The ever-evolving SARS-CoV-2 variants necessitate the development of additional oral antivirals. This study presents the systematic design of quinoline-containing SARS-CoV-2 papain-like protease (PL^pro) inhibitors as potential oral antiviral drug candidates. By leveraging the recently discovered Val70^Ub binding site in PL^pro, we designed a series of quinoline analogs demonstrating potent PL^pro inhibition and antiviral activity. Notably, the X-ray crystal structures of 6 lead compounds reveal that the 2-aryl substitution can occupy either the Val70^Ub site as expected or the BL2 groove in a flipped orientation. The in vivo lead Jun13296 exhibits favorable pharmacokinetic properties and potent inhibition against SARS-CoV-2 variants and nirmatrelvir-resistant mutants. In a mouse model of SARS-CoV-2 infection, oral treatment with Jun13296 significantly improves survival, reduces body weight loss and lung viral titers, and prevents lung tissue damage. These results underscore the potential of quinoline PL^pro inhibitors as promising oral SARS-CoV-2 antiviral candidates, instilling hope for the future of SARS-CoV-2 treatment.

Bovine respiratory syncytial virus (BRSV) is a major respiratory pathogen in cattle and is relevant to the livestock industry worldwide. BRSV is most severe in young calves and is often associated with stressful management events. The disease is responsible for economic losses due to lower productivity, morbidity, mortality, and prevention and treatment costs. As members of the same genus, bovine and human RSV share a high degree of homology and are similar in terms of their genomes, transmission, clinical signs, and epidemiology. This overlap presents an opportunity for One Health approaches and translational studies, with dual benefits; however, there is still a relative lack of studies focused on BRSV, and the continued search for improved prophylaxis highlights the need for a deeper understanding of its immunological features. BRSV employs different host-immunity-escaping mechanisms that interfere with effective long-term memory responses to current vaccines and natural infections. This review presents an updated description of BRSV’s immunity processes, such as the PRRs and signaling pathways involved in BRSV infection, aspects of its pathogeny, and the evading mechanisms developed by the virus to thwart the immune response.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced impaired antiviral immunity and excessive inflammatory responses cause lethal pneumonia. However, the in vivo roles of key pattern recognition receptors that elicit protective antiviral and fatal inflammatory responses, specifically in the lungs, are not well described. Coronaviruses possess single-stranded RNA genome that activates TLR7/8 to induce an antiviral interferon (IFN) and robust inflammatory cytokine response. Here, using wild-type and TLR7-deficient (TLR7 ^−/− ) mice infected with mouse-adapted SARS-CoV-2 (MA-CoV-2), we examined the role of TLR7 in the lung antiviral and inflammatory response and severe pneumonia. We showed that TLR7 deficiency significantly increased lung virus loads and morbidity/mortality, which correlated with reduced levels of type I IFNs ( Ifna/b ), type III IFNs ( Ifnl ), and IFN-stimulated genes (ISGs) in the lungs. A detailed evaluation of MA-CoV-2-infected lungs revealed increased neutrophil accumulation and lung pathology in TLR7 ^−/− mice. We further showed that blocking type I IFN receptor (IFNAR) signaling enhanced SARS-CoV-2 replication in the lungs and caused severe lung pathology, leading to 100% mortality compared to infected control mice. Moreover, immunohistochemical assessment of the lungs revealed increased numbers of SARS-CoV-2 antigen-positive macrophages, pneumocytes, and bronchial epithelial cells in TLR7 ^−/− and IFNAR-deficient mice compared to control mice. In summary, we conclusively demonstrated that despite TLR7-induced robust lung inflammation, TLR7-induced IFN/ISG responses suppress lung virus replication and pathology and provide protection against SARS-CoV-2-induced fatal pneumonia. Additionally, given the similar disease outcomes in control, TLR7 ^−/− , and IFNAR-deficient MA-CoV-2-infected mice and coronavirus disease 2019 (COVID-19) patients, we propose that MA-CoV-2-infected mice constitute an excellent model for studying COVID-19. IMPORTANCE: Severe coronavirus disease 2019 (COVID-19) is caused by a delicate balance between a strong antiviral and an exuberant inflammatory response. A robust antiviral immunity and regulated inflammation are protective, while a weak antiviral response and excessive inflammation are detrimental. However, the key host immune sensors that elicit protective antiviral and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge are poorly defined. Here, we examined the role of viral RNA-mediated TLR7 activation in the lung antiviral and inflammatory responses in SARS-CoV-2-infected mice. We demonstrate that TLR7 deficiency led to a high rate of morbidity and mortality, which correlated with an impaired antiviral interferon (IFN)-I/III response, enhanced lung virus replication, and severe lung pathology. Furthermore, we show that blocking IFN-I signaling using anti-IFN receptor antibody promoted SARS-CoV-2 replication in the lungs and caused severe disease. These results provide conclusive evidence that TLR7 and IFN-I receptor deficiencies lead to severe disease in mice, replicating clinical features observed in COVID-19 patients.

Development of novel means of control for Avian Pathogenic Escherichia coli (APEC) is dependent upon robust disease models. While a few APEC models have been described in the literature for mature laying hens, there is a lack of models describing APEC infection in younger birds. We describe here two studies focused on the development of an APEC airsacculitis disease model in young pullets and pre-lay hens. In the first study, four-week-old cockerels were inoculated with one of four APEC strains at one of four doses (0, 1 × 10², 1 × 10⁴, and 1 × 10⁶ CFU/mL) and evaluated for signs of airsacculitis via post-mortem gross lesion scoring for 10 days post-inoculation. Airsacculitis scores demonstrated a difference in disease timing and incidence by strain and dose within strain. However, the majority of airsacculitis lesions were only a score of 1 demonstrating low disease severity and a potential resistance of young birds to APEC infection. In the second study, 18-week-old hens previously vaccinated against Mycoplasma gallisepticum were inoculated with a virulent APEC strain. Evaluation of airsacculitis scores at 2-, 5-, and 7-days post-inoculation revealed a consistent increase in airsacculitis incidence. While further studies are needed to fully validate and characterize these models, the current results provide valuable information on the additional needs for developing an APEC model in pullets and the potential of Mycoplasma gallisepticum vaccination with APEC infection to be a promising disease model for in pre-lay hens.

"Acute gastrointestinal disease in a young bobcat (Lynx rufus)" published on 06 Oct 2023 by American Veterinary Medical Association.

Myelolipomas are benign neoplastic lesions composed of adipose and hematopoietic tissue. Excluding dogs and cats, myelolipomas have been extensively described in the spleen of cheetahs ( Acinonyx jubatus ), the liver of Goeldi’s monkeys ( Callimico goeldii ), and birds in the order Psittaciformes . To better describe the species diversity and the clinical and pathologic relevance of myelolipomas, we conducted a detailed literature review and a retrospective multi-institutional study of myelolipomas, excluding cases diagnosed in dogs and cats. A total of 52 cases from 27 different species were diagnosed or reported (65% mammals and 35% birds) from 8 institutions. Notably, 18 of 27 (67%) of the animal species diagnosed with myelolipoma in our study lacked previous documentation in the literature. In mammals, myelolipomas were diagnosed in the spleen, liver, and adrenal gland, and less commonly in lymph nodes, mesentery, broad uterine ligament, and subcutis; most often, these proliferations were incidental findings at autopsy unrelated to animal death or euthanasia. In birds, the most frequently affected location was the liver, followed by the kidney and celom, occasionally resulting in antemortem clinical disease and adverse outcomes. Myelolipomas had clinical and pathologic relevance in 9 of 52 (17%) cases including birds and mammals. Osseous metaplasia was found within the myelolipomas in 2 of 52 (4%) cases. We conclude that myelolipomas are present in more species than previously documented and most cases are probably underreported. The clinical relevance of a myelolipoma can be determined by postmortem examination, and depends on the species affected, the anatomic location, and the size of the lesion.