More Is Not Better When It Comes to T Cells and Tuberculosis
News May 14, 2018 | Original Story from the McGill University Health Centre.
Coloured X-ray of a patient's chest showing disseminated tuberculosis in the lungs. The lungs contain lesions (tubercles, pink) consisting of infected dead tissue. Credit: Du Cane Medical Imaging Ltd/Science Photo Library.
Historically, our view of host defense against infection was that we must eliminate pathogens to eradicate disease. However, this perspective has recently been challenged as scientists have taken a lesson from plant biologists about an ancient strategy involving the ability to “tolerate” rather than “resist” infection to maintain health. This concept, referred to as “disease tolerance”, provides an opportunity to develop new strategies that mitigate the consequences of infection.
Since the discovery of Mycobacterium tuberculosis, or Mtb, (the bacteria causing TB) over a century ago, great progress has been made in defining strategies that facilitate elimination of the bacteria. For instance, the discovery of antibiotics was a major breakthrough in the treatment of active TB. However, greater than 90 per cent of TB-infected individuals tolerate the bacteria without any treatment.
Dr. Maziar Divangahi, a pulmonary immunologist at the Research Institute of the McGill University Health Centre (RI-MUHC), and a professor of Medicine at McGill University in Montreal, has been trying to explain why the vast majority of people infected with Mtb can tolerate the infection without developing disease. Clinicians refer to this condition as “latent tuberculosis”, and it affects a quarter of the global population. “TB is a perfect example of disease tolerance,” says Dr. Divangahi who is also the associate director of the Translational Research in Respiratory Diseases Program at the RI-MUHC and a member of the McGill International TB Centre.
Dr. Divangahi’s team found that rather than fighting to resist the pathogen, the body’s tolerance to Mtb is the key mechanism for preventing the spread of the infection. More surprisingly, they found that having excessive levels of T cells, which are known as soldiers of our immune system, could cause more harm than good.
“We always thought that having more T cells would provide better protection against TB. Instead, we found that it could imbalance disease tolerance causing extensive tissue damage and ultimately killing the host,” says Dr. Divangahi, lead author of the study published today in Science Immunology, who is the also the associate director of the Meakins-Christie Laboratories.
Disease tolerance versus host resistance
Our body’s defense system is divided into two arms: one is resistance, which aims to eliminate the pathogen, while the other is tolerance, which is designed to control the tissue damage caused by the infection.
“While disease tolerance is an established field of research in simple organisms such as plants, our understanding of this host defense strategy in humans is very limited,” says Dr. Divangahi.
Although, immunologists and vaccinologists have made progress in the study of host resistance to infectious diseases, little is known about the mechanisms of disease tolerance in humans.
A key protein in disease tolerance
Dr. Divangahi’s team determined that a protein in the mitochondria called cyclophilin D (CypD) acts as a key checkpoint for T cell activation. Through collaboration with Dr. Russell Jones from McGill University, who is an international expert in T cell biology, they identified that CypD is required for controlling T cell metabolism. “T cells are traditionally considered to be important in eliminating Mtb,” says Dr. Divangahi. “However, we found that increasing T cell activation in mice by eliminating a metabolic checkpoint unexpectedly compromised host survival without any impact on the growth of Mtb.”
“In contrast to conventional thinking, we show that T cells are essential for regulating the body’s tolerance to Mtb infection,” explains one of the study’s first authors, Dr. Nargis Khan, who is currently a postdoctoral fellow in Dr. Divangahi’s lab at the RI-MUHC.
Giving the widespread drug resistance to various Mtb strains the limited pipeline of effective antibiotics and the lack of an efficient vaccine, alternative approaches to treat TB are urgent. “If we could understand the mechanisms of ‘natural immunity’ that controls TB in 90-95 per cent of infected individuals,” says Dr. Divangahi,“we will able to design a novel therapy or vaccine to substantially reduce the world wide burden of this ancient disease.”
This article has been republished from materials provided by McGill University Health Centre. Note: material may have been edited for length and content. For further information, please contact the cited source.
Mitochondrial cyclophilin D regulates T cell metabolic responses and disease tolerance to tuberculosis. Fanny Tzelepis, Julianna Blagih, Nargis Khan, Joshua Gillard, Laura Mendonca, Dominic G. Roy, Eric H. Ma, Philippe Joubert, Russell G. Jones and Maziar Divangahi. Science Immunology 11 May 2018: Vol. 3, Issue 23, eaar4135, DOI: 10.1126/sciimmunol.aar4135.
Herpesvirus and Alzheimer's Link: High abundance of Herpes genes in postmortem Alzheimer's brain tissueNews
Data from three different brain banks to suggest that human herpesviruses are more abundant in the brains of Alzheimer's patients and may play a role in regulatory genetic networks that are believed to lead to the disease.READ MORE
Bloodstains at Crime Scenes Can Now be Used to Determine Age of SuspectNews
A new blood test, which could be performed at a crime scene, could help determine the age of a suspect or victim within just an hour.
Comments | 1 ADD COMMENT
Alexander Gregor | May 14, 2018
I'm Alexander Gregor from USA, I have been suffering from (HERPES) disease for the past 13 months and had constant pain, especially in my knees. During the first month , I had faith in God that I would be healed someday.This disease started to circulate all over my body and I have been taking treatment from my doctor, a few weeks ago I came on search on the internet if I could get any information concerning the prevention of this disease, on my search I saw a testimony of someone who has been healed from (Hepatitis B and Cancer) by this Man DR JOHN and she also gave the email address of this man and advise we should contact him for any sickness that he would be of help, so I wrote to DR JOHN telling him about my (HERPES Virus) he told me not to worry that I was going to be cured!! hmm i never believed it,, well after all the procedures and remedy given to me by this man few weeks later I started experiencing changes all over me as the DR assured me that I have cured, after 2 weeks i went to my doctor to confirmed if I have been finally healed behold it was TRUE, So friends my advice is if you have such sickness or any other like HSV1,2,HPV1,2,3,CANER HIV,COLE SORES,TOOTH JOHN, ETC you can email DR JOHN on firstname.lastname@example.org sir I am indeed grateful for the help I will forever recommend you to my friends!!! with your lovely Email Address or you can also phone/Whats App him on this number +2347064365391