Browsing by Author "Henao-Tamayo, Marcela, committee member"

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Open Access
Bovine tuberculosis surveillance at cattle abattoirs in Ireland, 2008
(Colorado State University. Libraries, 2017) Gompo, Tulsi Ram, author; Olea-Popelka, Francisco, advisor; Rao, Sangeeta, committee member; Henao-Tamayo, Marcela, committee member
Bovine tuberculosis (TB) surveillance is an ongoing program among abattoirs (slaughterhouses) in Ireland. It is a key complementary tool in addition to the tuberculin skin test to detect infected herds. A retrospective cross-sectional study was conducted to assess the association between potential risk factors and the risk of detection, and the subsequent risk of confirmation of bovine TB lesions for cattle slaughtered in 2008 in Irish abattoirs. Consequently, the abattoirs were ranked based on their efficiencies of detecting suspected bovine TB lesions and their subsequent confirmation in laboratory. A database containing cattle records was obtained from the Center for Veterinary Epidemiology and Risk Analysis (CVERA) at University College Dublin, Ireland, that includes the results of animal movements, tuberculin test results, number of suspected bovine TB lesions detected during slaughter of animals and number of lesions confirmed as Mycobacterium bovis (M. bovis) in laboratory. The known potential risk factors impacting bovine TB lesions detection in Irish abattoirs were animal and herd level characteristics: age, sex, herd type, length of time a herd free from bovine TB after restriction, animal origin and District Electoral Division (DED) risk class. The data were analyzed to control for these potential risk factors when assessing the probability of detecting suspected bovine TB lesions among abattoirs in Ireland. Descriptive analysis was performed to assess the distribution of cattle slaughtered over the different abattoir. Univariable logistic regression was applied to evaluate an association between the risk factors and detection of bovine TB lesions in the abattoirs. Multivariable logistic regression analysis was performed to calculate the adjusted risk of bovine TB lesion detection and confirmation for each abattoir. During 2008, a total of 1,362,195 attested cattle were slaughtered in total thirty-five abattoirs in Ireland. Overall, 3,437 lesions (0.25%, or 25 per 10,000 slaughtered cattle) were detected, and from these, 2,187 (62.68%) bovine TB lesions were confirmed as caused by M. bovis in the laboratory. The crude detection risks varied from 0 to 56 lesions per 10,000 animals slaughtered. The average crude confirmation risks ranged from 0 to 100%. Ultimately, the abattoirs were ranked (1 being the best and 35 the worst) according to their effectiveness of bovine TB lesions detection and confirmation after adjusting the potential risk factors. There is a considerable variability in efficiencies of Irish abattoirs in detecting and confirming bovine TB lesions. It is thus recommended that Irish abattoirs should be monitored regularly with regards their bovine TB slaughter surveillance effectiveness. Also, the abattoirs with lower than expected effectiveness should be strengthened in order to meet the required standards of the Irish bovine TB slaughter surveillance program.
Open Access
Defining interactions between Mycobacterium leprae and Langerhans cells
(Colorado State University. Libraries, 2021) Fletcher, Darcy, author; Belisle, John, advisor; Henao-Tamayo, Marcela, committee member; Hess, Ann, committee member; Zabel, Mark, committee member
Leprosy is a chronic infection that affects the skin and peripheral nerves. Written accounts of the disease date back to at least 600 BC. Mycobacterium leprae, the causative agent of leprosy was first discovered by Dr. Gerhard Armauer Hansen in 1873. Leprosy remains a major health problem in several low- and middle-income countries including Brazil, India, and Indonesia. There are numerous clinical presentations of the disease which presents many challenges for controlling the disease including diagnosis, treatment regimen and duration, and occasional instances of drug resistant cases. Further challenges exist in studying the disease, knowledge of the intricate interactions with innate immune cells has made advances in some cell subsets but is limited in others leaving an incomplete picture of the disease. These gaps limit advances in disease management. M. leprae is an obligate, intracellular pathogen that grows preferentially between 33-35° C and selectively invades peripheral nerves and skin-resident innate immune cells including macrophages. Numerous host cells including macrophages and Schwann cells have been studied to understand their interaction with M. leprae, but other skin-resident immune cells like dendritic cells, specifically Langerhans cells, have not been studied as extensively. The findings that M. leprae antigens can be presented via CD1a on Langerhans cells has spurred interest in understanding how Langerhans cells interact and uptake M. leprae leading to downstream effects on T cell activation and overall immune responses. The hypothesis of this study is that M. leprae interacts with Langerhans cells via various cell surface receptors that influence a Th1 or Th2 immune response. This study interrogates the complex interactions between Mycobacterium leprae and Langerhans cells via multiple cell surface receptors. In Chapter 2, an ex vivo optical tissue clearing method was modified for fragile skin samples to analyze innate cell recruitment to the site of infection. Colocalization between Langerhans cells and a closely related mycobacterial spp. to M. leprae, M. haemophilum, was observed in a 3D optically cleared tissue. These observations indicate that wholistic insight of bacteria/innate immune cell interactions can be gleaned using experimentally infected tissues or human skin biopsies. Chapter 3 presents the contributions from multiple cell surface receptors present on Langerhans cells in recognizing and binding M. leprae. Langerin was found to play a role in binding M. leprae, however, was not the only cell surface receptor involved in recognition of M. leprae. CD5+ Langerhans cells can be separated into CD5high and CD5low LCs that have differences in binding capacity for M. leprae. This study builds the foundation to explore the wholistic contributions of Langerhans cells interactions and uptake of M. leprae. Further work should be conducted to identify M. leprae ligand(s) for CD5 and downstream effects on cytokine secretion and T cell activation.
Open Access
Impact of activated and resting mesenchymal stem cells on immune responses and gut microbiome and immune responses to gut bacteria in dogs with inflammatory bowel disease
(Colorado State University. Libraries, 2019) Soontararak, Sirikul, author; Dow, Steven, advisor; Twedt, David, committee member; Lappin, Michael, committee member; Henao-Tamayo, Marcela, committee member
Idiopathic inflammatory bowel disease (IBD) is one of the common diseases that causes gastrointestinal tract (GI) disorder and encompasses a group of unknown causes of chronic gastroenteropathies found to have persistent or recurrent GI signs along with intestinal and/or gastric inflammation. Similar to IBD in humans, the pathogenesis of IBD in dogs remains undiscovered, but it is believed to involve an interaction between the abnormal host immune response against intestinal microbiota and predisposing genetic and environmental factors. IBD is mostly incurable with long-term complications despite receiving standard treatments that are typical combinations of food trial, antibiotics, anti-inflammatory and immunosuppressive drugs. However, the therapeutic outcome of medical treatment appears to be multifactorial and inconsistent therapeutic responses ranging from transient recovery to no response have been found. One of the alternative treatments that potentially accelerates therapeutic effects is the use of mesenchymal stem cell (MSC) administration. Therefore, the goal of the research presented in this dissertation was to comprehensively investigate the impact of activated and resting MSCs on immune responses, cells regeneration and gut microbiome for treatment of IBD with a specific emphasis on gaining an improved understanding of the immune responses to the gut bacteria in dogs with IBD. In the first part of the study, we needed to have better understanding of immunopathogenesis in IBD. Although it is not clear what triggers the intestinal inflammations in IBD affected dogs, we hypothesized that the disease may be mediated, in part, by an abnormal immune response directed against intestinal bacteria. We found the substantially greater percentages and overall binding of IgG and IgA with their intestinal bacteria in IBD dogs than healthy dogs, and the primary production of anti-bacterial antibodies occurs locally in the gut rather than systemically. The IgG-binding bacteria triggered an increase of phagocytosis and pro-inflammatory cytokine production by macrophages. Moreover, Actinobacteria (Collinsella genus) was the preferential target for the mucosal IgG immune response to dysbiotic bacteria. We concluded that the mucosal antibody binding to commensal gut bacteria was substantially greater in dog with IBD compared to a healthy, and that the immune response targeted particular bacteria and triggered the pro-inflammatory response in IBD. We noted that the more extensive studies in dogs with IBD and compared to animals with other causes for GI dysfunction may be required. Then, we focused on the use of MSCs as an alternative treatment for IBD in animals and humans. To address this question, we used a mouse model of IBD to investigate the effectiveness of using 2 types of mesenchymal stem cells (induced pluripotent MSC [iMSC] and conventional adipose-derived MSC [adMSC]) for the treatment of IBD. The impact of MSCs on immune responses, cells regeneration and the gut microbiome were evaluated. We found that iMSC and adMSC treatment effects were equivalent on the basis of significantly improving clinical abnormalities and decreasing inflammation inside the gut. Both types of MSC also stimulated a significant increase in intestinal epithelial cell proliferation and amplified intestinal angiogenesis. Furthermore, the abnormal microbiome found in mice with IBD was returned to nearly normal values in terms of complexity and composition in mice with IBD treated with adMSC or iMSC. We concluded therefore that the administration of iMSC enhanced the overall intestinal healing, suppressed inflammation, and microbiome restoration with equal effectiveness as treatment using adMSC in a mouse model of IBD. The future studies in animal model including spontaneous IBD in dog or large scale of clinical trial for long-term follow-up to determine iMSC safety and efficacy is required before clinical translation. Finally, we investigated possible ways to improve the efficacy of mouse and dog MSC treatment by preactivating the MSC with inflammatory cytokines (IFN-g or TNF-a) or TLR agonists (TLR3 or TLR9 agonists). We investigated the response of canine MSCs to the 4 activating stimuli, including measurement of cell surface phenotype and cytokine release. Contrary to previous studies in other species including mouse and man, we found that the pre-activation of dog MSC generally had little effect on either phenotype or function. Therefore, we concluded that the ex-vivo preactivation of canine MSCs by inflammatory cytokines or TLR agonists is not warranted in terms of augmenting the functionality of the cells. We further concluded that dog MSC may be hyporesponsive to preactivating stimuli compared to those of MSC from other species such as mouse and man. Further studies are required for better understanding of the biology of canine MSCs and their responses to immune activation. Overall, the work described in this dissertation has increased our understanding regarding the immunopathogenesis of the IBD in dogs. The studies have also demonstrated the equivalent activity of iMSC and conventional adMSC for treatment of IBD, and also documented a previously undescribed restorative effect of MSC on the intestinal microbiome. These studies also illustrated species specific differences in the responsiveness of MSC to common immune stimuli. These studies provide a robust foundation for further research and hopefully this work can help stimulate new investigations into alternative treatments for IBD in dogs and humans.
Embargo
Non-tuberculous mycobacterium pulmonary disease: challenges and strategies for the preclinical modeling of M. abscessus and M. avium complex
(Colorado State University. Libraries, 2024) Pearce, Camron, author; Gonzalez-Juarrero, Mercedes, advisor; Jackson, Mary, committee member; Henao-Tamayo, Marcela, committee member; Amberg, Gregory, committee member
Mycobacterium avium complex (MAC) and Mycobacterium abscessus (Mab) each present significant clinical challenges. Both mycobacterial complexes are notorious for their ability to cause chronic and severe pulmonary infections, resistance to standard antibiotics, and intricate host-pathogen interactions that complicate disease management. Although in vitro characterization and preclinical mouse models are important for developing novel therapies, they often fail to replicate the full complexity of human disease. This dissertation presents work evaluating the efficacy of inhaled antibiotics delivered via liquid aerosol in treating MAC pulmonary infections in mice and explores a cystic fibrosis-like mouse strain as a potential preclinical model for Mab pulmonary infection. Building on the Mab studies, whole-body plethysmography (WBP) was established as a robust tool for longitudinally studying the effects of Mab pulmonary infection. This technique enabled monitoring of respiratory parameters and provided a detailed assessment of mouse respiratory function over time. Subsequently, a machine learning (ML) pipeline was developed to classify infection status based on WBP data, which demonstrated the potential of WBP-coupled infection studies to monitor disease progression. By identifying the respiratory parameters most predictive of infection, this work showed the potential for WBP modelling to not only track disease progression, but also better align preclinical mouse models with clinically relevant patient-reported outcomes.