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Potential clinical test and treatment for preterm birth

A molecule has been identified that drives inflammation. It may answer a key question about what causes mild prenatal infections that trigger preterm birth and a potential way to suppress that response.


Scientists have identified a molecule driving rampant prenatal inflammation, an important step to developing a clinical test for early detection. The research was conducted at Cincinnati Children's Hospital Medical Center. The data is published in the March 9 issue of The Journal of Clinical Investigation Insight (JCI Insight).

Implicated is a molecular signal which helps regulate our immune system. It's called type I Interferon receptor or IFNAR. INFAR signals can induce infection-driven preterm birth. The problem begins in pregnant women who develop viral and bacterial infections that are subclinical — or without symptoms severe enough to identify as potentially lethal to pregnancy.

Researchers established that during subclinical infections, INFAR receptors on the surface of blood immune cells are tagged with protein type I Interferon (type I IFN). These tags spurs the production of pro-inflammatory cytokines — a type of signaling molecule secreted by immune cells — which in turn induce a secondary inflammatory response and thus preterm births.


"Preterm birth is a leading worldwide cause of illness and death in infants. Biological processes linking pathogens to cause preterm birth have so far been unknown. Identifying type I IFN/IFNAR as an immunologic driver provides a biomarker, and a potential therapeutic target for reducing preterm birth risk."

Senad Divanovic PhD, Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, and lead investigator.


Although inflammation from microbial infection is known to play a part in preterm birth, it wasn't understood why. Not all microbes found in maternal or fetal tissues of pregnant women induce preterm birth. So the answer must be in another biological trigger. To find that trigger, researchers induced preterm birth in mice, analyzed blood and uterine samples from rhesus monkeys, and examined donated human tissues searching for indicators of type I IFN/IFNAR.

Despite differences between mammal biology in pregnancy and birth, animal models are still useful for studying molecular processes. Immune responses across mammal species are fairly conserved. In fact, the study revealed how highly conserved type I Interferon primes an inflammatory response in non-human primates. In human immune cells, a secondary inflammatory response can also be heightened by cytokines which then induces a preterm birth.

In pregnant wild type mice (mice not genetically altered) researchers tested the role of type I IFN/IFNAR to an initial viral (flu or influenza) infection prior to a secondary bacterial inflammation. The viral infection activated type I IFN/IFNAR and then initiated an overabundance of systemic inflammatory cytokines, such as Interleukin (IL-6), in blood and reproductive sites.


When researchers genetically deleted type I IFN, IFNAR or IL-6 in mice — or gave neutralizing antibodies to IL-6 — no preterm births occur in mice.


Divanovic reports that the research team is now trying to determine exactly where in the body sensitization to pro-inflammatory pathways begin. The team also wants to widen their analysis of different molecular and bacterial stimuli to determine how regulation of type I IFN can be controlled during infection, and if susceptibility to preterm birth can be modified.

Finally, they want to test inhibition of type I IFN/IFNAR to see if it prevents preterm birth in non-human primates and then, can such an approach be clinically tested for preterm birth risk in humans.

Abstract
Preterm birth (PTB) is a leading worldwide cause of morbidity and mortality in infants. Maternal inflammation induced by microbial infection is a critical predisposing factor for PTB. However, biological processes associated with competency of pathogens, including viruses, to induce PTB or sensitize for secondary bacterial infection–driven PTB are unknown. We show that pathogen/pathogen-associated molecular pattern–driven activation of type I IFN/IFN receptor (IFNAR) was sufficient to prime for systemic and uterine proinflammatory chemokine and cytokine production and induction of PTB. Similarly, treatment with recombinant type I IFNs recapitulated such effects by exacerbating proinflammatory cytokine production and reducing the dose of secondary inflammatory challenge required for induction of PTB. Inflammatory challenge–driven induction of PTB was eliminated by defects in type I IFN, TLR, or IL-6 responsiveness, whereas the sequence of type I IFN sensing by IFNAR on hematopoietic cells was essential for regulation of proinflammatory cytokine production. Importantly, we also show that type I IFN priming effects are conserved from mice to nonhuman primates and humans, and expression of both type I IFNs and proinflammatory cytokines is upregulated in human PTB. Thus, activation of the type I IFN/IFNAR axis in pregnancy primes for inflammation-driven PTB and provides an actionable biomarker and therapeutic target for mitigating PTB risk.

Funding support for the research came in part from: the Cincinnati Children's Perinatal Institute Pilot and Feasibility Award; the Burroughs Wellcome Fund (Preterm Birth Research Grant #1015032); the March of Dimes Prematurity Research Center Ohio Collaborative for an Innovation Catalyst Grant (22-FY16-125); the National Institutes of Health (T32AI118697); and the Cincinnati Children's Perinatal Infection and Inflammation Collaborative.


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Mar 21, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   



Inflammation in response to infection is known to play a part in preterm birth.
A study reveals just how type I Interferon primes a initial inflammatory response
followed by a second inflammatory response which leads to preterm birth.
Image Credit: Pinterest

 


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