Decreased Pattern Recognition Receptor Signaling, Interferon-Signature, and Bactericidal/Permeability-Increasing Protein Gene Expression in Cord Blood of Term Low Birth Weight Human Newborns

Abstract

BackgroundMorbidity and mortality rates of low birth weight (LBW) newborns at term are higher than rates in normal birth weight (NBW) newborns. LBW newborns are at greater risk to acquire recurrent bacterial and viral infections during their first few weeks of life possibly as an outcome of compromised innate immune functions. As adaptive immunity is in a naive state, increased risk of infection of LBW as compared to NBW newborns may reflect impairments in innate immunity.MethodologyTo characterize the increased susceptibility to infections in LBW newborns we used microarray technology to identify differences in gene expression in LBW newborns (n = 8) compared to NBW newborns (n = 4) using cord blood. The results obtained from the microarray study were validated on a larger number of samples using real time RT-PCR (LBW = 22, NBW = 18) and western blotting (LBW = 12, NBW = 12). The Interferome database was used to identify interferon (IFN) signature genes and ingenuity pathway analysis identified canonical pathways and biological functions associated with the differentially expressed genes in LBW newborns. ELISAs for IFNs and bactericidal/permeability-increasing protein were performed in both LBW and NBW newborns and in adults (LBW = 18, NBW = 18, Adults = 8).Principal FindingsUpon microarray analysis, we identified 1,391 differentially expressed genes, of which, 1,065 genes were down-regulated and 326 genes were up-regulated in the LBW compared to NBW newborns. Of note, 70 IFN-signature genes were found to be significantly down-regulated in LBW compared to NBW newborns. Ingenuity pathway analysis revealed pattern recognition receptors signaling including Toll-Like Receptors (TLRs) -1, -5, and -8 genes and IFN signaling as the most significantly impacted pathways. Respiratory infectious diseases were the most significantly affected bio-functions in LBW newborns.Conclusion and SignificanceDiminished PRRs, IFN-signature, and BPI gene expression raises the possibility that impairments in these pathways contribute to the susceptibility of LBW term infants to infection.

Genome Wide Screening of Candidate Genes for Improving Piglet Birth Weight Using High and Low Estimated Breeding Value Populations

“…In human, many immune response related genes are down-regulated in low birth weight newborns compared to normal birth weight newborns 72. Interestingly, some genes in our study, including RPL34 , RPS17 and RPL9 (Additional File 2: Table S1), were the same down-regulated genes previously reported in human 72, suggesting that these genes might be important in antiviral innate immune response affected by a maternal viral infection in fetal development. Given their known developmental role in Rab GTPase activator activity, metal ion binding, and zinc ion binding (Additional File 2: Table S3), additional candidate genes ( TBC1D19 , WDFY3 , and ADH4 ) were also identified in this study and suggest that these genes might be involved in embryonic or fetal development in pigs, respectively.…”

Protecting the Newborn and Young Infant from Infectious Diseases: Lessons from Immune Ontogeny

“…But while most APPs (e.g. Lactoferrin, BPI, and cathelicidin anti-microbial peptide 18, also called LL-37) have lower constitutive plasma concentrations in preterm and low birth weight newborns, term infant plasma contains substantially higher levels (Singh et al, 2013;Strunk et al, 2009). The importance of APP production for early life innate immunity becomes evident in cases of selected APP deficiency, because lower serum levels of cathelicidin, for example, are associated with increased severity of acute bacterial respiratory infection in early childhood (Battersby et al, 2016;Mansbach et al, 2012).…”

Decreased Toll-Like Receptor-4/Myeloid Differentiation Factor 88 Response Leads to Defective Interleukin-1β Production in Term Low Birth Weight Newborns

“…7,8 Therefore, a proper balance between pro-and antiinflammatory cytokines is maintained through a tightly regulated feedback mechanism for adequate immune responses toward the pathogenic infections. 17 Defects in function of TLR signaling in preterm newborns compared with term healthy newborns and adults are known. 9,10 Low birth weight (LBW) is associated with high risk of neonatal mortality in the perinatal period because of higher frequency and severity of microbial infection compared with normal birth weight (NBW) newborns.…”