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Our Infectious Respiratory Disease Research

What does it take to outwit lung disease? Bold, brave research! Our investigators are involved in projects that cover all the bases, from studying how diseases work to developing real-world therapies.

Below, you’ll learn more about the research projects we are currently funding. Interested in applying for a research grant? Learn about our opportunities here

Infectious Disease Research Projects

2021

Dr. Tetyana Kendzerska

Associations of Sleep Disordered Breathing and Positive Airway Pressure Treatment with Risks of Contracting COVID-19 and Serious COVID-19 Complications: A Population-Based Study

Amount: $15,000.00

Obstructive sleep apnea (OSA) is the most common sleep-related breathing disease, affecting up to 30% of adult Canadians. It is caused by blockage of the upper airway during sleep, which obstructs breathing throughout the night. A focus on OSA during the COVID-19 outbreak is of substantial interest for the following reasons. OSA may cause harm through low oxygen level, increased inflammation, stress on the heart, and blood vessel dysfunction associated with stopping breathing episodes, likely making COVID-19 infection worse. Individuals with OSA often suffer from obesity, lung or heart diseases, previously shown to be related to severe COVID-19. Finally, positive airway pressure treatment (PAP) recommended for individuals with significant OSA may facilitate the spread of the virus, which causes COVID-19. Therefore, OSA likely contributes to a greater risk of COVID-19 or serious complications from COVID-19. However, more research is needed to determine whether individuals with OSA should be considered a vulnerable group.

Our study will investigate relationships between clinically significant OSA requiring PAP treatment and the risk of contracting COVID-19 or serious complications from COVID-19 (emergency department visits, hospitalizations, mortality). We will also examine whether the presence of heart and lung diseases affects this relationship. Next, we will assess temporal changes in OSA-related health care during the COVID-19 outbreak and the relationship between different components of OSA-related health care since the outbreak and poor COVID-19-related outcomes.

We will use provincial health administrative databases to address our research aims. Health care administrative data are generated at every encounter with the health care system, whether through a visit to a physician’s office, a diagnostic procedure, or hospital admission. To complement results obtained using health administrative data, we will use already collected self-reported data from a national community-based survey.
We have assembled the necessary expertise, preliminary data, and analytic techniques to accomplish our study aims. We are uniquely positioned to conduct this research with access to high-quality health administrative data through ICES on the provincial level and self-reported data through the community-based survey “How are you coping during COVID-19?” (the number of respondents on Feb 10, 2021, was approximately 12,500). With this unique data, we will address the limitations of published studies to determine whether OSA is a potentially significant risk factor for developing a severe form of COVID-19.

Our research aims are directly relevant to the Lung Health Foundation’s missions of improving the lung health of Canadians and protecting Canadians from the impact of COVID-19. Findings from this research will confirm if OSA should be a recognized risk factor for developing a severe form of COVID-19. Positive findings would support screening for OSA and subsequent treatment when assessing individuals with suspected or confirmed COVID-19 infection. Positive findings would also lead healthcare providers to educate individuals with OSA about their greater risk of infection and the importance of protective measures against COVID-19, including the importance of vaccination. Negative findings would provide reassurance. Furthermore, given that the COVID-19 pandemic may have a major effect on OSA health care, finding from this study will support the need of developing new clinical pathways for these individuals (e.g., home sleep studies, telemedicine) during the later stages of the pandemic and post-pandemic.

Dr. Jim Sun

Role of FAK in host immunity against tuberculosis

Amount: $15,000.00

Tuberculosis (TB) is a devastating lung disease caused by the bacterium Mycobacterium tuberculosis (Mtb), and is the leading cause of infectious disease related deaths worldwide. Inhaled Mtb are engulfed by special cells in the lung called macrophages, which normally kill invading bacteria. However, Mtb reprograms host macrophages to disable their ability to kill the bacteria, and remains sheltered from antibiotic treatment, thus creating challenges for anti-TB drug discovery. Key to this is the ability of Mtb to manipulate host cell death as a means to hide from the immune system. As such, it is critical to understand the mechanisms underlying how Mtb controls cell death. The knowledge gained will be instrumental in the development of alternative therapies or vaccination efforts again TB.

Our research has revealed Focal Adhesion Kinase as a key host protein that is hijacked by Mtb during infection to control cell death. However, we still do not understand the specific molecular mechanism of how FAK modulates cell death during Mtb infection and the impact of this protein in animal models of TB infection. As such, our objective is to determine the role and function of FAK in TB using the mouse model of infection.

We will use genetic and pharmacological approaches to modulate the expression and activation of FAK in macrophages and mice. The function of FAK during Mtb infection will be analyzed using these macrophages and mice to study the inflammatory response and specific cell death pathways using cell biology and immunology methods. The impact of FAK in TB will be determined by measuring bacterial burden in organs of infected mice and lung histopathology.

The identification and molecular characterization of FAK introduces a new host target that would be suitable for TB host directed therapy. The concept of targeting host proteins for treatment of TB is innovative as it can be the singular means to overcome drug resistance and latent TB infections.

The proposed research will become an essential piece of the puzzle to advance host-directed therapy efforts against TB with the prospect of eliminating this deadly lung disease, which aligns with the mission of the LHF to improve lung health of Canadians. The threat of TB in our country persists as multi-drug resistant TB strains are now common and increasingly cause infections even in developed countries, which render many front-line drugs inadequate. As such, the proposed research will be critical to evaluate the suitability of novel host targets such as FAK for translational potential. The development of new therapies for TB will benefit lung health of Canadians, particularly in the Indigenous and foreign-born population, who are much more vulnerable to this devastating disease.

2020

Dr. Vanessa D’Costa

Investigating the Pathogenesis of the Multidrug-resistant Lung Pathogen “Acinetobacter baumannii”

Amount: $50,000

In healthcare settings, lung infections caused by infectious bacteria are often spread from patient to patient, despite the hospital’s best attempts to sterilize patient rooms, tools, and equipment. One infectious microbe that has become a global problem is a bacteria called Acinetobacter baumannii. This bacteria can survive on hospital surfaces for over a month, and has evolved the ability to take up genetic material from its environment for its own use that includes drug resistance genes that allows it to survive drug treatments prescribed by physicians to kill bacteria. The healthcare community is running out of drug options to treat Acinetobacter, and as a result, scientists are trying to identify creative ways to develop new drugs.

In intensive care units, critically ill patients are given an instrument called a ventilator, which is used to help them breathe when they cannot do so on their own. The bacteria Acinetobacter causes lung infections in patients, but can often survive sterilization of this breathing tool, and be spread from patient to patient in hospital wards. Despite the fact that Acinetobacter has become so problematic in healthcare settings, we know very little about how it causes infection. Better understanding the mechanisms of infection can provide new clues as to how we can develop new therapeutic strategies.

The objective of this research is to better understand how Acinetobacter causes infection. Acinetobacter lives inside cells within the human body during the infection process, therefore we are specifically interested in understanding how it survives the defense mechanisms in human cells in order to cause infection.

We have developed a way to mimic infection in the lab using cells from the human respiratory tract. We will use this model system to study defense processes in human cells undergoing infection by Acinetobacter. This will be accomplished using techniques to visualize infection and human cellular processes under the microscope.

Acinetobacter infection is poorly understood at a cellular level. This research will represent the first comprehensive insights as to how this important clinical pathogen causes infection

Dr. Dawn Bowdish

Early Life Adversity Increases the Risk of Invasive Pneumococcal Infection

Amount: $50,000

Pneumonia is the 4th leading cause of hospitalization in Canada. People who have been hospitalized for pneumonia are at increased risk of having heart problems and developing lung disease. For reasons we don’t understand, children born to mothers who were overweight or obese, or had a lot of stress during pregnancy seem to have permanent changes to their immune systems, and possibly lungs, that leave them more vulnerable to infections, especially pneumonia. We do not understand why this happens and therefore we are not able to reduce the risk of getting pneumonia or the long-term health consequences that follow, in these children.

Our goal is to understand whether the lung and immune systems develop differently in babies born to mothers who have experienced metabolic adversity (i.e. are overweight or obese or have eaten a high fat diet during pregnancy) compared to mothers who have not experienced this adversity. We will determine whether these changes increase susceptibility to infection with the bacteria Streptococcus pneumoniae.

We have combined the expertise of a fetal physiologist (Sloboda) with an immunologist (Bowdish) to develop a mouse model of prenatal adversity. We feed pregnant mouse mothers a high fat diet during pregnancy and lactation and when the mice are old enough to stop nursing, we give them a healthy diet. Even though these offspring are not overweight and look perfectly normal, we have found that they more susceptible to infection than mice born to mothers who had ideal pregnancies. We will study the immune systems and the lungs of the offspring to determine how eating a high fat diet during pregnancy alters the development of these systems. We will infect both groups of mice (i.e. those born to mothers who have eaten a poor diet during pregnancy and those who have not) and study how their lungs and immune systems respond.

To our knowledge this is the first time a mouse model of maternal obesity has been used to study the risk of infection. Until now we knew that children born to mothers who were obese, had a poor diet, or were experiencing stress had an increased risk of infection, but we had no way of figuring out how or why this happens. Our study will allow us to discover how prenatal changes in the immune system and lungs can change infection risk in children. We need to do this before we can discover new ways to protect these children from infections with Streptococcus pneumoniae.

S. pneumoniae infections take a major toll on the health of Ontarians, especially the most disadvantaged people. The vaccine is not as effective in children or adults who are obese or have chronic health conditions, which are more common in individuals born or living under adverse conditions. The aim of our project is to understand the pathways that lead to an increased risk of pneumococcal infection so that we can start to prevent its occurrence, and the long-term health consequences of these infections in the most vulnerable Ontarians.

Dr. Chris Verschoor

Chronic Inflammation as a Determinant of Influenza Vaccine Efficacy and Respiratory Outcomes in Older Adults

Amount: $49,786

Influenza disproportionately impacts adults older than 65 with respect to rates of infection, hospitalization, and death. Even of greater concern are the rates of immediate and delayed post-influenza hospitalization outcomes that older adults face: for example, within 1 week of being admitted to hospital with influenza, adults older than 65 are significantly more likely to have a heart attack, and both lung and physical function is impaired for at least two years afterwards. Although natural aging is certainly relevant in these observations, factors related to overall health are likely more important. Chronic inflammation is related to the incidence of a vast array of age-related adverse health outcomes, including frailty, cardiovascular disease, chronic lung disease, diabetes, arthritis, and mortality, but little is known regarding its role in the protection against influenza.

We hypothesize that chronic inflammation is a significant determinant of poor vaccine responses and influenza infection in older adults, and drives the relationship between frailty and vaccine responses. To test these hypotheses, we will: 1) estimate the effect of chronic inflammation on vaccine responses, 2) measure levels of chronic inflammation in people that developed an influenza infection and those that did not, and 3) investigate whether chronic inflammation mediates the relationship between frailty and vaccine responses.

This research will be based on a recently completed double-blind, randomized trial that compared high dose and standard dose vaccination in community-dwelling adults 65 and older. Specifically, we will take advantage of banked biospecimens from this trial to measure three major inflammatory proteins in serum (C-reactive protein, tumour necrosis factor, interleukin-6) prior to vaccination, and determine their association with vaccines responses, as well as influenza infection. For our third aim we will use a common statistical approach to measure mediation.

Our proposed study represents one of the most comprehensive investigations of the role of chronic inflammation in vaccine responsiveness and respiratory outcomes to date. We fill several large knowledge gaps in the literature, namely: 1) the degree to which chronic inflammation effects vaccine responses in older adults,; 2) whether chronic inflammation is predictive of these responses or respiratory outcomes such as influenza infection; and 3) the specific role that chronic inflammation plays in the relationship between frailty and vaccine responses. Page 3 3 / 10 Application for Ontario Lung Association (OLA) – Team Breathe Research Award (Grant-in-Aid for Basic Science or Clinical Research)

A better understanding of chronic inflammation as a determinant of influenza protection will be important to establish which older adults are at the greatest risk for developing influenza and for the design of future vaccines aimed at protecting these vulnerable individuals.

Dr. Theodore Marras

Pilot Study of Point-of-Use Microbial Water Filters as Adjunctive Management in Patients with Mycobacterium Avium Pulmonary Disease

Amount: $49,219

Mycobacterium avium complex (MAC) bacteria can cause chronic lung infections with severe symptoms (cough, weight loss, fatigue and sweats), destroy lung tissue leading to shortness of breath and the need for oxygen treatment, and reduce survival. Treating this infection typically requires three antibiotics for 18 months. Success of treatment is measured in part by testing sputum (phlegm) to determine whether the germ persists. The source of MAC is from water, including treated water used for bathing and drinking. It is believed that inhaling water droplets during bathing and drinking water is the most important source of infection, cause of persistent infection despite using antibiotics, and cause of recurrent infection after finishing antibiotic therapy. It is extremely difficult to eliminate MAC from plumbing systems, but microbial filters installed at the point of use (showerhead, faucet) will prevent bacteria from passing and prevent exposure from this source. Microbial water filters require both installation and monthly replacement to be effective.

The objective of our project is to test the effectiveness of microbial water filters a very large, lengthy and expensive study of patients with MAC lung infection would be required. We plan to test whether such a study is feasible.

In our pilot study, a small number of patients with MAC lung infection will be randomized to either “usual care” (typical antibiotic treatment and lung health measures) or filters plus “usual care”. We will determine if patients will use filters in the treatment and prevention of MAC lung infection and whether a large scale study is feasible. If a large scale trial is indeed feasible, it will compare the outcomes between patients who use filters and patients who do not.

No studies have tested whether microbial water filters prevent recurrent infection in patients with MAC lung disease. Our pilot study will tell us if it is feasible to do a study of filters in preventing recurrent MAC lung infection and would provide the information required to design a full scale study.

More than 5000 people in Ontario have Mycobacterium avium complex (MAC) lung disease and this number is growing quickly. Treatment is very difficult, usually requiring three antibiotics for 18 months. Recurrence after treatment is extremely common. Finding a way to reduce recurrence of MAC lung disease will prevent unnecessary ongoing complicated antibiotic treatment and prevent progressive lung damage caused by MAC.

Dr. Jim Sun

Targeting PPM1A In Vivo for Host-directed Tuberculosis Therapy

Amount: $50,000

Tuberculosis (TB) is a devastating lung disease caused by the bacterium Mycobacterium tuberculosis (Mtb), and is the leading cause of infectious disease related deaths worldwide. Inhaled Mtb are engulfed by special cells in the lung called macrophages, which normally kill invading bacteria. However, Mtb reprograms host macrophages to disable their ability to kill the bacteria, and remains sheltered from antibiotic treatment, thus creating challenges for anti-TB drug discovery. The global emergence of multidrug-resistant TB further compounds this crisis. As such, there is an urgent need to develop novel and alternative therapies that can overcome the development of drug resistance and the intracellular nature of the infection. Host-directed therapy (HDT) targets host-cell proteins and pathways to boost the ability of macrophages to kill Mtb, rather than targeting the bacteria directly. Such a strategy can circumvent the development of antimicrobial resistance and induce killing of dormant bacteria that are highly tolerant to most antibiotics, thereby possessing the potential to be used as an alternative approach to treating infectious diseases.

Our research has revealed the phosphatase PPM1A as an ideal host protein to develop HDT for TB. We discovered that deletion of PPM1A improved the innate immune response to TB infection and resulted in enhanced intracellular killing of Mtb by macrophages. Importantly, we have designed and synthesized a novel small molecule inhibitor of PPM1A (SMIP-30) using medicinal chemistry. SMIP30 blocked the phosphatase activity of PPM1A at low micromolar concentrations and boosted the ability of macrophages to kill Mtb through a mechanism dependent on induction of autophagy, a key process that leads to the elimination of invading pathogens. The objective of this project is therefore to determine the translational potential of SMIP-30 using the mouse model of TB infection. The proposed research will provide proof of concept that targeting PPM1A can be a viable HDT strategy for TB.

The mouse model of TB infection will be used to determine the appropriate dose and route of SMIP-30 administration, the immunological effects of SMIP-30 on macrophage activation, and the efficacy of SMIP-30 as a host-directed treatment for TB. Readouts for immunological effects will include cytokine profiles and activation of autophagy markers. Efficacy of SMIP-30 for TB HDT will be determined by measuring bacterial burden in organs of infected mice and lung histopathology.

The concept of HDT (targeting human proteins) for TB is innovative as it can be the singular means to overcome drug resistance and latent TB infections. We have also created the first novel compound with a unique mechanism of action to activate macrophage autophagy, which will advance TB HDT.

The proposed research will become an essential piece of the puzzle to advance host-directed therapy efforts against TB with the prospect of eliminating this deadly lung disease, a long-standing mission of the Ontario Lung Association. The threat of TB in our country persists as multi-drug resistant TB strains are now common and increasingly cause infections even in developed countries, which render many front-line drugs inadequate. As such, the proposed research will be critical to evaluate the efficacy and translational potential of our new compound as an alternative therapeutic approach for TB. The development of new HDT for TB will benefit lung health of Canadians, particularly in the Indigenous and foreign-born population, who are much more vulnerable to this devastating disease.

Dr. Chris Verschoor

Examining the Relationship Between Biological Age and Influenza Vaccine Responses in Older Adults

Amount: $15,000

Influenza disproportionately impacts adults older than 65 with respect to rates of infection, hospitalization, and death. Even of greater concern are the rates of immediate and delayed post-influenza hospitalization outcomes that older adults face: for example, within 1 week of being admitted to hospital with influenza, adults older than 65 are significantly more likely to have a heart attack, and both lung and physical function is impaired for at least two years afterwards. Although natural aging is certainly relevant in these observations, factors related to overall health are likely more important. Chronic inflammation is related to the incidence of a vast array of age-related adverse health outcomes, including frailty, cardiovascular disease, chronic lung disease, diabetes, arthritis, and mortality, but little is known regarding its role in the protection against influenza.

We hypothesize that chronic inflammation is a significant determinant of poor vaccine responses and influenza infection in older adults, and drives the relationship between frailty and vaccine responses. To test these hypotheses, we will: 1) estimate the effect of chronic inflammation on vaccine responses, 2) measure levels of chronic inflammation in people that developed an influenza infection and those that did not, and 3) investigate whether chronic inflammation mediates the relationship between frailty and vaccine responses.

This research will be based on a recently completed double-blind, randomized trial that compared high dose and standard dose vaccination in community-dwelling adults 65 and older. Specifically, we will take advantage of banked biospecimens from this trial to measure three major inflammatory proteins in serum (C-reactive protein, tumour necrosis factor, interleukin-6) prior to vaccination, and determine their association with vaccines responses, as well as influenza infection. For our third aim we will use a common statistical approach to measure mediation.

Our proposed study represents one of the most comprehensive investigations of the role of chronic inflammation in vaccine responsiveness and respiratory outcomes to date. We fill several large knowledge gaps in the literature, namely: 1) the degree to which chronic inflammation effects vaccine responses in older adults,; 2) whether chronic inflammation is predictive of these responses or respiratory outcomes such as influenza infection; and 3) the specific role that chronic inflammation plays in the relationship between frailty and vaccine responses.

A better understanding of chronic inflammation as a determinant of influenza protection will be important to establish which older adults are at the greatest risk for developing influenza and for the design of future vaccines aimed at protecting these vulnerable individuals.