Breaking News
October 18, 2018 - Health Highlights: Oct. 15, 2018
October 18, 2018 - Largest study of ‘post-treatment controllers’ reveals clues about HIV remission
October 18, 2018 - Bad Blood in Silicon Valley: A conversation with John Carreyrou
October 18, 2018 - ANTRUK’s Annual Lecture sends out message on shortage of funds for antibiotic research
October 18, 2018 - NAM special publication outlines steps to ensure interoperability of health care systems
October 18, 2018 - Novel method uses just a drop of blood to monitor effect of lung cancer therapy
October 18, 2018 - New blood test could spare cancer patients from unnecessary chemotherapy
October 18, 2018 - Training young researchers to work with data volumes arising in the health sector
October 18, 2018 - New Metrohm IC method is reliable and convenient to use for zinc oxide assay
October 18, 2018 - Global AIDS, TB fight needs more money: health fund
October 18, 2018 - Understanding the forces that cause sports concussions
October 18, 2018 - Research points to new target for treating periodontitis
October 18, 2018 - New tool improves assessment of postpartum depression symptoms
October 18, 2018 - From Biopsy to Diagnosis
October 18, 2018 - Sexual harassment and assault linked to worse physical/mental health among midlife women
October 18, 2018 - Stumped by medical school? A Q&A with a learning specialist
October 18, 2018 - Targeting immune checkpoints in microglia could reduce out-of-control neuroinflammation
October 18, 2018 - FDA Approves Talzenna (talazoparib) for gBRCAm HER2-Negative Locally Advanced or Metastatic Breast Cancer
October 18, 2018 - Sleeping Beauty technique helps identify genes responsible for NAFLD-associated liver cancer
October 18, 2018 - Many U.S. adults confused about primary care, study shows
October 18, 2018 - UC researcher focuses on light-mediated therapies to target breast cancer
October 18, 2018 - With philanthropic gifts, Stanford poised to make major advances in neurosciences | News Center
October 18, 2018 - Mice study shows antibiotics are not always necessary to cure sepsis
October 18, 2018 - Researchers discover why heart contractions are weaker in individuals with HCM
October 18, 2018 - Participation in organized sport during childhood may have long-term skeletal benefits
October 18, 2018 - Probiotic/antibiotic combination could eradicate drug-resistant bacteria
October 17, 2018 - More Socioeconomic Challenges for Hispanic Women With HIV
October 17, 2018 - 49,XXXXY syndrome – Genetics Home Reference
October 17, 2018 - Scientists uncover possible new causes of Tourette syndrome
October 17, 2018 - Girl undergoes unusual heart surgery after compassionate-use exemption | News Center
October 17, 2018 - Health Issues That Are Sometimes Mistaken for Gluten Sensitivity
October 17, 2018 - Elective induction of labor at 39 weeks may be beneficial option for women and their babies
October 17, 2018 - New smart watch algorithms can accurately monitor wearers’ sleep patterns
October 17, 2018 - Researchers demonstrate epigenetic memory transmission via sperm
October 17, 2018 - FDA, DHS announce memorandum of agreement to address cybersecurity in medical devices
October 17, 2018 - Health Tip: Know the Risks of Chicken Pox
October 17, 2018 - Immunotherapy effective against hereditary melanoma
October 17, 2018 - Researchers reveal new mechanism for how animal cells stay intact | News Center
October 17, 2018 - Alzheimer's Goes Under the Cryo-Electron Microscope
October 17, 2018 - Medicare for all? CMS chief warns program has enough problems already
October 17, 2018 - Metrohm Raman introduces Mira P handheld Raman system
October 17, 2018 - Expanding the knowledge about hippocampus to better understand cognitive deficits in MS
October 17, 2018 - Study of Nigerian breast cancer patients reveals prevalence of aggressive molecular features
October 17, 2018 - Many healthy children may have metabolic risk factors, finds study
October 17, 2018 - A new antibiotic could be a better, faster treatment for tuberculosis
October 17, 2018 - “I will not become a Robot Doctor”: A medical student vows to practice compassion
October 17, 2018 - Study findings may explain sporadic outbreaks of C. difficile infections in hospitals
October 17, 2018 - Purdue researchers develop new chemical process to find better drug ‘fits’ for patients
October 17, 2018 - Yale researchers develop way to attack RNA with small-molecule drugs
October 17, 2018 - New pragmatic study launched to understand the effectiveness of new type 2 diabetes drug
October 17, 2018 - Alnylam Announces Plan to Initiate Rolling Submission of a New Drug Application and Pursue Full Approval for Givosiran
October 17, 2018 - Nine cases of polio-like illness suspected in children in illinois
October 17, 2018 - Eisai enters into agreement with Eurofarma for development and sales of lorcaserin in 17 countries
October 17, 2018 - Patients once thought incurable can benefit from high-dose radiation therapy
October 17, 2018 - Researchers awarded grant to advance testing of experimental heroin vaccine
October 17, 2018 - Researchers examine SSRI use during pregnancy and major gestational malformations
October 17, 2018 - FDA grants Rare Pediatric Disease Designation for Immusoft’s Iduronicrin genleukocel-T
October 17, 2018 - Reliable Respiratory announces acquisition of Attleboro Area Medical Equipment
October 17, 2018 - Study reveals link between childhood abuse and higher arthritis risk in adulthood
October 17, 2018 - Research shows people over 65 are not performing enough physical activity
October 17, 2018 - FDA Approves Liletta (levonorgestrel-releasing intrauterine system) 52 mg to Prevent Pregnancy for up to Five Years
October 17, 2018 - Weight gain after smoking cessation linked to increased short-term diabetes risk
October 17, 2018 - Researchers find opportunity to control salt-sensitive hypertension without exercising
October 17, 2018 - Women not warned about cancer associated with breast implants
October 17, 2018 - Metrohm offers robust handheld Raman analyzer for Defense and Security
October 17, 2018 - Modeling Non-Numerical Data in Systems Biology
October 17, 2018 - Research aims to address health disparities in African-American men
October 17, 2018 - Human and cattle decoys trap outdoor-biting mosquitoes in malaria endemic regions
October 17, 2018 - High Circulating Prolactin Level Inversely Linked to T2DM Risk
October 17, 2018 - Study finds gene variant predisposes people to both Type 2 diabetes and low body weight
October 17, 2018 - Metrohm software products make it easy to comply with ALOCA and ALCOA+ guidelines
October 17, 2018 - Network of doctors identify the cause of 31 new conditions
October 17, 2018 - Notable improvement in brain cancer survival among younger patients but not much for elderly
October 17, 2018 - Scientists shed light on roles of transcription factors, TP63 and SOX2, in squamous cell carcinoma
October 17, 2018 - Costs of Medicare Diabetes Prevention Program may be higher than expected reimbursement
October 17, 2018 - Misuse of prescription opioids or benzodiazepines associated with suicidal thoughts
October 17, 2018 - New research seeks to address sex disparities in women’s health
October 17, 2018 - C-Section Rates Have Nearly Doubled Since 2000: Study
October 17, 2018 - Talking to Your Kids About STDs
October 17, 2018 - New classification of periodontal and peri-implant diseases and conditions
Researchers describe key role of enzyme in regulating immune response against Chagas disease parasite

Researchers describe key role of enzyme in regulating immune response against Chagas disease parasite

image_pdfDownload PDFimage_print

In an article published recently in the journal Nature Communications, researchers affiliated with the University of São Paulo (USP) in Brazil describe the central role played by an enzyme called phosphatidylinositol 3-kinase gamma (PI3Kγ) in regulating the immune response against Trypanosoma cruzi, the protozoan parasite that causes Chagas disease.

“Our results show that the expression of PI3Kγ increases during infection by T. cruzi in both mice and humans. This appears to be essential to avoid excessive inflammation that might injure the organism and also to control heart parasitemia,” said Maria Claudia da Silva, lead author of the study and a researcher at the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP).

According to the authors, molecules capable of modulating the cellular signaling pathway mediated by this enzyme may in future be tested as a treatment for Chagas disease, which affects some 7 million people in Latin America – 2 million-3 million in Brazil alone.

The study was conducted at the Center for Research on Inflammatory Diseases (CRID), one of the Research, Innovation and Dissemination Centers (RIDCs) supported by the São Paulo Research Foundation – FAPESP. It was part of the master’s and PhD research of Maria Claudia da Silva, supervised by João Santana da Silva and Thiago Mattar Cunha, professors at FMRP-USP.

Transmitted by insects known as triatomine or kissing bugs (mainly Triatoma infestans in South America), as well as by transfusions of blood from donors with Chagas disease and by the ingestion of contaminated food, T. cruzi stays with the patient for life. The initial acute phase of infection may be asymptomatic or may cause fever, nausea, headache, inflamed and painful lymph glands, skin rash, swollen eyelids, and enlarged liver and spleen.

Without treatment, complications can arise years later in the chronic phase. The most frequent are heart ventricle enlargement, which affects approximately 30% of patients and typically leads to heart failure, and esophagus or colon enlargement, which affects up to 10% of patients and can lead to loss of peristaltic movement and sphincter dysfunction. Most infected people remain asymptomatic even with large numbers of parasites circulating in the organism.

“In our experimental model, we used a strain of the parasite that prefers heart tissue,” João Santana da Silva said. “The initial tests showed that PI3Kγ-deficient mice developed severe cardiomyopathy in the acute phase and died after a short time, but we had no idea why this happened.”

In further tests, the CRID researchers found that the levels of the parasite in the blood of mice genetically modified not to express PI3Kγ were the same as in wild mice, which could express the enzyme and survive infection.

According to Santana da Silva, the mice that died from infection by T. cruzi were expected to have more parasites in their bloodstream than those that survived.

“However, when we looked at their hearts, we found that PI3Kγ-deficient mice had far higher parasitemia levels and much more severe inflammation [myocarditis],” he said. “The immune system was producing proinflammatory molecules in an uncontrolled manner, injuring the heart tissue, and even so, it was unable to kill the parasites efficiently.”

Defective macrophages

During Maria Claudia da Silva’s PhD research, the group investigated how the immune response to the parasite is modified by the absence of PI3Kγ. According to Cunha, studies in the literature show that the enzyme participates in a signaling pathway that plays a key role in the migration of defense cells to inflammation sites in the organism.

In the case of infection by T. cruzi, under normal conditions, signaling proteins called chemokines are produced by the parasite when it infects host cells. The chemokines activate macrophages and dendritic cells, the front line of the immune system, which migrate to the site and kill the invaders.

Although the defense mechanism is not 100% efficient, the researchers explained that it manages to keep parasitemia levels low, and most infected individuals have no symptoms during the acute phase.

“Our results show that when the signaling pathway mediated by PI3Kγ is not active in macrophages, these defense cells lose their capacity to kill the parasites and control the inflammation,” Cunha said. “To prove that the problem resided specifically in macrophages, we used an animal model called conditional knockout, in which PI3Kγ is missing only in macrophages.”

The CRID group did not fully elucidate the mechanism but found that without the enzyme, the macrophages produce less nitric oxide, which is required to kill the parasites and acts in conjunction with a pro-inflammatory cytokine called interferon gamma (IFNγ).

“If the macrophages don’t express PI3Kγ, they can’t kill the parasites even in the presence of IFNγ,” Santana da Silva said.

Evidence in humans

In partnership with Edecio Cunha Neto, a researcher at USP’s Medical School in São Paulo (FM-USP), the CRID team studied tissue from patients who developed cardiopathy in the chronic phase of Chagas disease and who underwent biopsy or heart transplant. They also analyzed a database containing information on all molecules expressed in the heart tissue.

The study showed that individuals with higher levels of PI3Kγ had lower levels of heart parasitemia than those who expressed less PI3Kγ, although both groups presented with myocarditis. In addition, all had higher levels of PI3Kγ and of all molecules in the pathway mediated by this enzyme than non-Chagas patients with chronic congestive heart failure.

“These findings suggest that this enzyme is also involved in control of the parasite in humans,” Santana da Silva said. “In our in vitro experiments, we observed that human macrophages failed to kill the intracellular pathogen when infected with T. cruzi after treatment with the PI3Kγ inhibitor. How this happens is something we have yet to understand.”

Preliminary results also show that in patients who develop cardiopathy in the chronic phase of infection by T. cruzi, there is a higher incidence of a polymorphism (a variation in the gene that encodes the enzyme) that may be associated with lower activity of PI3Kγ than in patients who develop chronic disease in other organs, such as the spleen or intestine.

“We’re currently writing another paper in which we raise the hypothesis that people with a certain polymorphism in the gene that encodes PI3Kγ run a greater risk of developing cardiopathy in the chronic phase,” Cunha said.

Another possible line of investigation, he added, would be to determine whether the rare cases of patients who die of sudden myocarditis during the acute phase of Chagas disease are associated with lower levels of PI3Kγ, as the researchers observed in mice.

Santana da Silva is also interested in investigating the signaling pathways that modulate PI3Kγ production in the human organism.

“Drugs are available to inhibit PI3Kγ production but not to stimulate it,” he said. “We now need to investigate the regulatory pathways mediated by PI3Kγ in search of molecules that induce the release of these substances. We’ve already performed lab tests on some molecules that display this type of action. It’s basic science, but there are potential applications for the control of parasitemia in both the acute and chronic phases.”

According to Cunha, activating the enzyme “is no easy task” and could have implications for other pathological conditions. “Inhibitors of the PI3Kγ pathway are being tested for the treatment of cancer and inflammatory diseases,” he said.

Source:

http://agencia.fapesp.br/study-describes-enzymes-key-role-in-immune-response-to-chagas-disease-parasite-/28199/

Tagged with:

About author

Related Articles