| Abstract: | The pre- and postnatal environment may represent a window of opportunity for allergy and asthma prevention, and the hygiene hypothesis implies that microbial agents may play an important role in this regard. Using the cowshed-derived bacterium Acinetobacter lwoffii F78 together with a mouse model of experimental allergic airway inflammation, this study investigated the hygiene hypothesis, maternal (prenatal) microbial exposure, and the involvement of Toll-like receptor (TLR) signaling in prenatal protection from asthma. Maternal intranasal exposure to A. lwoffii F78 protected against the development of experimental asthma in the progeny. Maternally, A. lwoffii F78 exposure resulted in a transient increase in lung and serum proinflammatory cytokine production and up-regulation of lung TLR messenger RNA. Conversely, suppression of TLRs was observed in placental tissue. To investigate further, the functional relevance of maternal TLR signaling was tested in TLR2/3/4/7/9−/− knockout mice. The asthma-preventive effect was completely abolished in heterozygous offspring from A. lwoffii F78–treated TLR2/3/4/7/9−/− homozygous mother mice. Furthermore, the mild local and systemic inflammatory response was also absent in these A. lwoffii F78–exposed mothers. These data establish a direct relationship between maternal bacterial exposures, functional maternal TLR signaling, and asthma protection in the progeny.Allergic bronchial asthma has become a major public health burden in industrialized countries, and the incidence of this chronic inflammatory disease has been steadily growing over the last decades. Although many susceptibility genes have been identified (Moffatt et al., 2007; Vercelli, 2008), genetics alone cannot explain the velocity of these changes. Additional factors must have contributed to the growing incidence of asthma. In agreement with the hygiene hypothesis, epidemiological studies indicate that lack of early childhood exposure to microbial agents may contribute to increased susceptibility to the development of allergic diseases (Strachan, 2000). Moreover, environments characterized by a diverse and concentrated microbial milieu, such as traditional farming sites, may protect from allergic diseases (Riedler et al., 2001; Majkowska-Wojciechowska et al., 2007; Midodzi et al., 2007; von Mutius and Radon, 2008). In this regard, analysis of cowshed dust samples has identified the Gram-negative, nonpathogenic bacterium Acinetobacter lwoffii F78 as a potential allergo-protective agent (Korthals et al., 2008). Although experimental approaches using a mouse model of acute allergic airway inflammation suggest a strong allergy protective potential of this bacterial strain (Debarry et al., 2007), nothing is known about the effects of prenatal exposure to A. lwoffii F78 and possible downstream mechanisms affecting allergic inflammatory responses in the progeny.Respiratory allergies, including bronchial asthma, are chronic inflammatory diseases that are based on a complex deregulated interaction of both innate and adaptive immune responses (Hammad and Lambrecht, 2008; Holgate and Polosa, 2008). Regarding the maturation of the adaptive immune system, it is now well established that the development of functionally active T cell subsets starts already prenatally (Warner et al., 2000), and it has been proposed that immunoprogramming by environmental influences may occur at this early developmental stage. Indeed, studies have demonstrated that many factors affecting the initiation and course of respiratory allergies appear to act within a narrow window of opportunity, either prenatally and/or early in life (Ege et al., 2006; Rowe et al., 2007). It is still unresolved, however, how protective signals are transferred from the mother to the developing fetus.Regarding mechanisms by which A. lwoffii F78 may exert its protective effects, consideration must be given to innate immune processes that participate in initial microbial recognition. Innate immunity functions as a first line of defense that uses, in addition to physical barriers, a pattern recognition receptor (PRR) system that can identify a broad spectrum of microbial components. Toll-like receptors (TLRs) are a major class of PRRs expressed by several cell types, including epithelium and immune cells, that play a vital role in the initiation of the immune response (Gon, 2008; Kawai and Akira, 2009).Combining prenatal exposure to the cowshed bacterium A. lwoffii F78 with a mouse model of allergic airway inflammation, we show in this report that prenatal exposure to farming-related microbes protects from the development of allergic phenotypes in the next generation. The process by which this protection is achieved involves a low level, local, and systemic maternal innate immune response, and the transference of protective immunity from the mother to the fetus is fully dependent on the action of the maternal TLR2, 3, 4, 7, and/or 9. |
