Previous studies show microbial components display pathogen-associated molecular patterns (PAMPs) that are recognized by the innate immune system and serve to trigger inflammation. In Gram-positive bacteria, cell wall (CW) is a complex exopolymer that harbors several PAMPs that potently activate inflammation when released into the bloodstream during bacterial infection or when explosively discharged during bacterial lysis by common antibiotics. It is known that CW binds to innate immune Toll-like receptors (TLRs), particularly TLR2, and initiates signaling leading to inflammation. TLR2 is abundant in the embryo, however, little is known of the outcome of activation of this cascade in the fetus and it is unknown if TLR2 ligands, such as CW, cross the placenta. The current study shows that maternal infections cause a signaling event which leads to the proliferation and reorganization of neurons in the developing brain that is defective in some way, maybe due to overcrowding.
The current study shows that pieces of the bacterial cell wall cross the placenta and travel to the fetal brain, triggering proliferation of immature neurons. Working in cells growing in the laboratory and in mice, the researchers showed how pieces of the pneumococcal cell wall bind to the protein platelet activating factor receptor (PAFr) for transport across the placenta and entry into the fetal brain. There, rather than triggering inflammation and cell death, within hours the bacterial cell wall had switched on expression of the protein FoxG1, a transcription factor that drives neural proliferation. It was observed that proliferation occurred early in pregnancy deep in a region of the brain called the ventricular zone and within days, a 50% increase was documented in neurons in the cortical plate, which becomes the cortex.
The team also reported that a component of the innate immune system played a key role in driving proliferation rather than inflammation. The protein named toll-like receptor 2 (TLR2) helps cells recognize and defend against bacteria. Evidence suggests that TLR2 partners with a related protein, TLR6, to drive proliferation in response to bacterial cell wall. Results show that mice exposed to bacterial cell wall early in fetal development later performed below average on measures of memory and cognitive functioning. Data findings show that treatment of maternal infection by the antibiotic ampicillin, which destroys bacteria and sends pieces of the cell wall into the bloodstream, led to a similar neuronal increase.
The lab state that the data raises questions about which class of antibiotics should be used to treat bacterial infections during pregnancy. They go on to add that their findings suggests widely used antibiotics like ampicillin that cause bacteria to burst and release cell wall may lead to changes in the developing brain, changes which did not occur in mice treated with antibiotics like clindamycin that kill without releasing cell wall. The group stress that additional studies are needed to understand the long-term impact of different classes of antibiotics on pregnancy outcomes.
The team surmise that additional research is needed to understand how bacterial cell wall signaling induces proliferation via this newly identified pathway that links the innate immune receptor TLR2 with the transcription factor FoxG1 to drive neural proliferation in the fetus. For the future, the researchers state that this same mechanism might lead to new strategies to repair or replace neurons lost to illness or injury.
Michelle Petersen is the founder of Healthinnovations, having worked in the health and science industry for over 21 years, which includes tenure within the NHS and Oxford University. Healthinnovations is a publication that has reported on, influenced, and researched current and future innovations in health for the past decade.
Michelle has been picked up as an expert writer for Informa publisher’s Clinical Trials community, as well as being listed as a blog source by the world’s leading medical journals, including the acclaimed Nature-Springer journal series.
Healthinnovations is currently indexed by the trusted Altmetric and PlumX metrics systems, respectively, as a blog source for published research globally. Healthinnovations is also featured in the world-renowned BioPortfolio, BioPortfolio.com, the life science, pharmaceutical and healthcare portal.
Most recently the Texas A&M University covered The Top 10 Healthinnovations series on their site with distinguished Professor Stephen Maren calling the inclusion of himself and his team on the list a reflection of “the hard work and dedication of my students and trainees”.
Michelle Petersen’s copy was used in the highly successful marketing campaign for the mega-hit film ‘Jumanji: The Next Level, starring Jack Black, Karen Gilian, Kevin Hart and Dwayne ‘The Rock’ Johnson. Michelle Petersen’s copywriting was part of the film’s coverage by the Republic TV network. Republic TV is the most-watched English language TV channel in India since its inception in 2017.
An avid campaigner in the fight against child sex abuse and trafficking, Michelle is a passionate humanist striving for a better quality of life for all humans by helping to provide traction for new technologies and techniques within healthcare.