Study shows maternal bacterial infections trigger abnormal neurogenesis in fetal brain.


Infection and inflammation during pregnancy have been associated with adverse outcomes, such as preterm birth, abortion, and postnatal cognitive disorders. Yet how microbial products circulating in the maternal bloodstream affect fetal development is poorly understood.  Now, a study from researchers at St. Jude Children’s Research Hospital shows how pieces of bacterial cell wall cross the placenta and enter developing neurons, altering fetal brain anatomy and cognitive functioning after birth. The team state that their findings provide a possible mechanism that might underlie the association between maternal bacterial infections during pregnancy and an increased risk of autism and other cognitive problems in children; the research also raises questions about which class of antibiotics should be used to treat such infections.  The opensource study is published in the journal Cell Host & Microbe.

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.

Source: St. Jude Children’s Research Hospital

 

Maternal infection during pregnancy is associated with adverse outcomes for the fetus, including postnatal cognitive disorders. However, the underlying mechanisms are obscure. We find that bacterial cell wall peptidoglycan (CW), a universal PAMP for TLR2, traverses the murine placenta into the developing fetal brain. In contrast to adults, CW-exposed fetal brains did not show any signs of inflammation or neuronal death. Instead, the neuronal transcription factor FoxG1 was induced, and neuroproliferation leading to a 50% greater density of neurons in the cortical plate was observed. Bacterial infection of pregnant dams, followed by antibiotic treatment, which releases CW, yielded the same result. Neuroproliferation required TLR2 and was recapitulated in vitro with fetal neuronal precursor cells and TLR2/6, but not TLR2/1, ligands. The fetal neuroproliferative response correlated with abnormal cognitive behavior in CW-exposed pups following birth. Thus, the bacterial CW-TLR2 signaling axis affects fetal neurodevelopment and may underlie postnatal cognitive disorders. Bacterial Peptidoglycan Transverses the Placenta to Induce Fetal Neuroproliferation and Aberrant Postnatal Behavior. Tuomanen et al 2016.

Maternal infection during pregnancy is associated with adverse outcomes for the fetus, including postnatal cognitive disorders. However, the underlying mechanisms are obscure. We find that bacterial cell wall peptidoglycan (CW), a universal PAMP for TLR2, traverses the murine placenta into the developing fetal brain. In contrast to adults, CW-exposed fetal brains did not show any signs of inflammation or neuronal death. Instead, the neuronal transcription factor FoxG1 was induced, and neuroproliferation leading to a 50% greater density of neurons in the cortical plate was observed. Bacterial infection of pregnant dams, followed by antibiotic treatment, which releases CW, yielded the same result. Neuroproliferation required TLR2 and was recapitulated in vitro with fetal neuronal precursor cells and TLR2/6, but not TLR2/1, ligands. The fetal neuroproliferative response correlated with abnormal cognitive behavior in CW-exposed pups following birth. Thus, the bacterial CW-TLR2 signaling axis affects fetal neurodevelopment and may underlie postnatal cognitive disorders. Bacterial Peptidoglycan Transverses the Placenta to Induce Fetal Neuroproliferation and Aberrant Postnatal Behavior. Tuomanen et al 2016.

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