Breaking News
December 17, 2018 - CTF along with NTAP and Sage announce first-ever open data portal for neurofibromatosis
December 17, 2018 - Intimacy: The Elusive Fountain of Youth?
December 17, 2018 - Will saliva translate to a real diagnostic tool?
December 17, 2018 - DFG establishes nine new Research Units and one new Clinical Research Unit
December 17, 2018 - Assisted living’s breakneck growth leaves patient safety behind
December 17, 2018 - America’s teens report dramatic increase in their use of vaping devices in just one year
December 17, 2018 - Enlarged heart linked to a higher risk of dementia
December 17, 2018 - Prostate cancer detection using MRI now first-line investigation tool
December 17, 2018 - Loughborough academics part of new project investigating effectiveness of personalized breast cancer screening
December 17, 2018 - Adolescents who use cognitive reappraisal had better metabolic measures, shows study
December 17, 2018 - Probiotics may offer therapeutic benefits for biopolar patients
December 17, 2018 - Stealth BioTherapeutics Granted Fast Track Designation for Elamipretide for the Treatment of Dry Age-Related Macular Degeneration with Geographic Atrophy
December 17, 2018 - Studies reveal role of red meat in gut bacteria, heart disease development
December 17, 2018 - Eisai enters into agreement with Eurofarma for its anti-obesity agent lorcaserin
December 17, 2018 - Researchers use brain connectome to reassess neuroimaging findings of Alzheimer’s disease
December 17, 2018 - “Miracle” baby survives Ebola in Congo and rapid a new Ebola detection device
December 17, 2018 - Mechanisms behind neonatal diabetes uncovered
December 17, 2018 - AHF urges the WHO to expedite approval process for vaccine effective against Ebola
December 17, 2018 - Study finds misuse of benzodiazepines to be highest among young adults
December 17, 2018 - TGen receives PayPal grant to underwrite costs of genetic tests for children with rare disorders
December 17, 2018 - New research highlights why HIV-infected patients suffer higher rates of cancer
December 17, 2018 - Antibiotic-resistant bacteria could soon be targeted with Alzheimer’s drug
December 17, 2018 - Rutgers scientists take an important step in making diseased hearts heal themselves
December 17, 2018 - Tailored Feedback at CRC Screen Improves Lifestyle Behaviors
December 17, 2018 - Loss of two genes drives a deadly form of colorectal cancer, reveals a potential treatment
December 17, 2018 - How the Mediterranean Diet Can Help Women’s Hearts
December 17, 2018 - Sustained connections associated with symptoms of autism
December 17, 2018 - Concussion rates among young football players were higher than previously reported
December 17, 2018 - Cresco Labs granted approval to operate marijuana dispensary in Ohio
December 17, 2018 - Study provides insight into health risks facing new mothers
December 17, 2018 - AMSBIO expands Wnt signaling pathway product range to aid research
December 16, 2018 - Surgical treatment unnecessary for many prostate cancer patients
December 16, 2018 - Excess weight responsible for cancers globally finds report
December 16, 2018 - Regular sex associated with greater enjoyment of life in seniors
December 16, 2018 - Social stigma contributes to poor mental health in the autistic community
December 16, 2018 - Multidisciplinary team successfully performs complex surgery on patient suffering from enlarged skull
December 16, 2018 - Experts analyze data that can guide antidepressant discontinuation
December 16, 2018 - Menlo Therapeutics’ Successful Phase 2 Clinical Trial of Serlopitant Demonstrates Reduction of Pruritus Associated with Psoriasis
December 16, 2018 - Siblings of children with autism or ADHD are at elevated risk for both disorders
December 16, 2018 - New project aims to understand why and how metabolic disorders develop in patients
December 16, 2018 - Diets containing GM maize have no harmful effects on health or metabolism of rats
December 16, 2018 - Are doctors and teachers confusing immaturity and attention deficit?
December 16, 2018 - Hearing loss linked with increased risk for premature death
December 16, 2018 - Chromatrap buffer reagents for lysing cells offer many benefits
December 16, 2018 - Young Breast Cancer Patients Face Higher Risk for Osteoporosis
December 16, 2018 - 3-D printing offers helping hand to people with arthritis
December 16, 2018 - Community Health Choice helps manage complex and chronic care conditions
December 16, 2018 - Regular trips out could dramatically reduce depression in older age
December 16, 2018 - CWRU to use VivaLNK’s Vital Scout device for stress study in student athletes
December 16, 2018 - ‘Easy Way Out’? Stigma May Keep Many From Weight Loss Surgery
December 16, 2018 - Gout drug may protect against chronic kidney disease
December 16, 2018 - Talking about memories enhances the wellbeing of older and younger people
December 16, 2018 - Occupational exposure to pesticides increases risk for cardiovascular disease among Latinos
December 16, 2018 - A biomarker in the brain’s circulation system may be Alzheimer’s earliest warning
December 16, 2018 - Magnesium may play important role in optimizing vitamin D levels, study shows
December 16, 2018 - The effect of probiotics on intestinal flora of premature babies
December 16, 2018 - Parents spend more time talking with kids about mechanics of using mobile devices
December 16, 2018 - Biohaven Announces Positive Results from Ongoing Rimegepant Long-Term Safety Study
December 16, 2018 - Arterial stiffness may predict dementia risk
December 16, 2018 - Study explores link between work stress and increased cancer risk
December 16, 2018 - Sex work criminalization linked to incidences of violence finds study
December 16, 2018 - Johns Hopkins researchers discover swarming behavior in fish-dwelling parasite
December 16, 2018 - Schistosomiasis prevention and treatment could help control HIV
December 16, 2018 - Early postpartum opioids linked with persistent usage
December 16, 2018 - Johns Hopkins researchers identify molecular causes of necrotizing enterocolitis in preemies
December 16, 2018 - Advanced illumination expands capabilities of light-sheet microscopy
December 16, 2018 - Alzheimer’s could possibly be spread via contaminated neurosurgery
December 16, 2018 - Unraveling the complexity of cancer biology can prompt new avenues for drug development
December 16, 2018 - Inflammatory Bowel Disease, Prostate Cancer Linked
December 16, 2018 - Cannabis youth prevention strategy should target mental wellbeing
December 15, 2018 - Recent developments and challenges in hMAT inhibitors
December 15, 2018 - Sewage bacteria found lurking in Hudson River sediments
December 15, 2018 - CDC selects UMass Amherst biostatistician model that helps predict influenza outbreaks
December 15, 2018 - Researchers reveal brain mechanism that drives itch-evoked scratching behavior
December 15, 2018 - New computer model helps predict course of the disease in prostate cancer patients
December 15, 2018 - Obesity to Blame for Almost 1 in 25 Cancers Worldwide
December 15, 2018 - How the brain tells you to scratch that itch
December 15, 2018 - New findings could help develop new immunotherapies against cancer
December 15, 2018 - World’s largest AI-powered medical research network launched by OWKIN
December 15, 2018 - Young people suffering chronic pain battle isolation and stigma as they struggle to forge their identities
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