Crucial mechanism driving colliding epidemics of smoking, TB unlocked by scientists

 

---

TB is an infectious disease that kills 1.5 million people each year, and smoking is the biggest driver of the global TB epidemic. Medical scientists at Trinity College Dublin and St James's Hospital in Ireland have unlocked the mechanism underlying the connection between smoking and Tuberculosis (TB). This discovery will considerably strengthen anti-smoking efforts to control TB and uncovers new therapy and vaccine options for TB. Their research has just been published in the top respiratory Journal, the American Journal of Respiratory and Critical Care Medicine. The research was funded by the Health Research Board (HRB) and The Royal City of Dublin Hospital Trust.

Tuberculosis spreads from person to person by inhaling infected droplets made when the TB sufferer coughs. The World Health Organization has designated TB a global emergency. Nine million people fall ill with TB each year, and it is the greatest killer worldwide due to a single bacterial infection. Many countries have recurring outbreaks and multi-drug resistant TB cases.

After infection most people do not become ill with TB, but immunosuppressed patients are susceptible. Smoking increases a person's susceptibility to infection by TB, risk of recurrence, mortality and persistent infectiousness. However, until now the exact reason or mechanism behind this connection between smoking and TB has been unknown.

The research team conducted the study with smokers, ex-smokers and non-smokers attending the bronchoscopy suite at St James's Hospital in Dublin. They found that the white blood cells located in the lungs of smokers and ex-smokers, which are responsible for fighting infections, showed a weakened response to the TB infection. In the smoker's lungs, these cells malfunction, and fail to make the chemical messengers that would normally fight the TB bacteria. In fact, the researchers found that these cells suppress the lungs' immunity after infection, which gives the TB bacteria a chance to take over.

Joseph Keane is Professor of Medicine at Trinity and St James's Hospital, HRB Clinician Scientist, and the senior author of the study. He said: "TB remains a huge global health problem, affecting millions worldwide. It has been known for some time that smokers are more susceptible to getting TB and nearly 80% of the world's one billion smokers live in countries of high TB prevalence. Therefore, while HIV is a key driver of the disease, numerically, smoking is more prevalent than HIV, making smoking the biggest global driver of the TB epidemic."

"This study provides evidence which explains the link between smoking and TB and should considerably strengthen anti-smoking efforts to control TB. However, the widespread emergence of multi-drug resistance TB means we badly need new therapy and vaccine options for TB. We are already applying the findings of this study to develop new treatment options."

---

Story Source:

The above story is based on materials provided by Trinity College Dublin. Note: Materials may be edited for content and length.

---

Journal Reference:

1. Seónadh M O'Leary, Michelle M Coleman, Wui Mei Chew, Colette Morrow, Anne Marie McLaughlin, Laura E Gleeson, Mary P O'Sullivan, Joseph Keane. Cigarette Smoking Impairs Human Pulmonary Immunity toMycobacterium tuberculosis. American Journal of Respiratory and Critical Care Medicine, 2014; 141112083842005 DOI: 10.1164/rccm.201407-1385OC

---

 

Host genetics can contribute to lung damage in severe tuberculosis

---

Schematic illustration of a hypothetical model to explain the high and low involvement of the P2X7R during severe and mild TB.

A third of the global population is infected with the bacterial pathogen, a mycobacterium, that causes tuberculosis (TB). Most carriers control the infection and are asymptomatic, but severe forms of the disease (more common in children and immune-compromised adults, and often caused by particularly aggressive -- or hypervirulent -- mycobacterial strains) kill over a million people every year. An article published on July 3rd in PLOS Pathogens now identifies a factor made by the host that exacerbates lung damage in severe TB. The results also suggest why gene mutations that render the factor inactive are common.

To understand the mechanisms underlying aggressive TB, Elena Lasunskaia from the Universidade Estadual do Norte Fluminense, Rio de Janeiro, Maria Regina D'Império-Lima from the Universidade de São Paulo, Brazil, and colleagues studied mouse models which recapitulate the symptoms of severe pulmonary TB in humans. Like human patients, mice infected with two different hypervirulent mycobacterial strains develop necrotic lesions in the lung, that is, areas of dead cells that break open and release their contents. The necrotic debris contains molecules that promote an influx of immune cells from the host, and the resulting local inflammation causes further damage to the lung tissue.

One of the contents of necrotic debris is the energy-storage molecule ATP, and when it is found outside cells, it is known to stimulate immune cells through the binding to the P2X7 receptor (P2X7R). The researchers asked whether this molecular pathway plays a role in the severe forms of TB that are associated with lung necrosis. They studied mice that were lacking P2X7R and found that those mice survived otherwise deadly infections with either of the two hypervirulent mycobacterial strains.

A more detailed analysis suggested that P2X7R has a dual role in the development of aggressive TB. First, it appears to facilitate the dissemination of hypervirulent mycobacteria by killing infected immune cells but releasing their content, namely viable mycobacteria that have survived the process. Second, P2X7R also seems to contribute to lung inflammation and damage by promoting widespread tissue destruction.

The better outcomes in mice without P2X7R were only seen after infection with hypervirulent mycobacteria. When the researchers infected mice with a less aggressive TB strain, they found that P2X7R actually helped to control this infection. In this case, P2X7R-mediated stimulation of infected immune cells did not result in the cell death and release of viable mycobacteria, and so actually contained the infection rather than spreading it.

The observed opposite effects of P2X7R on lung infection with hypervirulent and less aggressive mycobacterial strains, respectively, could explain an epidemiological puzzle: P2X7R loss-of-function alleles (that is defective variants of the P2X7R gene) are common in humans despite the fact that they are linked to a higher risk of developing pulmonary TB. Based on their results, the researchers suggest that such variants might increase the risk of mild TB but reduce the risk of severe TB. This, they say "could explain why evolutionary pressure has maintained these gene polymorphisms at high rates in the human population."

They also state that their study "provides a perspective for the development of new therapeutic approaches in which drugs designed to inhibit P2X7R are used to ameliorate the outcomes of aggressive forms of TB."

---

Story Source:

The above story is based on materials provided by PLOS. Note: Materials may be edited for content and length.

---

Journal Reference:

1. Eduardo P. Amaral, Simone C. M. Ribeiro, Verônica R. Lanes, Fabrício M. Almeida, Marcelle R. M. de Andrade, Caio Cesar Barbosa Bomfim, Érika M. Salles, Karina R. Bortoluci, Robson Coutinho-Silva, Mario H. Hirata, José M. Alvarez, Elena B. Lasunskaia, Maria Regina D'Império-Lima. Pulmonary Infection with Hypervirulent Mycobacteria Reveals a Crucial Role for the P2X7 Receptor in Aggressive Forms of Tuberculosis. PLoS Pathogens, 2014; 10 (7): e1004188 DOI: 10.1371/journal.ppat.1004188