Understanding the role of innate immune training in prevention of respiratory infections

Traditionally, the body defences against infection have been thought of as being divided into two main components: the innate and adaptive immune systems. Major characteristics of each are listed below. nonspecific Barrier function Epithelial cells secreting antiviral/bacterial proteins Bone marrow derived inflammatory cells that kill and remove pathogens Surface Pattern Recognition Receptors recognize Microbe Associated Molecular Patterns and Danger Associated Molecular Patterns Traditionally not thought to have “memory” responses Provides pathogen specificity through memory responses B cells, antibodies T cells, cytotoxicity Specific surface receptors bacillus calmette-guerin vaccination induces a greater innate response against other infectious agents providing protection for up to 3 months. Low dose LPS exposure induced an increased inflammatory response upon re-exposure whereas an initial high dose exposure suppresses inflammation upon subsequent exposure. Obesity pathogenesis involves innate immune training, with the Western diet, LPS, and inflammatory cytokines increasing obesity risk by inducing systemic inflammation, setting of a self-perpetuating feedforward cycle. Prenatal exposures may prime more mature responses to postnatal exposures. Infancy appears to be a developmental stage where innate immune training maybe most effective, especially in accelerating maturation of both innate and adaptive immune responses. Both the innate and adaptive immune systems are immature at birth and mature in response to beneficial environmental exposures. Maturation of the adaptive immune system is the topic of a different presentation and won't be considered further. We recently examined immune response to toll-like receptor-lipopolysaccharide (TLR-LPS) and viral (poly I:C, immiquimod) stimuli of blood mononuclear cells collected at birth (cord blood) and at 5 years of age. These stimuli induced expression of sets of interferon response genes and secretion of inflammatory cytokines. At birth, the bacterial network was poorly organized, with lower connectivity compared to the viral network. Master regulator analyses showed that the bacterial network at birth was regulated by IRF1, with the viral network regulated by interferon regulatory factor 7 (IRF7). Examining the networks in individual children showed that those with less organized and more proinflammatory bacterial network were at increased risk of severe lower respiratory illnesses (sLRI) in the first year of life. The organization of the viral networks did not predict sLRI. Examining these networks from peripheral blood monocytes collected at 5 years of age showed little change in the viral network but major changes in organization and increased connectivity for the bacterial network. Both networks were regulated by IRF7. These data show that major developmental changes occurred in the bacterial but not viral networks and that immaturity in the bacterial network predicted risk of sLRI in the first year of life, am exposure we have previously shown increases asthma risk. The “farming effect” has suggested that exposure to diverse microbial communities during prenatal development and in early life can reduce early allergic sensitization and asthma risk. The question remains how this occurs. Bacterial lysates have been used for decades in Europe to prevent respiratory infections and wheezing in children. We conducted a proof-of-concept study to determine whether a commonly used bacterial lysate product, OM85, could prevent sLRI in high-risk infants in early life. We treated infants for the first two winters of their lives with OM85 and recorded sLRIs. Compared to placebo, OM85 increased the time to the first sLRI, reduced the cumulative frequency of sLRI and reduced the number of days infants had sLRIs during the first year of life. Examining bacterial and viral interferon response networks showed that OM85 accelerated maturation of the bacterial response network, with little effect on the viral response network. These data demonstrate the potential for accelerating innate immune maturation and reducing asthma risk. Increasing evidence shows that the maternal gut microbiome during pregnancy has a major influence on the maturation of the immune system at birth and on allergic outcomes in offspring. The composition of the maternal gut microbiome is influenced by environmental exposures and this, in turn, influences fetal immune development. Animal studies giving OM85 to pregnant dams influence fetal immune development and provided offspring with protection against allergic sensitization and “type 2” inflammation by increasing mucosal-homing regulatory T-cells and facilitating more balanced immune response to infective and inflammatory stimuli. These data highlight the possibility of treating pregnant women with “benign” TLR-ligands to reduce offspring risk of early life sLRI, early allergic sensitization, and reduce asthma risk. Peter D. Sly is solely resonsible for the content of this presentation. Open access publishing facilitated by The University of Queensland, as part of the Wiley - The University of Queensland agreement via the Council of Australian University Librarians. The author declares no conflict of interest. This article represents a conference presentation and there are no data to share.