THE SCIENCE OF INFECTIOUS DISEASES
MICROBES, DRUG RESISTANCE AND THE SCIENCE OF INFECTIOUS DISEASES
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Microbes exist in the environment and in our bodies. Some can be the culprits in disease while many others help us to stave off illness. Only recently have researchers had the tools to study the profound impact microbes have on human health. The Department of Molecular Genetics at the University of Toronto is at the forefront of better understanding how microbes thrive in the environment, how they have evolved to infect us, and what we can do to stop the spread of disease. This knowledge will be critical in helping address global challenges, including the development of new strategies to cripple HIV, thwart tuberculosis, combat invasive fungal infections and, most importantly, halt microbial drug resistance. A healthy human body contains over
Modern medicine has revolutionized how we deal with infectious diseases, as vaccines, antibiotics and improved sanitation have transformed our capacity to prevent death from infections, which was once commonplace. These advances have added more than 30 years to the life expectancy of the average Canadian. Remarkably, infectious diseases still remain one of medicine’s greatest challenges, both in the developed and developing worlds. Every time a new antibacterial or antiviral drug is invented, drug-resistant microbes can evolve at an alarming pace. This fact is already a deadly reality for people living with HIV and tuberculosis, and many other infectious diseases. We are now in danger of entering an era where our most valuable medicines fail to treat infections that would otherwise be easily cured.
10 times
RESISTANCE FOR SELECTED BACTERIA/ANTIBACTERIAL DRUG COMBINATIONS, 2013—World Health Organization (WHO)
Number of bacteria/antibacterial drug resistance combinations for which data was obtained:
more microbial cells than human cells. A small number of these microbes are pathogens that cause life-threatening infectious diseases. These pathogens pose one of the greatest threats to health worldwide as they evolve rapidly—much faster than we do—and can become resistant to the drugs we use to kill them.
>5 (n=89) 2-5 (n=22) 1 (n=3)
National data not available or no information obtained or not applicable
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UNIVERSITY OF TORONTO DEPARTMENT OF MOLECULAR GENETICS
Throughout its more than 40-year history, the Department of Molecular Genetics has conducted a remarkable diversity and depth of research: the first positional cloning of a human disease gene for cystic fibrosis; the discovery of cancer stem cells; and in the last decade, the invention of robotics to decipher constellations of genetic interactions, as well as the development of new methods to study large molecules. Half of our 100 faculty members are based on campus, and the other half at world-renowned research institutes located at The Hospital for Sick Children and Sinai Health System. They are training 300 graduate students in SIX CUTTING-EDGE FIELDS within the broader area of molecular genetics. Today, the department is a premier venue for biomedical and life sciences research and education in Canada, and abroad.
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TACKLING DRUG RESISTANCE IN DEADLY DISEASES
Combatting Fungi...................................................6 Fighting Tuberculosis..............................................8
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THWARTING HIV AND VIRAL THREATS
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BRINGING THE MICROBIOME BACK INTO BALANCE
CONTROLLING THE LETHAL SPREAD OF INFECTIOUS DISEASES
Halting the Spread of HIV.............................................10 Staying Ahead of Viral Threats.....................................12
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DIRECTING THE IMMUNE SYSTEM TO FIGHT INFECTIONS
Discovering How to Leverage the Immune Response to Treat Infection................................................. 14
“ Good” Gut Bacteria Prevent Colon Cancer and Other Illnesses.......................................................16 Using Viruses Against Bacteria ..................................18
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INDUCED CANCERS – THE ROLE OF EPIGENETICS AND VIRUSES
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New Insights into Cancer Genes............................20 Fighting Virus-Induced Cancers............................22
Fighting Infectious Diseases........................................24 Conquering Legionnaires’ Disease...............................26 Finding New Targets to Fight Bacterial Infections...........28
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TACKLING DRUG RESISTANCE IN DEADLY DISEASES
Combatting Fungi Fungi exist everywhere—in the environment and in our bodies. Though most fungal pathogens pose no serious threat to a healthy person, they can be deadly for those with compromised immune systems such as patients with HIV/AIDS or cancer, those recovering from an organ transplant, or those who spend time in the hospital intensive care unit. What is worse, becoming infected may result in the need to halt certain treatments that weaken the immune system, such as chemotherapy. Our current arsenal of antifungal drugs is ineffective. Mortality rates are high, claiming 1.5 million lives each year. Dr. Leah Cowen’s lab has made groundbreaking discoveries that have uncovered the Achilles heel of drug-resistant fungi—openings that we can exploit to cripple the pathogen’s ability to cause disease. Armed with this knowledge, the Cowen lab is working to develop more effective therapeutics to combat deadly fungal infections in the future, and block the emergence of drug resistance.
Three-dimensional image of the fungus Candida albicans.
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Almost one million new cases of cryptococcal meningitis occur each year, resulting in
625,000
deaths, most in sub-
Antimicrobial resistance threatens the prevention and treatment of infections caused by bacteria, parasites, viruses and fungi.
Saharan Africa. (CDC)
Blastomycosis is caused by Blastomyces, a fungus that lives near major rivers and the Great Lakes in the U.S. and Canada. (CDC)
CDC - Centers for Disease Control and Prevention
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TACKLING DRUG RESISTANCE IN DEADLY DISEASES
Fighting Tuberculosis Tuberculosis (TB) is a highly infectious airborne disease and the second leading cause of death due to infectious diseases worldwide. In 2013 alone, 1.5 million people around the world died from tuberculosis. Drug resistance among the infected is growing, especially in Asia and the developing world. Infection does not confer immunity, and even increases the likelihood of repeat infections. The current tuberculosis vaccine works only in young infants, and its protection lasts just over a decade. Many find out they are infected only when they become elderly or immunocompromised. The lab of Dr. Jun Liu is now zeroing in on what makes some vaccine strains better than others in order to engineer the most effective vaccine against this deadly disease. By discovering the most effective vaccine strain and cloning a major gene from it, the team was able to improve all vaccine strains. The lab’s next goal will be to develop a second vaccine that is effective when administered in later life. The team is also exploring methods to detect, and eliminate, dormant tuberculosis.
Three-dimensional image of Mycobacterium tuberculosis.
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In 2014, there were about
480,000 new cases
More than
95 %
of TB deaths occur in low- and middle-income countries. (WHO)
of multidrug-resistant tuberculosis. (WHO)
Globally,
6 % of new TB cases and 20 % of previously treated TB cases are estimated to be drug resistant. (WHO)
WHO - World Health Organization
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THWARTING HIV AND VIRAL THREATS
Halting the Spread of HIV According to the World Health Organization (WHO), there were approximately 35 million people worldwide living with HIV/AIDS in 2013. Of those, an estimated 19 million people did not know they had the virus, and 3.2 million were children under the age of 15. When faced with an illness where patients must take medication daily for decades, the likelihood of missing a dose inadvertently goes up. But the result of this can be disastrous if the illness is AIDS, for it speeds up the emergence of drug-resistant strains which can then circulate in the population. A better solution, according to the lab of Dr. Alan Cochrane, would be to disable the virus’s ability to develop resistance, and stop its progression altogether. The Cochrane lab has made a groundbreaking new discovery that has shown it is actually possible to halt the progression of AIDS. The team has identified that certain drugs have the ability to stop the virus from replicating. Another important benefit of understanding the general mechanism of how to stop virus replication is that it can be applied to a myriad of infectious diseases such as influenza, herpes and many others.
Three-dimensional image of HIV.
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In 2013,
12.9 million people living with HIV
worldwide
An estimated
75,500 Canadians
were living with HIV in 2014. (CATIE)
were receiving antiretroviral therapy. (WHO)
In 2014, an estimated
44,073 people
were diagnosed with HIV/AIDS in the United States. (CDC) WHO - World Health Organization CDC - Centers for Disease Control and Prevention CATIE - Community AIDS Treatment Information Exchange
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THWARTING HIV AND VIRAL THREATS
Staying Ahead of Viral Threats RNA viruses, such as influenza and HIV, infect millions of people worldwide. The ability of these viruses to change quickly makes them difficult to prevent and treat; variants soon emerge that are resistant to prior vaccination and antiviral drugs, and their ability to change rapidly facilitates viral transmission from animals to humans. The deadly coronaviruses causing SARS and MERS provide recent examples of such cross-species transmission. By studying a coronavirus that causes the common cold in humans, Dr. James Rini and his team have discovered one of the ways in which RNA viruses change. The work has implications for the design of vaccines and efforts aimed at the prediction of new viral threats, an important aspect of public health planning and preparedness.
Three-dimensional image of influenza virus.
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8,098 people worldwide
became sick with SARS during the 2003 outbreak. (WHO)
774 people died of SARS during the 2003 outbreak. (WHO)
A total of
438 Canadians had SARS in 2003 and
44 Canadians died as a result of the infection. (WHO)
WHO - World Health Organization
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DIRECTING THE IMMUNE SYSTEM TO FIGHT INFECTIONS Discovering How to Leverage the Immune Response to Treat Infection Gonorrhea, a sexually transmitted disease, is one of the most prevalent bacterial infections in the world, causing nearly half a million new cases of the sexually transmitted disease each day. It is a re-emerging problem in North America because antibioticresistant superbugs have begun to appear, setting the stage for untreatable infections. Gonorrhea remains a leading cause of uterine scarring and sterility in women, and it can blind infants who are born to infected mothers. It also increases the infectiousness of HIV. It was the lab of Dr. Scott Gray-Owen that uncovered how the immune process meant to fight gonorrhea was actually driving HIV replication. A recent landmark discovery from the Gray-Owen lab has now shown how gram-negative bacteria—a broad class of bugs that cause diseases ranging from gonorrhea to pneumonia and meningitis—can trigger a reaction from our immune system. This discovery could lead to new therapies and treatments that use the immune system, rather than antibiotics, to fight infections.
Three-dimensional image of the Neisseria gonorrhoeae bacterium.
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There are an estimated
Resistance of gonorrhea to antibiotics has increased rapidly, reducing treatment options. (WHO)
357 million
new infections with chlamydia, syphilis, trichomoniasis and gonorrhea each year. (WHO)
Globally, there are approximately
78 million
new infections of gonorrhea annually. (WHO)
WHO - World Health Organization
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BRINGING THE MICROBIOME BACK INTO BALANCE “ Good” Gut Bacteria Prevent Colon Cancer and Other Illnesses Scientists now know that one of the causes of colon cancer is the “Western diet”—a diet high in refined carbohydrates. What we eat goes through one of the most microbial-dense environments on the planet: our digestive system. There, the food comes into contact with gut microbes, which can turn food into cancercausing compounds that mutate our DNA, and fuel the growth of tumours in the colon. A multidisciplinary team including Dr. William Navarre discovered that a simple change in diet—reduction of carbohydrates—was as effective at clearing out cancer-causing microbes as were antibiotics. Today, a richer understanding of the microbiome is leading researchers to understand that not all bacteria are harmful; some bacteria are helpful, and some are harmful only under certain circumstances. Now, the team is working to categorize the 500 different species of bacteria in the gut to identify the cancer-causing microbes. Knowing which microbes are driving the development of colon cancer can lead to revolutionary, yet simple and inexpensive pathways to the diagnosis and treatment of this deadly disease.
Three-dimensional image of Lactobacillus bacteria.
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The body hosts
trillions
Micro-organisms play an important role in obesity, autoimmune diseases, diabetes, cancer, arthritis, asthma and cardiovascular disease.
of micro-organisms, including bacteria, viruses and protists.
Microbial cells outnumber host cells by a factor of at least
10 to one.
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BRINGING THE MICROBIOME BACK INTO BALANCE
Using Viruses Against Bacteria Researchers have come to recognize the importance of the microbiome to human health—hundreds of different microbial species that inhabit all areas of our body. Recent studies have correlated disturbances in the microbiome with inflammatory bowel diseases, obesity, diabetes, cancer and mental health. Meanwhile, antibiotic-resistant bacteria have become a major problem. New approaches are needed to combat these dangerous human pathogens. To find these approaches, researchers are seeking technologies that allow them to eliminate specific bacterial species within the microbiome while leaving the rest undisturbed. Dr. Alan Davidson’s lab focuses on engineering phages and phage-related entities for the purpose of treating specific bacterial diseases and manipulating the human microbiome in precise ways. (Phages are viruses that typically infect and kill only a subset of strains in a single bacterial species and are therefore the ideal tool for the targeted destruction of bacteria.) The agents they are developing will be effective for combatting antibiotic-resistant bacteria and for alleviating illnesses resulting from imbalances in the microbiome.
Three-dimensional image of bacteriophage viruses infecting a bacterial cell.
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Each year in the U.S., at least
Infections from the deadly
carbapenem-resistant Enterobacteriaceae (CRE) bacteria are on the
rise among patients in medical facilities and have become resistant to most antibiotics. (CDC)
2 million people become infected with antibiotic resistant bacteria; at least 23,000 people die as a direct result. (CDC)
Antimicrobial resistance significantly impedes our ability to fight infectious diseases, leading to more hospitalizations and hospital stays. (Canadian Antimicrobial Resistance Surveillance System Report 2016)
CDC - Centers for Disease Control and Prevention
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INDUCED CANCERS – THE ROLE OF EPIGENETICS AND VIRUSES
New Insights into Cancer Genes Frequently occurring classes of cancers are caused by mutations in genes that control the “epigenetic” state of the cell (switched on or off by environmental factors). These epigenetic states modulate the gene expression program of the cell, but how these altered gene expression programs then cause cancer is not known. Using budding yeast, Dr. Marc Meneghini and his team investigated a particular category of epigenetic regulators whose dysfunction is highly correlated with cancer. The human versions of these genes cause cancer by tipping the balance of the cellular state away from differentiation (where cells are typically non-dividing) and towards proliferation. Dr. Meneghini’s group has found that in yeast these epigenetic factors control both differentiation and proliferation in a manner similar to their human counterparts, validating the usefulness of yeast studies for understanding the role of epigenetic factors in cancer. Their findings have revealed that these factors impact proliferation and differentiation in yeast through their control of cellular metabolism and energy production, offering a new perspective on how human cancers occur.
Three-dimensional image of cancer cells.
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Inherited genetic mutations play a major role in about
The most commonly mutated gene in all cancers is TP53, which produces a protein that suppresses the growth of tumors. (National Cancer Institute)
5 to 10% of all cancers. (National Cancer Institute)
More than 100 cancer types exist, each requiring unique diagnosis and treatment. (WHO)
WHO - World Health Organization
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INDUCED CANCERS – THE ROLE OF EPIGENETICS AND VIRUSES
Fighting Virus-Induced Cancers Epstein-Barr virus (EBV) is a human herpes virus that infects more than 90 per cent of the population. It is responsible for inducing mononucleosis (often referred to as the kissing disease). Astonishingly, it can also provoke several types of cancers in the human body, accounting for about 200,000 new cases per year. For example, up to 25 per cent of children receiving an organ transplant will get an EBV-induced cancer. There are currently no specific treatments for any EBV cancers and no vaccine to prevent EBV infection. The laboratory of Dr. Lori Frappier studies how EBV impacts the functions of human cells in ways that encourage cancer to grow. A clearer understanding of these mechanisms will lead to new therapeutics to address the EBV infection and, even more pointedly, EBV-induced cancers.
Three-dimensional image of the Epstein-Barr virus.
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Almost all cervical cancers
It is estimated that viral infections contribute to
are caused by Human Papilloma Viruses. (WHO)
15–20% of all human cancers.
(US National Center for Biotechnology)
Both
Heptatitis B and C viruses
can cause the long-term (chronic) infections that increase a person’s chance of liver cancer. (WHO)
WHO - World Health Organization
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CONTROLLING THE LETHAL SPREAD OF INFECTIOUS DISEASES
Fighting Infectious Diseases All bacteria contain small chromosomes called plasmids. These carry genes that benefit the bacterial host but are often harmful to humans and animals. Some of the genes carried on plasmids confer virulence and resistance to antibiotics. Plasmids can transfer directly from one bacterium to another and this contributes to the rapid spread of the traits they convey and—important for medicine—the rapid spread of disease between patients in hospitals and other environments where pathogenic bacteria are found. Dr. Barbara Funnell’s research provides fundamental insights into the nature of the interactions of DNA and proteins, and the ways in which chromosomes segregate during the cell cycle and reproduction. A better understanding of these processes will lead to better ways to fight bacterial disease. Dr. Funnell’s team studies the chromosome segregation process of bacterial plasmids—how they are inherited by growing bacterial cells. They have uncovered a novel transport mechanism that moves plasmids as “cargo” within cells to ensure faithful and stable maintenance. This system works with only two plasmid proteins, which act in a concerted and dynamic way.
bacterial plasmid
Three-dimensional image of bacterial structure.
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C. difficile, one of the most common causes of hospital infections afflicts people on antibiotics and in health care settings.
75,000 people die each year as a result of hospital infections. (CDC)
The most common pathogenic bacteria causing disease in humans are Staphylococcus,
Streptococcus gram-negative bacilli.
and
CDC - Centers for Disease Control and Prevention
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CONTROLLING THE LETHAL SPREAD OF INFECTIOUS DISEASES
Conquering Legionnaires’ Disease Legionella, the bacterium causing legionnaires’ disease—a kind of atypical pneumonia—thrive in the environment, but rarely cause infection. However, this bacterium can be deadly for elderly or immunocompromised populations. Legionella can multiply in stagnant water, grocery store misters, hot tubs, air conditioners and even hotel showers. Dr. Alex Ensminger and his team are interested in understanding why the genome of Legionella makes it adept at persisting in the environment. Understanding these mechanisms can help to inform how other pathogens, such as Salmonella and Listeria, thrive in the environment, cause disease and resist treatment.
Three-dimensional image of Legionella bacteria.
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Inhalation of contaminated aerosols is the most common form of transmission of the bacterium that causes legionnaire’s disease.
60% to 70%
of those diagnosed with legionnaire’s disease are male. (CDC)
Of the reported cases of legionnaire’s disease,
75% to 80%
of those infected are over 50 years of age. (CDC)
CDC - Centers for Disease Control and Prevention
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CONTROLLING THE LETHAL SPREAD OF INFECTIOUS DISEASES
Finding New Targets to Fight Bacterial Infections While most of the microbial world is harmless, or even beneficial to us, some bacteria specialize in causing disease. This includes Salmonella and Listeria, which represent a constant threat to our health and our economy. The rise of antibiotic resistance in these bacteria creates a new challenge for preventing and treating infections. Dr. John Brumell’s lab recently discovered a new step in the spread of Listeria within our bodies during infection. Essentially, these bacteria disguise themselves as cellular “garbage.” This causes the neighbouring host cells to take up the bacteria, thereby spreading the bacteria within the body. By understanding this mechanism of spread, new therapies to target Listeria infection are now possible.
Three-dimensional image of Listeria monocytogenes, gram-positive bacterium with flagella which causes listeriosis.
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Antimicrobial resistance is an
increasingly serious threat to global public health,
with new resistance mechanisms emerging and spreading globally. (WHO)
There are high proportions of antibiotic resistance in bacteria that cause common infections (e.g. urinary tract infections, pneumonia, bloodstream infections) in all regions of the world. (WHO)
Approximately
1,600 illnesses and
260 deaths
due to listeriosis occur annually in the United States. (CDC)
WHO - World Health Organization CDC - Centers for Disease Control and Prevention
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SAVING AND IMPROVING LIVES GLOBALLY By supporting excellence in molecular genetics research at U of T, you will be contributing to longer life and better health for people across Canada and around the world. Scientists from the Department of Molecular Genetics are contributing to a broader understanding of human health and disease. Their groundbreaking discoveries are revealing key facets of microbes, pathogens and the immune system, which will help us to not only engineer specific treatments, but also contribute to knowledge that may help prevent tomorrow’s outbreaks. Funding this work as well as the capital infrastructure required to support it will accelerate the exciting research underway – fundamental research that has the potential to save and improve the lives of millions around the world.
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photography: shutterstock, blausen.com, u of t archives
moleculargenetics.utoronto.ca Michelle Coutinho Senior Development Officer University of Toronto Faculty of Medicine Office of Advancement C. David Naylor Building 6 Queen’s Park Crescent Toronto, Ontario M5S 3H2 Canada T: 416-946-8103 michelle.coutinho@utoronto.ca