Impact of Cigarette Smoke Exposure on Innate Immunity: A Caenorhabditis elegans Model

BACKGROUND: Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD) and lung cancer. Respiratory bacterial infections have been shown to be involved in the development of COPD along with impaired airway innate immunity. METHODOLOGY/PRINCIPAL FINDINGS: To address the in vivo impact of cigarette smoke (CS) exclusively on host innate defense mechanisms, we took advantage of Caenorhabditis elegans (C. elegans), which has an innate immune system but lacks adaptive immune function. Pseudomonas aeruginosa (PA) clearance from intestines of C. elegans was dampened by CS. Microarray analysis identified 6 candidate genes with a 2-fold or greater reduction after CS exposure, that have a human orthologue, and that may participate in innate immunity. To confirm a role of CS-down-regulated genes in the innate immune response to PA, RNA interference (RNAi) by feeding was carried out in C. elegans to inhibit the gene of interest, followed by PA infection to determine if the gene affected innate immunity. Inhibition of lbp-7, which encodes a lipid binding protein, resulted in increased levels of intestinal PA. Primary human bronchial epithelial cells were shown to express mRNA of human Fatty Acid Binding Protein 5 (FABP-5), the human orthologue of lpb-7. Interestingly, FABP-5 mRNA levels from human smokers with COPD were significantly lower (p = 0.036) than those from smokers without COPD. Furthermore, FABP-5 mRNA levels were up-regulated (7-fold) after bacterial (i.e., Mycoplasma pneumoniae) infection in primary human bronchial epithelial cell culture (air-liquid interface culture). CONCLUSIONS: Our results suggest that the C. elegans model offers a novel in vivo approach to specifically study innate immune deficiencies resulting from exposure to cigarette smoke, and that results from the nematode may provide insight into human airway epithelial cell biology and cigarette smoke exposure

Mode of genetic inheritance modifies the association of head circumference and autism-related symptoms: a cross-sectional study.

Frequently individuals with autism spectrum disorder (ASD) have been noted with a larger head circumference (HC) than their typical developing peers. Biologic hypotheses suggest that an overly rapid brain growth leads to the core symptoms of ASD by impairing connectivity. Literature is divided however where deleterious, protective and null associations of HC with ASD symptoms in individuals with ASD have been found.Individuals (n = 1,416) from the Autism Genetic Resource Exchange with ASD were examined for associations of HC with ASD like symptoms. Mixed models controlling for sex, age, race/ethnicity, simplex/multiplex status and accounting for correlations between siblings were used. Interactions by simplex/multiplex were explored. Adjustments for height in a sub-population with available data were explored as well.A Significant interaction term (p = 0.03) suggested that the effect of HC was dependent on whether the individual was simplex or multiplex. In simplex individuals at mean age (8.9 years) 1 cm increase in head circumference was associated with a 24% increase in the odds of a high social diagnostic score from the Autism Diagnostic Interview-Revised (odds ratio  = 1.24, p = 0.01). There was no association in multiplex individuals. Additionally, individuals classified with a non-verbal IQ 110 non-verbal IQ also had an increased HC (0.4 cm p = 0.04), relative to a mid-range non-verbal IQ group, and were 90% multiplex. HC effects do not appear to be confounded by height, however, larger samples with height information are needed.The potential link between brain growth and autism like symptoms is complex and could depend on specific etiologies. Further investigations accounting for a likely mode of inheritance will help identify an ASD subtype related to HC

Odds Ratio of Non-Verbal Classification from the ADI-R.

<p>Bold highlights HC association.</p>*<p>Indicates significant association at alpha <0.05.</p>†<p>Males compared to females.</p>‡<p>Verses Non-Hispanic whites.</p

Odds Ratio of High Social Diagnostic Algorithm Score in Simplex Individuals.

<p>Bold highlights HC association.</p>*<p>Indicates significant association at alpha <0.05.</p>†<p>Males compared to females.</p>‡<p>Verses Non-Hispanic whites.</p

Odds Ratio of High Social Diagnostic Algorithm Score in Multiplex Individuals.

*<p>Indicates significant association at alpha <0.05.</p>†<p>Males compared to females.</p>‡<p>Verses Non-Hispanic whites.</p

Population Characteristics.

<p>-not available.</p

Mean head circumference and 95% CI of NVIQ groups at mean age (9.2 years) in males adjusted for race/ethnicity and simplex status.

<p>This pattern was not different in females. Group 1 is >90% simplex individuals, group 2 is 22% simplex, and group 3 is >90% multiplex.</p