Browsing by Author "Southard, Teresa L."

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    Investigation of SARS-CoV-2 infection and associated lesions in exotic and companion animals
    Rotstein, David S.; Peloquin, Sarah; Proia, Kathleen; Hart, Ellen; Lee, Jeongha; Vyhnal, Kristin K.; Sasaki, Emi; Balamayooran, Gayathriy; Asin, Javier; Southard, Teresa L.; Rothfeldt, Laura; Venkat, Heather; Mundschenk, Peter; McDermott, Darby; Crossley, Beate; Ferro, Pamela; Gomez, Gabriel; Henderson, Eileen H.; Narayan, Paul; Paulsen, Daniel B.; Rekant, Steven; Schroeder, Megan E.; Tell, Rachel M.; Torchetti, Mia Kim; Uzal, Francisco A.; Carpenter, Ann; Ghai, Ria (SAGE, 2022-01-18)
    Documented natural infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in exotic and companion animals following human exposures are uncommon. Those documented in animals are typically mild and self-limiting, and infected animals have only infrequently died or been euthanized. Through a coordinated One Health initiative, necropsies were conducted on 5 animals from different premises that were exposed to humans with laboratory-confirmed SARS-CoV-2 infection. The combination of epidemiologic evidence of exposure and confirmatory real-time reverse transcriptase-polymerase chain reaction testing confirmed infection in 3 cats and a tiger. A dog was a suspect case based on epidemiologic evidence of exposure but tested negative for SARS-CoV-2. Four animals had respiratory clinical signs that developed 2 to 12 days after exposure. The dog had bronchointerstitial pneumonia and the tiger had bronchopneumonia; both had syncytial-like cells with no detection of SARS-CoV-2. Individual findings in the 3 cats included metastatic mammary carcinoma, congenital renal disease, and myocardial disease. Based on the necropsy findings and a standardized algorithm, SARS-CoV-2 infection was not considered the cause of death in any of the cases. Continued surveillance and necropsy examination of animals with fatal outcomes will further our understanding of natural SARS-CoV-2 infection in animals and the potential role of the virus in development of lesions.
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    Pharmacological and genetic activation of cAMP synthesis disrupts cholesterol utilization in Mycobacterium tuberculosis
    Wilburn, Kaley M.; Montague, Christine R.; Qin, Bo; Woods, Ashley K.; Love, Melissa S.; McNamara, Case W.; Schultz, Peter G.; Southard, Teresa L.; Huang, Lu; Petrassi, H. Michael; VanderVen, Brian C. (PLOS, 2022-02-01)
    There is a growing appreciation for the idea that bacterial utilization of host-derived lipids, including cholesterol, supports Mycobacterium tuberculosis (Mtb) pathogenesis. This has generated interest in identifying novel antibiotics that can disrupt cholesterol utilization by Mtb in vivo. Here we identify a novel small molecule agonist (V-59) of the Mtb adenylyl cyclase Rv1625c, which stimulates 3’, 5’-cyclic adenosine monophosphate (cAMP) synthesis and inhibits cholesterol utilization by Mtb. Similarly, using a complementary genetic approach that induces bacterial cAMP synthesis independent of Rv1625c, we demonstrate that inducing cAMP synthesis is sufficient to inhibit cholesterol utilization in Mtb. Although the physiological roles of individual adenylyl cyclase enzymes in Mtb are largely unknown, here we demonstrate that the transmembrane region of Rv1625c is required during cholesterol metabolism. Finally, the pharmacokinetic properties of Rv1625c agonists have been optimized, producing an orally-available Rv1625c agonist that impairs Mtb pathogenesis in infected mice. Collectively, this work demonstrates a role for Rv1625c and cAMP signaling in controlling cholesterol metabolism in Mtb and establishes that cAMP signaling can be pharmacologically manipulated for the development of new antibiotic strategies.