What’s New in Research April 2017
Improving How Newborns Respond to Vaccines
Newborn babies are especially susceptible to diseases and infections as their immune systems are not yet equipped to fight viruses, bacteria and other pathogens. Vaccines are available to protect against devastating diseases like pneumonia, but newborns fail to respond optimally to most vaccines and may require a series of shots in order to gain protection. Discoveries over the past 20 years have yielded new ways to strengthen the immune system’s response through the addition of an ingredient, known as an adjuvant, to standard vaccines. However, adjuvanted vaccines specifically tailored to boost the immune response of the newborn have not been developed. In new studies published in JCI Insight and The Journal of Allergy and Clinical Immunology, investigators examine novel vaccine formulations that protect against Streptococcus pneumoniae and Human Immunodeficiency Virus (HIV) respectively, as model vaccines to adjuvant.
S. pneumoniae infection can cause meningitis, sepsis, ear infections and pneumonia, and is responsible for approximately 10 percent of worldwide deaths in children less than 5 years of age. Such pneumococcal diseases often strike in resource-poor settings, making a single, effective dose of the vaccine at birth especially desirable. Infants can receive a three-dose schedule of a vaccine against pneumococcal diseases starting at birth, but studies have found that their responsiveness to the vaccine is suboptimal. To improve responsiveness, researchers investigated how human newborn and adult white blood cells responded to an adjuvanted version of the vaccine as well as the effects in a rhesus macaque model. Annette Scheid, MD, an attending neonatologist in BWH’s Department of Pediatric Newborn Medicine, was asked to join the project at an early stage to lead the team in establishing parameters for measuring the safety of the vaccine formulation and quantifying any local or systemic side effects.
“For any animal or clinical vaccine trials, having measures of safety are as important as measures proving the efficacy of a given formulation,” Scheid explains. As Scheid and her colleagues report in JCI Insight, a single dose of the adjuvanted vaccine at birth dramatically enhanced responsiveness, and using their approach, the team observed a reduction in local and systemic inflammation associated with the adjuvant, a molecule named 3M-052 that is designed to stay at the site of injection, while maintaining the vaccine’s efficacy.
In a second study published in The Journal of Allergy and Clinical Immunology, Scheid and her colleagues examined the effectiveness of using a nanoparticle-based delivery system to target delivery of an adjuvant and HIV antigen specifically to dendritic cells, limiting potential side effects. The adjuvanted nanoparticles produced a robust, adult-like response in neonatal cells in the lab and in a mouse model. Scheid tested different nanoparticle formations and led experiments performed with confocal microscopy to examine intracellular trafficking of nanoparticles in human cells.
“The persistently high global burden of infections in the very young provides a compelling rationale for developing additional safe and effective early life vaccines,” the authors write.
The research was funded by the Bill & Melinda Gates Foundation, the National Institutes of Health/NIAID, the European Research Council and Boston Children’s Hospital. The Levy Laboratory also received sponsored research support from 3M Drug Delivery Systems.
Papers cited: Dowling DJ et al. “TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth.” JCI Insight DOI: 10.1172/jci.insight.91020
Dowling DJ et al. “Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses” J Allergy Clin Immunol DOI: 10.1016/j.jaci.2016.12.985
An Intriguing New Gene Candidate in the Search for Alzheimer Disease Therapies
Tau pathology is one of the defining features of Alzheimer disease (AD), which is the most common form of dementia in older age. While symptomatic treatments exist, there are currently no preventive therapies for AD. Investigators at BWH and Rush University Medical Center reported the discovery of a new gene that is associated with Tau accumulation. Published in Molecular Psychiatry, the paper describes the identification and validation of a genetic variant within the protein tyrosine phosphatase receptor-type delta (PTPRD) gene.
Tau accumulates in several different conditions in addition to AD, including certain forms of dementia and Parkinsonian syndromes as well as chronic traumatic encephalopathy that occurs with repeated head injuries.
“Aging leads to the accumulation of many different pathologies in the brain; one of the most common forms of pathology is the neurofibrillary tangle (NFT) that was at the center of our study,” said co-principal investigator David Bennett, MD, who directs the Alzheimer Disease Center at Rush University Medical Center in Chicago. “The NFT is thought to be more closely related to memory decline than other forms of aging-related pathologies, but there are still very few genes that have been implicated in the accumulation of this key feature of Alzheimer disease and other brain diseases.”
Leveraging autopsies from 909 individuals participating in studies of aging based at Rush University, the team of investigators assessed the human genome for evidence that a genetic variant could affect NFT.
Lead author Lori Chibnik, PhD, of BWH said, “The variant that we discovered is common: most people have one or two copies of the version of the gene that is linked to accumulating more pathology as you get older. Interestingly, tangles can accumulate through several different mechanisms, and the variant that we discovered appears to affect more than one of these mechanism.”
The reported results offer an important new lead as the field of neurodegeneration searches for robust novel targets for drug development. In addition, the advent of new techniques to measure Tau in the brains of living individuals with positron emission tomography (PET) offers a biomarker for therapies targeting Tau.
“This study is an important first step; however, the result needs further validation and the mechanism by which the PTPRD gene and the variant that we have discovered contribute to the accumulation of NFT remains elusive,” said Phil De Jager, co-principal investigator at BWH. “Other studies in mice and flies implicate PTPRD in memory dysfunction and worsening of Tau pathology, suggesting that altering the level of PTPRD activity could be helpful in reducing an individual’s burden of Tau pathology.”
The study was supported by the National Institute on Aging.
Paper cited: Chibnik LB et al. “Susceptibility to neurofibrillary tangles: role of the PTPRD locus and limited pleiotropy with other neuropathologies” Molecular Psychiatry DOI: 10.1038/mp.2017.20
Putting Autoimmune Disease Genetic Links to the Test
Studies of autoimmune and inflammatory diseases have identified hundreds of genetic regions thought to be associated with these conditions. At the same time, studies of expression quantitative trait loci (eQTLs) have revealed the abundance of inherited variations in gene expression levels in the normal human population. While it is widely believed that the majority of disease-associated loci influence disease risk through regulatory variations in gene expression, this hypothesis has not been formally tested by verifying whether most of genetic loci influencing disease risk are also detectable as eQTLs. In an effort to examine this hypothesis, investigators at BWH and their colleagues took approximately 270 genetic loci associated with seven diseases and tried to map them back to causal genes using eQTLs in key immune cells. They report their results in Nature Genetics.
The team was able to resolve 55 of these associations to candidate genes with strong statistical consistency with variations of baseline gene expression in unstimulated immune cells. However, this is only a small fraction – about 25 percent – of the genetic loci examined. For the rest, the researchers did not observe any signal in the eQTL data that were consistent with autoimmune disease associations despite the fact that disease-relevant cell populations are easier to access from blood samples compared to other disease.
“Abundant caution must be exercised before pathological relevance is inferred for an observed eQTL simply on the basis of proximity to a disease association,” the authors write. “Strong-evidence of a shared genetic effect should therefore be established before time-consuming and costly experimental dissection of such effects is undertaken.”
This work was supported by NIH awards R01-MH101244-04, R01-GM105857-03, R01-GM078598-09 and U01-HG009088-01.
Paper cited: Chun S et al. “Limited statistical evidence for shared genetic effects of eQTLs and autoimmune-disease-associated loci in three major immune-cell types.” Nature Genetics DOI: 10.1038/ng.3795
Study highlights possible Achilles’ heel in key immune memory cells
The capacity for memory isn’t exclusive to the brain. The immune system, with its sprawling network of diverse cell types, can recall the pathogens it meets, helping it to swiftly neutralize those intruders upon future encounters.
For the last several years, BWH’s Thomas Kupper, MD, Chair of the Department of Dermatology, and his colleagues have been studying a unique kind of immune memory cell, known as a tissue-resident memory T (TRM) cell. Discovered more than 10 years ago by Rachael Clark, MD, PhD (also in BWH Dermatology), these cells live in peripheral tissues, like the skin, gut and joints, and are thought to be a key source of the immune system’s protective memory. Although much remains to be learned about the biology of these specialized memory T-cells, dysfunctional TRM cells are strongly implicated in autoimmune diseases, such as psoriasis, rheumatoid arthritis, inflammatory bowel disease and other conditions.
To uncover the key genetic signals that guide the development of TRM cells, Kupper and his colleagues, led by postdoctoral fellow Youdong Pan, PhD, took an unbiased approach. They measured the level of gene activity for every gene in the genome as the cells developed in mice. That led the team to a remarkable finding, reported in a recent issue of the journal Nature: genes involved in lipid metabolism are highly active in TRM cells, roughly 20- to 30-fold more active than in other types of T-cells. Among these genes are two key mediators of lipid uptake, fatty-acid-binding proteins 4 and 5 (Fabp4 and Fabp5).
Kupper and his colleagues teamed up with Gökhan Hotamisligil, PhD, an expert in lipid biology and metabolism at the Harvard T. H. Chan School of Public Health, to further dissect the roles of Fabp4 and Fabp5 in TRM cells. They found that TRM cells that lack both genes show a striking defect in their ability to import lipids. (Cells lacking just one of the genes are unaffected, likely because the two genes are highly related and perform overlapping functions.) Moreover, these Fabp4- and Fabp5-deficient TRM cells are significantly compromised both in their ability to protect against infection and their long-term survival in peripheral tissues.
Based on his team’s recent work, Kupper says the picture that is emerging of TRM cells highlights a unique dependence on fatty acids and other lipids as an energy source. Other types of T-cells can also metabolize lipids, but they cannot take them up from the environment, as TRM cells can. This could become an important Achilles’ heel for investigators to target in the future.
Drugs aimed at inhibiting lipid uptake could enable the selective removal of TRM cells from tissues, while leaving other types of T-cells intact. Current therapies for autoimmune disease are fairly broad in their activity — quieting down many types of immune cells, including TRM cells. But they work transiently, likely because TRM cells remain in place.
“I think the real potential pay off of this story is to try and use this new information therapeutically,” said Kupper. “While there are treatments for autoimmune diseases that impact pathogenic tissue-resident memory T-cells, none are able to effectively remove the cells from tissues. We’ve identified the first plausible mechanism for doing just that.”
Paper cited: Pan Y, et al. “Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism.” Nature DOI:10.1038/nature21379
Exploring a New Complication from an Emergent Tickborne Parasite
Babesiosis is a rare – but increasingly common – disease spread by ticks. After a bite from an infected tick, microscopic malaria-like parasites are transmitted into the host where they can infect and destroy red blood cells, causing nonimmune hemolytic anemia. Treatment with antimicrobials usually clears the parasite and resolves the anemia. However, sporadic cases of warm-antibody autoimmune hemolytic anemia (WAHA) have been observed in patients after treatments for babesiosis. This autoimmune form of anemia occurs when the body attacks its own red blood cells, eliminating these cells from circulation. To better understand this complication, BWH researchers led by Ann Wolley, MD, and Francisco Marty, MD, of the Division for Infectious Diseases conducted a retrospective analysis of patients who had been cared for at BWH from January 2009 through June 2016. Of 86 patients diagnosed with babesiosis during that time, six developed WAHA two to four weeks later, after the parasitic infection had been resolved. These six cases are presented in a study published online in the New England Journal of Medicine on March 8.
In general, people who have weakened immune systems and those who have undergone splenectomy are at higher risk for severe and relapsing babesiosis, but WAHA after babesiosis in patients without history of autoimmune diseases had not been defined previously. All six babesiosis patients with WAHA were asplenic, meaning that their spleens had previously been removed. The researchers found that WAHA was much more common among asplenic patients with babesiosis, affecting as many as one in three of these patients. Many of these patients needed to receive immunosuppressive treatment to address WAHA.
The research team offers both clinical observations on the six patients studied as well as plausible mechanisms that may explain post-babesiosis WAHA in asplenic patients. They also recommend that patients with worsening or recurring anemia after treatment be screened for WAHA, especially patients who are asplenic.
“The post-babesiosis WAHA syndrome can be a hematologic complication of babesiosis, and asplenic patients appear to be particularly at risk,” the authors write. “Understanding the activation of the immune response to babesiosis may elucidate the mechanisms of other causes of autoimmune hemolytic anemias.”
Paper cited: Woolley AE et al. “Post-Babesiosis Warm Autoimmune Hemolytic Anemia.” New England Journal of Medicine. DOI: 10.1056/NEJMoa1612165
Organ-on-a-Chip Model Offers Insights into Premature Aging and Vascular Disease
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic condition that causes premature and accelerated aging. Recently, researchers have been able to generate induced pluripotent stem cells from patients with HGPS to better understand the mechanisms of aging and look for new treatments. HGPS primarily affects vascular cells, which undergo biomechanical strains in blood vessels. However, the impact of these biomechanical strains on aging and vascular diseases has been challenging to study in the lab as most models fail to mimic the biomechanics that cells experience in the body. Using a new progeria-on-a-chip model, investigators from BWH, led by João Ribas, PhD candidate, and Ali Khademhosseini, PhD, of the Biomaterials Innovation Research Center, have developed a way to recapitulate blood vessel dynamics to better understand vascular disease and aging.
The new organ-on-a-chip device consists of a top fluidic channel and underlying vacuum channel, which mimics, upon pressure, the mechanical stretching that cells experience within blood vessels. The team found that cells derived from HGPS donors but not from healthy donors showed an exacerbated response to biomechanical strain, with an increase in markers of inflammation, which are strongly associated with vascular disease and aging.
“Vascular diseases and aging are intimately linked yet rarely studied in an integrated approach,” the authors write. “Gaining a deeper understanding of the molecular pathways regulating inflammation during vascular aging might pave the way for new strategies to minimizing cardiovascular risk with age.”
Paper cited: Ribas J et al. “Biomechanical Strain Exacerbates Inflammation on a Progeria-on-a-Chip Model.” Small DOI: 10.1002/smll.201603737
Unusual metabolic activity illuminates embryonic development, cancer
Scientists seeking to understand embryonic development need to make room for metabolism, according to a new study, led by Olivier Pourquié of BWH and HMS that also has implications for regenerative medicine and cancer research.
For decades, scientists crowned cell signaling—that is, communication within and among cells—the king of embryonic development, decreeing which cells go where and what tissues they ultimately become. Energy metabolism, the thinking went, hummed along in the background, uniform across every cell.
The new study, published in Developmental Cell, reveals that a particular type of metabolism—one that is also a hallmark of cancer cells—actually varies in different parts of an embryo, surging in areas where the organism is busy growing longer.
Far from playing a passive role, the research reveals, this metabolic activity helps integrate cell signaling to control embryo elongation and cell fate.
“So far, the field has been concerned with genes and proteins; now we also have to include metabolites, because we show they control the expression of genes and signaling,” he said. “Developmental biologists have learned a lot by playing with genes and proteins, but we were a bit stuck because we were missing some factors. “I think metabolism will explain a lot about the phenomena we’ve been looking at.”
Paper cited: Oginuma M et al. “A Gradient of Glycolytic Activity Coordinates FGF and Wnt Signaling during Elongation of the Body Axis in Amniote Embryos.” Developmental Cell DOI: 10.1016/j.devcel.2017.02.001
-Adapted from a Harvard Medical School news story