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

Richa Rai,Shiva M Singh,Ashok Kumar,Geeta Rai,Lena Alexopoulou,Sudhir Kumar Chauhan,Vikas Vikram Singh

doi:10.1371/journal.pone.0062845

Richa Rai, Shiva M Singh + Show 5 more

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https://doi.org/10.1371/journal.pone.0062845

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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.

Highlights

Low birth weight (LBW) newborns suffer from higher infection, morbidity and mortality rates than normal birth weight (NBW) newborns [1,2,3]
Diminished Pattern recognition receptor (PRR), IFN-signature, and BPI gene expression raises the possibility that impairments in these pathways contribute to the susceptibility of low birth weight (LBW) term infants to infection
Down-regulation of genes appeared to be a more dominant event compared to up-regulation in LBW newborns (Figure 1) the expression pattern of C1 (NBW) appears similar to that of E2 (LBW)

Summary

Introduction

Low birth weight (LBW) (birth weight ,2500 g) newborns suffer from higher infection, morbidity and mortality rates than normal birth weight (NBW) (birth weight $2500 g) newborns [1,2,3]. Many immune response related genes like granzymes and bactericidal/permeability-increasing (BPI) protein were seen to be down-regulated in the LBW newborns. The information obtained from this study may provide us with a better understanding of the underlying mechanisms responsible for the underdeveloped immune response in the term LBW newborns and their increased susceptibility to infections. 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

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