Cookie Notice

This site uses cookies. By continuing to browse this site, you are agreeing to our use of cookies. Review our cookies information for more details.

OK
skip to main content

Innate immune training in at-risk infants protects against lung infections

Published: February 14, 2022

Severe lower respiratory infections during infancy have been implicated in the development of subsequent lung diseases such as asthma. While the exact mechanism(s) of how these lung infections increase asthma risk are unclear, airways inflammation resulting from developmentally dysregulated innate immune defense pathways in infants may contribute to this process. Until recently, it was generally believed that respiratory viruses were the main pathogens responsible for these asthma-associated lung infections. But emerging data from a number of key studies indicate an important parallel role for bacterial pathogens. These findings have prompted growing interest in the development of asthma-preventive approaches that target these severe lung infections in at-risk infants. In particular, microbial-derived immunostimulants (e.g. OM85 and MV130) are attracting attention for their potential to accelerate postnatal maturation of immune defenses during early postnatal life.  Recent clinical trials involving treatment of infants with microbial extracts have provided evidence of a reduction in the intensity and duration of severe lower respiratory infections in treated groups. Given that preventing severe lung infections in high-risk infants has the potential to protect against asthma, it is important to identify the effects of these microbial immunostimulants on the immune system.

In a recent issue of The Journal of Allergy and Clinical Immunology (JACI), Troy and colleagues applied a systems immunology-based approach to identify the nature of the protective mechanism of OM85 treatment in infants. The authors demonstrate for the first time, that OM85 treatment trains the innate immune system to increase resistance to severe lung infections in high-risk infants. This study used stored immune cell samples from a clinical trial of OM85 treatment for the primary prevention of severe lower respiratory illnesses in at-risk infants. OM85 is an agent containing 23 respiratory bacterial pathogens which has been used in Europe since 1980’s to prevent recurrent wheezy respiratory infection in children. The present study focused on the first year of life, in which infants received OM85/Placebo across their first winter and were monitored for respiratory symptoms to their first birthday. We hypothesized that OM85 treatment would enhance the functional maturation of key innate immune pathways that underly host defense against pathogens. To test this hypothesis, immune cells taken before and after the treatment period were cultured in vitro with a bacterial and a viral immune stimulant to see how each group responded to infection. Responses were then profiled using transcriptomics, gene network analyses and cytokine measurements. Gene network analysis methods consider gene pair co-expression relationships rather than relying on gene expression levels, which can unveil novel biological insight.

The OM85 treatment group showed a longer time to their first severe respiratory infection and had fewer days of respiratory symptoms throughout the study period. The OM85 treatment effects were stronger in relation to immune pathways triggered by bacterial as opposed to viral stimuli. Pro-inflammatory cytokine responses to bacterial stimulation were attenuated and the inflammatory gene network size/complexity was reduced in the OM85 treatment group. Although inflammatory pathways are important for antimicrobial defense, hyper-reactive inflammation can be a cause of morbidity. This reduction in bacterial-stimulated inflammation in vitro has also been found in asthma-resistant children that grow up on microbial-rich traditional farms. This may indicate that OM85 can mimic this natural form of immune training. The OM85 treatment group showed activation of interferon gene signaling in the OM85 group but not the Placebo group, in response to bacterial stimulation. There was evidence that OM85 rewired the gene networks underlying the bacterial defense pathways. TLR4, an early pathogen detector, showed coordinated expression with downstream interferon pathways, especially the master interferon regulator IRF7, consistent with a mild boosting of interferon gene signaling in the OM85 group. Only subtle changes were identified in the antiviral responsive pathways triggered by TLR3, between the OM85 and Placebo groups. Finally, TNF and IFNG were segregated in the OM85 treatment group gene network, two genes which are known to synergies to exaggerate inflammation. These innate immune changes are consistent with OM85-induced enhancement of bacterial pathogen detection/clearance capabilities in parallel with enhanced capacity to regulate ensuing inflammatory response intensity and duration.

The main target for the immune training effects of OM85 treatment may be innate immune pathways that primarily regulate host responses to bacterial as opposed to viral pathogens, which protects infants from severe respiratory infections.

The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

Full Article