, 4 and 9 and decreased neutrophil recruitment [109]. Most importantly, early-life exposure was associated with prolonged survival of pneumonia (with increased expression of IFN-g, IL-4 and monocyte chemoattractant protein-1) following infection.…”