Feb 3, 2022

Field Spotlight: Molecular Microbiology and Infectious Disease

microbiology
By Soha Usmani

*Thank you to those who provided and contributed material for this content* 

Many of our faculty members have uncovered important discoveries and are conducting vital and fascinating research in microbiology and infectious disease. The following are examples of standout projects and publication findings from our PIs:      

The primary specialty of the Brown lab is adenovirus research. One of their current projects aims to shed light on enteric adenoviruses, a causative agent of paediatric diarrhea, how their structural features help the virus infect intestinal cells and how other cells inhibit viral replication. The other project focuses on developing antivirals against severe infections caused by human adenoviruses as there are currently none approved. Ongoing experiments are examining how the digoxin steroid, previously demonstrated to delay and reduce viral yield, impacts viral replication and the host cell. Working with researchers from the British Columbia Centre for Disease Control, University of Guelph and Dalhousie University, the lab identified a new human adenovirus, assigned the designation of HAdV-D112 by the international Human Adenovirus Working Group. It was isolated from a conjunctivitis patient in Vancouver but couldn’t be typed by current PCR-based typing methods. Complete genome sequencing showcased it to be a fascinating recombinant adenovirus, representing a few existing types but with a stretch of amino acids in the major capsid protein not identified in any other human adenovirus to date.

The Brumell lab examines Salmonella and Listeria bacterial pathogenesis and interactions with their hosts, focusing on innate immunity. The lab also studies how host and pathogen interactions affect chronic diseases like IBD and arthritis. Examples of the group’s research include demonstrating how Salmonella type 3 effectors take advantage of host factors during infection and how type I interferons promote and autophagy pathways restrict Listeria monocytogenes spread.  

The Cochrane lab specializes in the necessary cis and trans-acting factors (aka DNA binding regulatory proteins) in HIV-1 replication by studying its RNA processing. Their work resulted in the discovery and characterization of multiple factors and detection of molecules that disturb viral RNA metabolism and, as a result, inhibit replication. The team subsequently showed that these molecules inhibit viruses from different families such as coronaviruses and adenoviruses, implicating them as broad-use antivirals. Ongoing work focuses on the mechanisms behind these compounds and the regulation of viral RNA processing.   

The Cowen lab is a leader in fungal pathogen research. For example, their work demonstrated that the chaperone protein Hsp90 is vital for enabling antifungal resistance and a crucial target for future therapeutics. They were also the first to synthesize and characterize inhibitors of Hsp90 through ascertaining differences between human and fungal versions of the protein via being part of the effort to generate the crystal structure of Candida albicans Hsp90 N-domain. Moreover, their work revealed differences between the fungal microbiomes in the lungs of healthy people versus those with respiratory diseases. The group did this by developing genomic approaches in characterizing the fungal members of the microbiome via high-throughput sequencing of ITS1, a spacer in ribosomal RNA, with phenotypic and genotypic analyses of isolates.  Dr. Cowen holds the Canada Research Chair in Microbial Genomics and Infectious Disease.  

The Davidson lab studies phages, the viruses that infect bacteria. Phages profoundly influence the environment and are abundant in the human microbiome. Research in this group is aimed at understanding how phages function and using this knowledge to design tools to improve human health. They also investigate the systems used by bacteria to resist phage attacks. In particular, they discovered and are characterizing anti-CRISPRs, proteins produced by phages that inhibit diverse CRISPR-Cas systems. Dr. Davidson holds the Canada Research Chair in Bacteriophage-Based Technologies.

The Ensminger lab is a leader in Legionella pneumophila research, the causative agent behind Legionnaire's disease and holds the largest stockpile of effector proteins compared to any bacterial species, with over 330 proteins. One of the areas of interest is pathogen evolution, focusing on L. pneumophila. In this arena, the group reconstructed the phylogeny of the L. pneumophila Philadelphia-1 lab strains—which was behind the 1976 American Legion’s outbreak—and its clinical ancestor through whole-genome sequencing. Other research areas include meta-effectors, which are proteins that target other effectors rather than host proteins and studying CRISPR-Cas arrays to investigate their past environmental struggles. Among the discoveries are that Legionella contains ubiquitin-specific deamidases among its effector collection, sequencing the first completed methylome of an L. pneumophila strain and finding the LME-1 genetic element as the first known target of the Legionella CRISPR-Cas system.  

The Frappier lab sheds light on how Epstein-Barr viral (EBV) proteins function to target cellular proteins and manipulate cellular processes. About 90% of the adult population have life-long infections with EBV. While often asymptomatic, this virus is the causative agent of mononucleosis and can sometimes lead to the development of multiple sclerosis or several types of cancer. How EBV manages to subvert all the host antiviral defences to enable its persistence and efficient infection is not well understood but is thought to involve the many proteins that the virus expresses. In a recent discovery, they uncovered a novel mechanism by which an EBV protein called BGLF2 inhibits the functions of cellular miRNAs by sequestering a cellular complex (RISC) required for miRNA function. As a result, BGLF2 inactivates multiple miRNAs, including let-7 family miRNAs, that control multiple processes central to oncogenesis (or cancer formation) and viral infection.  

The Funnell lab studies bacterial plasmid segregation or partitioning. Plasmids are crucial for bacterial pathogenicity and survival in their host since they can contain virulence and antibiotic resistance genes. The group specifically studies the P1 plasmid in E. coli which contains the ParA and ParB partitioning proteins and is homologous to systems in pathogenic bacteria such as Yersinia pestis, Salmonella typhimurium, and E. coli O157:H7 and Rhizobiaceae bacterial family, involved in nitrogen fixation in plants. The group uncovered crucial insights such as ATP inducing multiple active forms of ParA for plasmid partition and how ParA and ParB bridge and bind DNA.  

The Gray-Owen lab specializes in comprehending how human pathogens colonize host tissue and evade the immune system. The central family of interest is Neisseria bacterial species, responsible for gonorrhea and meningococcal meningitis. Their research uncovered that gonorrhea increases the risk of HIV transmission through releasing heptose phosphate, which activates the immune system and unwittingly activates the virus and increases the risk of sexual transmission. Among the group's other accomplishments include developing in vitro and in vivo models of neisserial infection and discovering a novel PAMP involved in the innate immune response against bacteria. They are also developing new antibiotics which activate bacterial cylindrical proteases and vaccines which offer broad protection against neisserial infections. His group also conducted crucial COVID-19 research for Canadian companies such as testing the efficacy of a TLR4-specific therapeutic antibody that could prevent lung damage in COVID-19 patients and demonstrating that a novel antimicrobial-coated mask inactivates 99%+ of SARS-CoV-2. Dr. Gray-Owen also co-launched the Emerging and Pandemic Infections Consortium.

The Liu lab aims to create tuberculosis (TB) vaccines to replace the BCG version through increased efficacy and safety. They developed a recombinant BCG vaccine and are currently developing an attenuated Mycobacterium tuberculosis vaccine. Recently, the lab has developed an effective, nasally delivered COVID-19 vaccine. Other areas include how Mycobacterium tuberculosis effector molecules interact with macrophages and discovering their non-coding small RNAs, which post-transcriptionally regulate metabolism, stress adaptation and virulence.   

The Meneghini lab uses budding yeast Saccharomyces cerevisiae for studying host mitochondria-virus interactions. The group unearthed that mitochondria play a role in viral innate immunity through discovering that an antiviral pathway requiring a mitochondrial endonuclease called Nuc1 attenuates the double-stranded RNA totivirus called L-A. This enzyme is homologous to endonuclease G, which facilitates mammalian apoptosis. Additionally, the L-A RNA-dependent RNA polymerase is analogous is homologous to other RNA viruses such as MERS and SARS-CoV-2.  

The Navarre lab aims to comprehend the evolution and health implications of bacteria-host interactions by studying endogenous microbiota in lab mice. The group compiled numerous newly discovered rare bacterial species from lab mice with intestinal inflammation. They also unearthed that the H-NS protein found in Salmonella and E. coli suppresses AT-rich gene expression, which is associated with foreign genes and indicates its role in virulence and deleting the linked genes poxA and yjeK significantly diminishes Salmonella virulence and increases antibiotic and cellular stress susceptibility. The lab also determined that poxA and yjeK are involved in post-translational modification, making them a potential new target for antimicrobial drugs. 

The Parkinson lab currently explores how microbiomes impact human chronic diseases such as obesity, IBD and malnutrition. They also research bacterial pathogens such as Neisseria gonorrhea and parasites such as the causative agents of toxoplasmosis, malaria and elephantiasis (Toxoplasma gondii, Plasmodium falciparum, and Brugia malayi). The group was behind the first genome-scale metabolic reconstruction for Toxoplasma gondii. It demonstrated evidence for a parasite evolutionary strategy where revamping enzyme gene expression related to energy production broadens the host range.      

The Reinke lab sheds light on microsporidia, obligate intracellular eukaryotic parasites that ubiquitously infect animal host species, including the model organism Caenorhabditis elegans. These pathogens have the smallest eukaryotic genomes and split off early from fungi, resulting in a limited number of conserved genes and proteins outside their group. Given their broad host range, they are a valuable model for pathogen evolution. Recently, the group identified and characterized a novel C. elegans gene called aaim-1. They found the Nematocida parisii species, a nematode infecting species of microsporidia, utilizes aaim-1 to ensure spores in the intestinal lumen are correctly oriented and distanced relative to the apical intestinal membrane, promoting their invasion. The AAIM-1 protein also curiously demonstrates antibacterial properties against Pseudomonas aeruginosa, simultaneously preventing bacterial infection while promoting microsporidia invasion. The lab also hosts a database on their website defining and cataloguing every known Microsporidia species.

The Rini lab studies interactions between the spike proteins (S-protein) of various coronavirus species and host cell receptors to shed light on host specificity, immune evasion due to the S-protein, and coronavirus family evolution. The lab helped ascertain how antibodies bind and inactivate the SARS-CoV-1 virus and is part of the team that synthesizes antibodies that can neutralize SARS-CoV-2. This team also collaborated with the Gingras lab to develop a blood/antibody test that can detect a prior infection with COVID-19 and a study suggesting that coronavirus antibodies last at minimum three months post-infection. The lab also provided purified spike proteins for a project on why children infected with COVID-19 generally have milder symptoms than adults.   

The Roy lab is focused on developing new compounds to control nematode parasites of humans, animals and crops. One of their pipelines yields prodrug molecules, including Selectivin, that turn lethal when activated inside the worm. A second pipeline developed by the Roy Lab identifies nematicidal compounds, including Nementin, that work by disrupting the nematodes’ neuromuscular control. Nementin disrupts nematodes by promoting the release of synaptic vesicles. Other characterized nematicidal molecules include nemadipine, dafadine, wact-11 and wact-86.   

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