Category Archives: Lung Injury and Infection

Lung Injury and Infection Theme: The respiratory system is exposed to many environmental insults throughout life that can result in acute or chronic injury to the lungs. Both infectious and non-infectious agents can trigger inflammation, which is essential to combat infections but also requires exquisite regulation to avoid counterproductive lung damage. In addition to major respiratory pathogens such as tuberculosis (TB), dysregulated inflammation triggered by bacteria and viruses is a major contributing factor to numerous respiratory diseases (e.g., cystic fibrosis, chronic obstructive pulmonary disease). This theme investigates the key molecular signaling pathways underlying pulmonary inflammation under these conditions, with the goal of developing new targeted therapies and biomarkers predictive of disease responses. Our researchers are also leaders in the performance of large-scale diagnostic and treatment studies involving patients infected with TB.

Major scientific objectives for the lung injury and infection theme include: (1) Identify the key molecular effectors of innate and adaptive immunity required for an integrated response to respiratory pathogens such as influenza, TB, and cryptococcus neoformans. (2) Dissect host-pathogen interactions driving chronic infections versus acute infectious pulmonary exacerbations in chronic lung diseases (eg. Pseudomonas in cystic fibrosis). (3) Investigate the molecular underpinnings of beneficial versus pathological responses by different components of lung mucosal immunity. (4) Explore the mechanistic links between cellular metabolism and fibrogenic processes in the lung.

View posts, news, and publications related to this research theme below.

Dragonfly wings are naturally antibacterial - article with Dao Nguyen

Dragonfly wings in the hospital

Did you know that dragonfly wings are naturally antibacterial?

Biofilms are colonies of bacteria that can attach securely to the surface of certain medical devices. Shockingly, a quarter of all nosocomial infections are reported to be associated with the use of infected equipment, based on American data.

RI-MUHC researcher Dao Nguyen shares some thoughts on combatting biofilms in this short article from Quebec Science. Her research team is looking at the wings of dragonflies and cicadas to better design safe antibacterial materials. Nanometric structures on dragaonfly and cicada wings actually kill bacteria by physical contact. Therefore, there is great interest to design and develop antibacterial materials that mimic this natural structure.

The research team will observe interactions between bacteria and these newly designed materials, then test the most promising against Pseudomonas aeruginosa. Pseudomonas aeruginosa is a bacteria responsible for hospital-acquired infections as well as fatal infections in people with cystic fibrosis. It has an ability to form biofilms and is naturally resistant to many drugs.

If the results are conclusive, the materials may eventually be used on a large scale to make safer medical devices and instruments.

Read the full article here (in French).

respiratory research grant results at the meakins-christie laboratories

Funding News – CIHR Project Grant

Congratulations to the following Spring 2019 Project Grant Recipients

Dr. Sushmita Pamidi received funding for her project co-led with Evelyn Constantin (CHHD program) entitled “Maternal sleep-disordered breathing during pregnancy and long-term health outcomes in children: the 3D pregnancy and birth cohort”. Dr. John Kimoff is a co-investigator on the grant.

Dr. Larry Lands is a co-applicant with Dr. Michael Parkins (University of Calgary) for the grant entitled “The influence of Cytomegalovirus infection on cystic fibrosis disease progression”.

View full CIHR Funding Decisions for the 2019 Spring Project Grant Competition.

Dorival Martins Relève étoile Jacques-Genest

Dr. Dorival Martins receives the Relève étoile Jacques-Genest Award

Congratulations to Dorival Martins Jr, postdoctoral fellow in Biochemistry, McGill University (supervisor: Dr. Dao Nguyen) for his Relève étoile Jacques-Genest award from the Fonds de recherche du Québec (FRQ) for the month of July.

Winning article: Martins D, McKay G, Sampathkumar G, Khakimova M, English AM, Nguyen D. Superoxide dismutase activity confers (p)ppGpp-mediated antibiotic tolerance to stationary-phase Pseudomonas aeruginosa. Proceedings of the National Academy of Sciences. 2018 Sep 25;115(39):9797-9802. doi: 10.1073/pnas.1804525115. Epub 2018 Sep 10. PMID: 30201715

Read the full news release here.

Dr. Erwan Pernet and Dr. Maziar Divangahi, scientists at the RI-MUHC and the Meakins-Christie Laboratories have identified a lipid target to tone down the hyper-active immunity to influenze infection

Flu treatment using lipid target

Dr. Maziar Divangahi and his postdoctoral fellow Dr. Erwan Pernet are on a promising path towards developing flu treatment using a lipid target. They identified a new role for the lipid mediator Leukotriene B4 in the lung. In a study published in Nature Microbiology, they show that the LTB4 molecule is capable of not only reducing collateral tissue damage caused by immune responses but also enhancing host survival.

“The influenza virus is not the only threat; the host’s own immune response is mainly responsible for jeopardizing host survival. Therefore, it is essential to understand the regulatory mechanisms that maintain the tight balance between protective and harmful immunity.”

– Erwan Pernet

Influenza remains a global public health challenge, according to the World Health Organization. Each year, there are an estimated one billion people cases worldwide, resulting in 290,000 to 650,000 influenza-related respiratory deaths.

Dr. Divangahi’s laboratory has focused on new immunotherapies targeting the immune system via host lipid mediators to either effectively kill the virus or limit lung tissue damage. In this study, they focused on the LTB4 lipid mediator and its effects on the immune response to flu infection. After working with mice lacking the receptor for LTB4, they were able to identify a network of regulatory mechanisms that maintain the tight balance between protective and harmful immunity. Also, of particular importance to future clinical studies was the finding that a single dose of LTB4 at the peak of disease was enough to significantly reduce lung immunopathology and tissue damage and improve host survival. 

“For the first time we show there is a subtype of macrophages in the lungs that are able to produce this immunoregulatory lipid (LTB4) to reduce the inflammation caused by another macrophage population that is responsible for causing lung tissue damage during influenza infection.”

– Maziar Divangahi

View the full publication here:

Leukotriene B4-type I interferon axis regulates macrophage-mediated disease tolerance to influenza infection. Pernet E, Downey J, Vinh DC, Powell WS, Divangahi M. Nat Microbiol. 2019 May 20. doi: 10.1038/s41564-019-0444-3. PMID: 31110361

The research was also featured in the CIHR-III (institute of Infection and Immunity) newsletter!

View articles and interviews about this research:

gut microbiome research

Anti-TB drugs can increase risk of TB re-infection

A study published in Mucosal Immunology by Drs. Irah King and Maziar Divangahi showed that anti-TB drugs ( anti-tuberculosis drugs) caused changes to gut microbiota, thereby compromising immunity. This then led to an increased susceptibility to Mycobacterium tuberculosis infection.

Current treatments for tuberculosis (TB) are very effective in controlling TB infection caused by Mycobacterium tuberculosis (Mtb). They don’t, however, always prevent reinfection. Why this happens is one of the long-standing questions in TB research.

Gut microbiota are critical to keeping us healthy; they help to digest food, combat pathogenic microbes and reinforce our immune system. Recent research has shown that chronic use of antibiotic leads to disruption of this community, which can in turn lead to dysregulation of the immune system.  It remains unclear, however, whether changes in the composition of the microbes living in our gut have an influence on TB infection. 

The research team treated mice with the most commonly used anti-TB drugs – isoniazid, rifampicin and pyrazinamide – for a period of eight weeks. They found that while all three drugs significantly altered the composition of the mice’s gut microbiome, only mice treated with isoniazid combined with pyrazinamide showed an increase in susceptibility to Mtb infection. Transplanting feces from healthy mice into animals treated with anti-TB drugs was sufficient to restore immunity to Mtb. The team also evaluated a number of lung cell types known to be important for resistance to Mtb infection. Following anti-TB treatment, alveolar macrophages, a type of immune cell located in the airways of mice and humans and the first cell to encounter Mtb upon infection, were compromised in their ability to kill Mtb.

“Anti-TB therapies have been incredibly efficient in controlling the TB epidemic by decreasing morbidity and mortality associated with Mtb. Now, this work provides a basis for novel therapeutic strategies exploiting the gut-lung axis in Mtb infection.’’

– Irah King

Read the full press release here:

View the full publication:

Intestinal dysbiosis compromises alveolar macrophage immunity to Mycobacterium tuberculosis. Khan N, Mendonca L, Dhariwal A, Fontes G, Menzies D, Xia J, Divangahi M, King IL. Mucosal Immunol. 2019 May;12(3):772-783. doi: 10.1038/s41385-019-0147-3. Epub 2019 Feb 19. PMID: 30783183

View articles and interviews about this research:

Divangahi and Nargis Khan Science immunology Tuberculosis publication

Beyond Killing Tuberculosis

Dr. Maziar Divangahi’s May 2018 publication in Science Immunology tries to explain why the vast majority of people infected with Mycobacterium tuberculosis (Mtb) can tolerate the infection without developing disease. 

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. The study determined that the mitochondrial protein cyclophilin D (CypD) acts as a key checkpoint for T cell metabolism and regulates disease tolerance in TB. (May 2018)

View articles and interviews about this research:

Flu vaccine and immunotherapies

Dr. Maziar Divangahi was interviewed by CBC Homerun 88.5 FM about his latest research on the flu vaccine. His lab has taken on the challenge of trying to understand how the mechanisms of the immune system fight the flu in the hopes of finding new immunotherapies to combat the virus.

The discovery of the RIPK3 protein that is involved in the regulation of immune response to the flu means help may be on the horizon. Their findings were published in the open-access journal PLoS Pathogens in 2017. (February 2018)

Full publication: RIPK3 interacts with MAVS to regulate type I IFN-mediated immunity to Influenza A virus infection. Downey J, Pernet E, Coulombe F, Allard B, Meunier I, Jaworska J, Qureshi S, Vinh DC, Martin JG, Joubert P, Divangahi M. PLoS Pathog. 2017 Apr 14;13(4):e1006326. doi: 10.1371/journal.ppat.1006326. eCollection 2017 Apr. PMID: 28410401

View articles and interviews about this research:

Cell 2018: BCG Educates hematopoietic stem cells to generate protective innate immunity against TB. M Divangahi

BCG-iv Induces Innate Immune Protection Against M. tuberculosis

Dr. Maziar Divangahi, his lab, and collaborators at McGill University and University of Montreal published a paper in Cell. Their work shows BCG-iv induces trained immunity through education of hematopoietic stem cells and offers long-term innate immune protection against M. tuberculosis infection. 

Up until now, efforts in generating a vaccine against TB have been mainly focused on T cells, with very disappointing outcomes in both pre-clinical as well as clinical trials. Now, Dr. Divangahi’s and Barreiro’s teams have shown for the first time that when BCG is administered to mice in a way that enables access to the bone marrow, it can reprogram stem cells. Dr. Eva Kaufmann, a postdoctoral fellow working on the project, was also interviewed by Radio-Canada. (January 2018) 

About the study

BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis by Eva Kaufmann, Joaquin Sanz, Jonathan L. Dunn, Nargis Khan, Laura E. Mendonça, Alain Pacis, Fanny Tzelepis, Erwan Pernet, Anne Dumaine, Jean-Christophe Grenier, Florence Mailhot-Léonard, Eisha Ahmed, Jad Belle, Rickvinder Besla, Bruce Mazer, Irah L. King, Anastasia Nijnik, Clinton S. Robbins, Luis B. Barreiro, and Maziar Divangahi, was published Jan. 11, 2018, in Cell. DOI: 10.1016/j.cell.2017.12.031

This study was funded by the Canadian Institutes of Health Research.

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Pulmonary research group in Canada: the Meakins-Christie Laboratories

Newborn screening for Cystic Fibrosis patients

A new study led by Dr. Larry Lands was recently published in the Journal of Cystic Fibrosis 2016. The study, led by a team from the Research Institute of the McGill University Health Centre (RI-MUHC) and Cystic Fibrosis Canada, reinforces the benefits of newborn screening for Cystic Fibrosis patients. Children with Cystic Fibrosis who are diagnosed through newborn screening are healthier and benefit more from new treatments.

About the study

The study, “The benefits of newborn screening for cystic fibrosis: The Canadian experience” was co-written by D.Y.F. Mak (Cystic Fibrosis Canada, Toronto, Canada), J. Sykes (Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Canada), A.L. Stephenson (Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Canada), and L.C. Lands (Research Institute of the McGill University Health Centre, Montreal, Canada).

This work was made possible through the in-kind support from Cystic Fibrosis Canada.

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respiratory research centre in Canada: The Meakins-Christie Laboraotories

Bacteria and Inflammation in Cystic Fibrosis

Dr. Dao Nguyen’s research team discovered that there are variants of Pseudomonas aeruginosa (LasR), a bacteria commonly found in Cystic Fibrosis patients, that can cause a lot of inflammation. The study was published in Science Advances 2015. In some cases, that inflammation leads to the need for lung transplants. Nguyen’s team is the first to make the connection between the bacteria and inflammation. (August 2015)

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