Medical Microbiology Commons^™

Attenuated Bacteria Potentiate The Outcome Of Immunotherapy With Pd-L1 Blockade In A Pre-Clinical Model Of Colorectal Cancer, Besan Haytham Mohammad Al-Saafeen

Theses

After more than a century of investigation, it has become evident that cancer development and progression occur at the expense of a dysfunctional immune system. This realization has ushered cancer immunotherapy as a new modality of treatment. In the last decade, the use of immune checkpoint inhibitors to treat cancer patients resulted in unprecedented and durable clinical benefits. However, the response rate in many cancers remains rather modest, with colorectal cancer being at the lower end of the spectrum. Previous work from our laboratory demonstrated the efficacy of using attenuated bacteria as immunomodulatory anti-cancer agents. The current study investigated the …

Advancing Rna Virus Discovery And Biology With Whole Genome Sequencing, Mariah Katherine Taylor

Theses and Dissertations (ETD)

Two RNA virus families that pose a threat to human and animal health are Hantaviridae and Coronaviridae. These RNA viruses which originate in wildlife continue and will continue to cause disease, and hence, it is critical that scientific research define the mechanisms as to how these viruses spillover and adapt to new hosts to become endemic. One gap in our ability to define these mechanisms is the lack of whole genome sequences for many of these viruses. To address this specific gap, I developed a versatile amplicon-based whole-genome sequencing (WGS) approach to identify viral genomes of hantaviruses and severe acute …

Intestinal Dysbiosis – A New Treatment Target In The Prevention Of Colorectal Cancer, Florinela-Andrada Dumitru, Sergiu Ioan Micu, Roxana Emanuela Popoiag, Marilena Musat, Andreea Daniela Caloian, Valentin Calu, Vlad Denis Constantin, Daniela Gabriela Balan, Cornelia Nitipir, Florin Enache

Journal of Mind and Medical Sciences

The gastrointestinal microbiome contains at least 100 trillion microorganisms (bacteria, viruses, fungi), whose distribution varies from the mouth to the rectum spatially and temporally throughout one's lifetime. The microbiome benefits from advancing research due to its major role in human health. Studies indicate that its functions are immunity, metabolic processes and mucosal barrier. The disturbances of these functions, dysbiosis, influence physiology, lead to diabetes, inflammatory bowel disease, obesity and colon tumorigenesis. The third most common form of cancer, colorectal cancer, is the result of many factors and genes, and although the link between dysbiosis and this type of cancer is …

Output Consistency Scale To Standardize Ostomate Output Description In Clinical Practice And Studies, Lisa Whisenhunt, Linda Xu, Fan Yang, Jacques Izard

Food for Health: Publications

Stool descriptors have become popular due to the large diffusion of the Bristol Stool Form Scale (BSFS) via clinical studies, clinical trials, and social media. The applications have been numerous and centered around standardization of terminology that can be used by health care professionals and patients alike, as well as individuals interested in their wellness and the associated partners in the wellness industry. For a portion of the population, the digestive content is rerouted to an external manufactured pouch or bag, making the use of the BSFS visual descriptors of stool difficult. From day one post-resection surgery, ostomates are challenged …

Chemotherapy-Induced Cognitive Impairment: Focus On The Intersection Of Oxidative Stress And Tnfα., Nicole G Rummel, Luksana Chaiswing, Subbarao Bondada, Daret K St Clair, D Allan Butterfield

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Chemotherapy-induced cognitive impairment (CICI) has been observed in a large fraction of cancer survivors. Although many of the chemotherapeutic drugs do not cross the blood-brain barrier, following treatment, the structure and function of the brain are altered and cognitive dysfunction occurs in a significant number of cancer survivors. The means by which CICI occurs is becoming better understood, but there still remain unsolved questions of the mechanisms involved. The hypotheses to explain CICI are numerous. More than 50% of FDA-approved cancer chemotherapy agents are associated with reactive oxygen species (ROS) that lead to oxidative stress and activate a myriad of …

Prion Disease: A Challenging Diagnosis, Jeffrey F. Spindel, Anita M. Fletcher, William T. Smith, Rodrigo Cavallazzi

The University of Louisville Journal of Respiratory Infections

Introduction: Human prion diseases are a group of rare encephalopathies resulting in rapidly progressive dementia and ultimately death. While there are no effective treatments for any form of prion disease, prompt and efficient diagnosis is essential to prevent the spread of the self-propagating protein, which may occur through aerosols, and avoid unnecessary or invasive testing. Diagnosis relies largely on physical examination, with many nonspecific findings, and laboratory testing, which has wide ranges of reported accuracy and high false positive rates with diseases such as Alzheimer’s dementia.

Methods: Patients who underwent testing for prion disease were retrospectively identified from the electronic …

Microbial Influence On Alzheimer's Disease, Ashley N. Hamby

The Cardinal Edge

No abstract provided.

Development Of A Recombinant Vaccine Against Human Onchocerciasis., David Abraham, John Graham-Brown, Darrick Carter, Sean A. Gray, Jessica A. Hess, Benjamin L. Makepeace, Sara Lustigman

Department of Microbiology and Immunology Faculty Papers

Introduction: Human onchocerciasis caused by the filarial nematode parasite Onchocerca volvulus remains a major cause of debilitating disease infecting millions primarily in Sub-Saharan Africa. The development of a prophylactic vaccine, along with mass drug administration, would facilitate meeting the goal of onchocerciasis elimination by 2030.

Areas covered: Models used to study immunity to Onchocerca include natural infection of cattle with Onchocerca ochengi and O. volvulus infective third-stage larvae implanted within diffusion chambers in mice. A vaccine, comprised of two adjuvanted recombinant antigens, induced protective immunity in genetically diverse mice suggesting that it will function similarly in diverse human populations. These …

Endophytes Of Brazilian Medicinal Plants With Activity Against Phytopathogens, Jucélia Iantas, Daiani Cristina Savi, Renata Da Silva Schibelbein, Sandriele Aparecida Noriler, Beatriz Marques Assad, Guilherme Dilarri, Henrique Ferreira, Jürgen Rohr, Jon S. Thorson, Khaled A. Shaaban, Chirlei Glienke

Pharmaceutical Sciences Faculty Publications

Plant diseases caused by phytopathogens are responsible for significant crop losses worldwide. Resistance induction and biological control have been exploited in agriculture due to their enormous potential. In this study, we investigated the antimicrobial potential of endophytic fungi of leaves and petioles of medicinal plants Vochysia divergens and Stryphnodendron adstringens located in two regions of high diversity in Brazil, Pantanal, and Cerrado, respectively. We recovered 1,304 fungal isolates and based on the characteristics of the culture, were assigned to 159 phenotypes. One isolate was selected as representative of each phenotype and studied for antimicrobial activity against phytopathogens. Isolates with better …

Assesment Of Antibiotic Resistant Gene Expression In Clinical Isolates Of Pseudomonas Aeruginosa, Dustin Esmond

Biology Theses

Increasing prevalence of nosocomial infections by antimicrobial resistant pathogens resulting in higher mortality rates and financial burden is of great concern. Pseudomonas aeruginosa represents one of six highly virulent “ESKAPE” pathogens that exhibit considerable intrinsic drug resistance as well as mechanisms for acquiring further resistance. As many of these mechanisms are regulated through gene expression, we sought to identify regulatory strategies and patterns at play in 23 clinical isolates collected from Baku, Azerbaijan and Tyler, Texas, USA. Real-time quantitative polymerase chain reaction was performed on six gene targets implicated in resistance and contrasted with antibiotic phenotypes. We found AmpC cephalosporinase …

Multiple Autonomous Cell Death Suppression Strategies Ensure Cytomegalovirus Fitness, Pratyusha Mandal, Lynsey Nagrani, Liliana Hernandez, Anita Louise Mccormick, Christopher Dillon, Heather Koehler, Linda Roback, Emad S Alnemri, Douglas Green, Edward Mocarski

Department of Biochemistry and Molecular Biology Faculty Papers

Programmed cell death pathways eliminate infected cells and regulate infection-associated inflammation during pathogen invasion. Cytomegaloviruses encode several distinct suppressors that block intrinsic apoptosis, extrinsic apoptosis, and necroptosis, pathways that impact pathogenesis of this ubiquitous herpesvirus. Here, we expanded the understanding of three cell autonomous suppression mechanisms on which murine cytomegalovirus relies: (i) M38.5-encoded viral mitochon-drial inhibitor of apoptosis (vMIA), a BAX suppressor that functions in concert with M41.1-encoded viral inhibitor of BAK oligomerization (vIBO), (ii) M36-encoded viral inhibitor of caspase-8 activation (vICA), and (iii) M45-encoded viral inhibitor of RIP/RHIM activation (vIRA). Following infection of bone marrow-derived macrophages, the virus initially …

Loss Of N1-Methylation Of G37 In Trna Induces Ribosome Stalling And Reprograms Gene Expression, Isao Masuda, Jae-Yeon Hwang, Thomas Christian, Sunita Maharjan, Fuad Mohammad, Howard Gamper, Allen R. Buskirk, Ya-Ming Hou

Department of Biochemistry and Molecular Biology Faculty Papers

N¹-methylation of G37 is required for a subset of tRNAs to maintain the translational reading-frame. While loss of m¹G37 increases ribosomal +1 frameshifting, whether it incurs additional translational defects is unknown. Here, we address this question by applying ribosome profiling to gain a genome-wide view of the effects of m¹G37 deficiency on protein synthesis. Using E coli as a model, we show that m¹G37 deficiency induces ribosome stalling at codons that are normally translated by m¹G37-containing tRNAs. Stalling occurs during decoding of affected codons at the ribosomal A site, indicating …

The Sulfur Microbial Diet And Risk Of Colorectal Cancer By Molecular Subtypes And Intratumoral Microbial Species In Adult Men, Daniel R. Sikavi, Long H. Nguyen, Koichiro Haruki, Tomotaka Ugai, Wenjie Ma, Dong D. Wang, Kelsey N. Thompson, Yan Yan, Tobyn Branck, Jeremy E. Wilkinson, Naohiko Akimoto, Rong Zhong, Mai Chan Lau, Kosuke Mima, Keisuke Kosumi, Teppei Morikawa, Eric B. Rimm, Wendy S. Garrett, Jacques Izard, Yin Cao, Mingyang Song, Curtis Huttenhower, Shuji Ogino, Andrew T. Chan

Department of Food Science and Technology: Faculty Publications

Introduction: We recently described the sulfur microbial diet, a pattern of intake associated with increased gut sulfur-metabolizing bacteria and incidence of distal colorectal cancer (CRC). We assessed whether this risk differed by CRC molecular subtypes or presence of intratumoral microbes involved in CRC pathogenesis (Fusobacterium nucleatum and Bifidobacterium spp.).

Methods: We performed Cox proportional hazards modeling to examine the association between the sulfur microbial diet and incidence of overall and distal CRC by molecular and microbial subtype in the Health Professionals Follow-Up Study (1986-2012).

Results: We documented 1,264 incident CRC cases among 48,246 men, approximately 40% …

The Immunoregulatory Landscape Of Human Tuberculosis Granulomas, Evan Li, Antony Rodriguez, Amber U Luong, David Allen, John Morgan Knight, Farrah Kheradmand, David B Corry

Faculty, Staff and Student Publications

The allergic airway diseases chronic rhinosinusitis (CRS), allergic fungal rhinosinusitis (AFRS), asthma, allergic bronchopulmonary mycosis/aspergillosis (ABPM/A), and cystic fibrosis (CF) share a common immunological signature marked by T H 2 and TH 17 cell predominant immune responses, the production of IgE antibody, and atypical inflammatory cell infiltrate that includes eosinophils and other innate immune effector cells. Severe forms of these disorders have long been recognized as being related to hypersensitivity reactions to environmental fungi. Increasingly however,environmental fungi are assuming a more primary role in the etiology of these disorders, with airway mycosis, a type of non-invasive airway fungal infection,recognized as …

Targeting Human Langerin Promotes Hiv-1 Specific Humoral Immune Responses., Jérôme Kervevan, Aurélie Bouteau, Juliane S Lanza, Adele Hammoudi, Sandra Zurawski, Mathieu Surenaud, Lydie Dieudonné, Marion Bonnet, Cécile Lefebvre, Hakim Hocini, Romain Marlin, Aurélie Guguin, Barbara Hersant, Oana Hermeziu, Elisabeth Menu, Christine Lacabaratz, Jean-Daniel Lelièvre, Gerard Zurawski, Véronique Godot, Sandrine Henri, Botond Z. Igyártó, Yves Levy, Sylvain Cardinaud

Department of Microbiology and Immunology Faculty Papers

The main avenue for the development of an HIV-1 vaccine remains the induction of protective antibodies. A rationale approach is to target antigen to specific receptors on dendritic cells (DC) via fused monoclonal antibodies (mAb). In mouse and non-human primate models, targeting of skin Langerhans cells (LC) with anti-Langerin mAbs fused with HIV-1 Gag antigen drives antigen-specific humoral responses. The development of these immunization strategies in humans requires a better understanding of early immune events driven by human LC. We therefore produced anti-Langerin mAbs fused with the HIV-1 gp140z Envelope (αLC.Env). First, we show that primary skin human LC and …

Targeted Oral Delivery Of Paclitaxel Using Colostrum-Derived Exosomes, Raghuram Kandimalla, Farrukh Aqil, Sara S. Alhakeem, Jeyaprakash Jeyabalan, Neha Tyagi, Ashish Agrawal, Jun Yan, Wendy Spencer, Subbarao Bondada, Ramesh C. Gupta

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) is the most common type accounting for 84% of all lung cancers. Paclitaxel (PAC) is a widely used drug in the treatment of a broad spectrum of human cancers, including lung. While efficacious, PAC generally is not well tolerated and its limitations include low aqueous solubility, and significant toxicity. To overcome the dose-related toxicity of solvent-based PAC, we utilized bovine colostrum-derived exosomes as a delivery vehicle for PAC for the treatment of lung cancer. Colostrum provided higher yield of exosomes and could be loaded with higher …

Inhibitory Molecules Pd-1, Cd73 And Cd39 Are Expressed By Cd8+ T Cells In A Tissue-Dependent Manner And Can Inhibit T Cell Responses To Stimulation, Corinne J. Smith, Christopher M. Snyder

Department of Microbiology and Immunology Faculty Papers

The salivary gland is an important tissue for persistence and transmission of multiple viruses. Previous work showed that salivary gland tissue-resident CD8+ T cells elicited by viruses were poorly functional ex vivo. Using a model of persistent murine cytomegalovirus (MCMV) infection, we now show that CD8+ T cells in the salivary gland and other non-lymphoid tissues of mice express multiple molecules associated with T cell exhaustion including PD-1, CD73 and CD39. Strikingly however, these molecules were expressed independently of virus or antigen. Rather, PD-1-expressing T cells remained PD-1+ after migration into tissues regardless of infection, while CD73 was activated on …

Habitual Sleep Duration And The Colonic Mucosa-Associated Gut Microbiota In Humans-A Pilot Study, Ritwick Agrawal, Nadim J Ajami, Sonal Malhotra, Liang Chen, Donna L White, Amir Sharafkhaneh, Kristi L Hoffman, David Y Graham, Hashem B El-Serag, Joseph F Petrosino, Li Jiao

Faculty, Staff and Students Publications

We examined the association between the colonic adherent microbiota and nocturnal sleep duration in humans. In a cross-sectional study, 63 polyp-free adults underwent a colonoscopy and donated 206 mucosal biopsies. The gut microbiota was profiled using the 16S rRNA gene sequencing targeting the V4 region. The sequence reads were processed using UPARSE and DADA2, respectively. Lifestyle factors, including sleep habits, were obtained using an interviewer-administered questionnaire. We categorized the participants into short sleepers (<6 h per night; n = 16) and normal sleepers (6–8 h per night; n = 47) based on self-reported data. Differences in bacterial biodiversity and the taxonomic relative abundance …

Accumulation Of Succinyl Coenzyme A Perturbs The Methicillin-Resistant Staphylococcus Aureus (Mrsa) Succinylome And Is Associated With Increased Susceptibility To Beta-Lactam Antibiotics, Christopher Campbell, Claire Fingleton, Merve S. Zeden, Emilio Bueno, Laura A Gallagher, Dhananjay Shinde, Jong-Sam Ahn, Heather M. Olson, Thomas L. Fillmore, Joshua N. Adkins, Fareha Razvi, Kenneth W. Bayles, Paul D. Fey, Vinai Chittezham Thomas, Felipe Cava, Geremy C. Clair, James P. O'Gara

Journal Articles: Pathology and Microbiology

Penicillin binding protein 2a (PBP2a)-dependent resistance to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) is regulated by the activity of the tricarboxylic acid (TCA) cycle via a poorly understood mechanism. We report that mutations in sucC and sucD, but not other TCA cycle enzymes, negatively impact β-lactam resistance without changing PBP2a expression. Increased intracellular levels of succinyl coenzyme A (succinyl-CoA) in the sucC mutant significantly perturbed lysine succinylation in the MRSA proteome. Suppressor mutations in sucA or sucB, responsible for succinyl-CoA biosynthesis, reversed sucC mutant phenotypes. The major autolysin (Atl) was the most succinylated protein in the proteome, …

Sars-Cov-2 Viral Proteins Nsp1 And Nsp13 Inhibit Interferon Activation Through Distinct Mechanisms, Christine Vazquez, Sydnie E Swanson, Seble G Negatu, Mark Dittmar, Jesse Miller, Holly Ramage, Sara Cherry, Kellie A Jurado

Department of Microbiology and Immunology Faculty Papers

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating global pandemic, infecting over 43 million people and claiming over 1 million lives, with these numbers increasing daily. Therefore, there is urgent need to understand the molecular mechanisms governing SARS-CoV-2 pathogenesis, immune evasion, and disease progression. Here, we show that SARS-CoV-2 can block IRF3 and NF-κB activation early during virus infection. We also identify that the SARS-CoV-2 viral proteins NSP1 and NSP13 can block interferon activation via distinct mechanisms. NSP1 antagonizes interferon signaling by suppressing host mRNA translation, while NSP13 downregulates interferon and NF-κB promoter signaling by limiting TBK1 …