Targeting the Toll-like receptor pathway as a therapeutic strategy for neonatal infection

Abstract

Toll-like receptors (TLRs) are crucial transmembrane receptors that form part of the innate immune response. They play a role in the recognition of various microorganisms and their elimination from the host. TLRs have been proposed as vital immunomodulators in the regulation of multiple neonatal stressors that extend beyond infection such as oxidative stress and pain. The immune system is immature at birth and takes some time to become fully established. As such, babies are especially vulnerable to sepsis at this early stage of life. Findings suggest a gestational age-dependent increase in TLR expression. TLRs engage with accessory and adaptor proteins to facilitate recognition of pathogens and their activation of the receptor. TLRs are generally upregulated during infection and promote the transcription and release of proinflammatory cytokines. Several studies report that TLRs are epigenetically modulated by chromatin changes and promoter methylation upon bacterial infection which have long-term influences on immune responses. TLR activation is reported to modulate cardiorespiratory responses during infection and may play a key role in driving homeostatic instability observed during sepsis. Although complex, TLR signalling and downstream pathways are potential therapeutic targets in the treatment of neonatal diseases. By reviewing the expression and function of key toll-like receptors, we aim to provide an important framework to understand the functional role of these receptors in response to stress and infection in premature infants.

Regulation of immune responses to infection through interaction between stem cell-derived exosomes and toll-like receptors mediated by microRNA cargoes

“…Each TLR (TLR4, TLR2, TLR5, TLR9) specifically recognizes bacterial PAMPs including peptidoglycan (PGN), lipoteichoic acid (LTA), lipopolysaccharide (LPS), flagellin, purines, and CpG-DNA. These events activate the nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB) which in turn triggers the expression of genes responsible for the synthesis and release of inflammatory mediators ( Figure 4 ) ( Zhang and Ghosh, 2001 ; Dias et al., 2021 ; Kircheis and Planz, 2023 ).…”

Effects of Sepsis on Immune Response, Microbiome and Oxidative Metabolism in Preterm Infants

“…The immune response in neonates is triggered by the innate immunity reacting to the exposure to an infectious agent. Local immune sentinel cells such as monocytes and macrophages are involved in pathogen-associated molecular patterns (PAMPs) recognition through the activation of pattern recognition receptors (PRRs), essentially Toll-like (TLRs) receptors but also other intracellular receptors that include nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and retinoic acid-inducible protein (RIG)-like receptors (RLRs) [ 21 ].…”

The potential role of adherence factors in probiotic function in the gastrointestinal tract of adults and pediatrics: a narrative review of experimental and human studies

“… 38 This study shows that isolated SLPs present in other Lactobacilli have a similar stimulatory effect and proposes it as a common feature of a number of Lactobacillus species. Given that the TLR2 signaling is an important pathway for host protection against infections, 159 isolated SLPs from L. helveticus could be considered for a supportive administration as probiotic molecules during human infant infections. Attempts have been made to use L. helveticus in infant infections.…”