The oligoadenylate-synthetase (Oas) gene locus provides innate immune resistance to virus infection. In mouse models, variation in the Oas1b gene influences host susceptibility to flavivirus infection. However, the impact of Oas variation on overall innate immune programming and global gene expression among tissues and in different genetic backgrounds has not been defined. We examined how Oas1b acts in spleen and brain tissue to limit West Nile virus (WNV) susceptibility and disease across a range of genetic backgrounds. The laboratory founder strains of the mouse Collaborative Cross (CC) (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, and NZO/HlLtJ) all encode a truncated, defective Oas1b, whereas the three wild-derived inbred founder strains (CAST/EiJ, PWK/PhJ, and WSB/EiJ) encode a full-length OAS1B protein. We assessed disease profiles and transcriptional signatures of F1 hybrids derived from these founder strains. F1 hybrids included wild-type Oas1b (F/F), homozygous null Oas1b (N/N), and heterozygous offspring of both parental combinations (F/N and N/F). These mice were challenged with WNV, and brain and spleen samples were harvested for global gene expression analysis. We found that the Oas1b haplotype played a role in WNV susceptibility and disease metrics, but the presence of a functional Oas1b allele in heterozygous offspring did not absolutely predict protection against disease. Our results indicate that Oas1b status as wild-type or truncated, and overall Oas1b gene dosage, link with novel innate immune gene signatures that impact specific biological pathways for the control of flavivirus infection and immunity through both Oas1b-dependent and independent processes.
BackgroundThe 2009 pandemic H1N1 influenza virus emerged in swine and quickly became a major global health threat. In mouse, non human primate, and swine infection models, the pH1N1 virus efficiently replicates in the lung and induces pro-inflammatory host responses; however, whether similar or different cellular pathways were impacted by pH1N1 virus across independent infection models remains to be further defined. To address this we have performed a comparative transcriptomic analysis of acute phase responses to a single pH1N1 influenza virus, A/California/04/2009 (CA04), in the lung of mice, macaques and swine.ResultsDespite similarities in the clinical course, we observed differences in inflammatory molecules elicited, and the kinetics of their gene expression changes across all three species. We found genes associated with the retinoid X receptor (RXR) signaling pathway known to control pro-inflammatory and metabolic processes that were differentially regulated during infection in each species, though the heterodimeric RXR partner, pathway associated signaling molecules, and gene expression patterns varied among the three species.ConclusionsBy comparing transcriptional changes in the context of clinical and virological measures, we identified differences in the host transcriptional response to pH1N1 virus across independent models of acute infection. Antiviral resistance and the emergence of new influenza viruses have placed more focus on developing drugs that target the immune system. Underlying overt clinical disease are molecular events that suggest therapeutic targets identified in one host may not be appropriate in another.
A 32-year old Filipino woman presented with a 3-year history of slowly enlarging left hemimandibular mass with no associated symptoms. Previous biopsy showed ameloblastoma. Imaging revealed a translucent mulitloculated mass with ill-defined borders. (Figure 1) On examination, the mass was irregularly shaped, measures 40 x 39 cm, slightly hyperpigmented and erythematous, warm with visible vessels. The patient underwent left segmental mandibulectomy with reconstruction and the specimen was sent for histopathologic evaluation. Received was a mandibulectomy specimen weighing 1850 grams and measuring 17 x 14.5 x 14 cm. The body, angle, ramus and condyles of the left hemimandible are no longer identifiable grossly. There are ten teeth attached. Cut sections show multiple cystic spaces which measure from 0.8 to 15.0 cm in widest diameter, filled with abundant red-brown necrotic debris and yellow-brown purulent material. The mass has a grey-tan soft to fibrous cut surface with focal gritty areas. (Figure 2) Microscopic examination shows a biphasic neoplasm composed of benign epithelial and malignant mesenchymal components. (Figure 3) The benign epithelial component is arranged in islands and strands with peripheral palisading, composed of bland cells without atypia. (Figure 4) The abundant mesenchymal component is composed of spindle cells in fascicles. The cells are moderately pleomorphic with enlarged hyperchromatic nuclei, prominent nucleoli, coarse chromatin and scant cytoplasm. The cells are suspended within loose stroma with variable degree of cellularity. Some mitoses are noted. (Figure 5) Ameloblastic fibrosarcoma (AFS) belongs to a group of odontogenic sarcomas in which the epithelial component is cytologically benign while the ectomesenchymal component shows malignant features. The AFS is the most common type among the odontogenic sarcomas. It is regarded as the malignant counterpart of ameloblastic fibroma (AF). Although most cases arise de novo, the documentation of a prior or pre-existing precursor lesion from ameloblastic fibroma suggests otherwise.1,2 A study by Kobayashi et al. suggested that up to one-third of AFS arise from AF while a review of literature by Lai et al. demonstrated that 51% of AFS had previously documented AF at the same site, providing supporting evidence of a malignant transformation.3 Ameloblastic fibrosarcoma has a reported age range of 3 - 89 years, with overall mean patient age of 27.3 years. In cases of prior diagnosis of AF, AFS can occur at a mean patient age of 33 years whereas a mean patient age of 23 years where no prior diagnosis of AF was documented.1,4 It mainly affects males in the third or fourth decade of life and the posterior mandible is the most commonly affected site, with ratio of mandibular to maxillary incidence of 4:1.1,3,4 The clinical presentation is usually that of a painful, enlarging mass and most lesions are radiographically translucent and multiloculated with ill-defined borders.2,4 The histologic features of AFS reveal a mixture of benign odontogenic epithelium ranging from budding and branching cords to large islands composed of columnar or cuboidal peripheral cells arranged in palisading pattern, and an abundant malignant mesenchymal component showing marked cellularity, nuclear pleomorphism, and moderate mitotic figures.1,2,3 Ameloblastic fibroma differs from AFS by having no malignant component and immunohistochemical stains have been suggested to provide distinction, particularly when identifying a low-grade fibrosarcoma. The malignant component of AFS will show positivity in p53 and PCNA and will have a higher Ki-67 expression than AF.3,4 Although AFS are low to intermediate-grade sarcomas, a high incidence of recurrence is reported - about one third of patients experience recurrence and overall mortality rate is 25%. However, only less than 5% of cases with metastases have been reported.1,3 Long term follow up is thus indicated. References Wright JM. Odontogenic Sarcomas. In: El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ, editors. WHO Classification of Head and Neck Tumours, WHO Classification of Tumours, 4th Edition, Volume 9. Lyon: International Agency for Research on Cancer IARC; 2017, p. 214. Servato JPS, De Faria PR, Ribeiro CV, Cardoso SV, Dias FL, Eisenberg ALA, Loyola AM. Ameloblastic fibrosarcoma: a case report and literature review. Braz Dent J 2017 Mar-Apr; 28(2):262-272. DOI: 1590/0103-6440201701050 PMID: 28492759 Loya-Solis A. Gonzalez-Colunga KJ, Perez-Rodriguez CM, Ramirez-Ochoa NS, Cecenas-Falcon L, Barboza-Quintana O. Ameloblastic fibrosarcoma of the mandible: a case report and brief review of the literature. Case Rep Pathol. 2015;2015:245026. Epub 2015 Mar 10 DOI: 1155/2015/245026 PMID: 25861504 PMCID: PMC4377457 Al Shetawi AH, Alpert EH, Buchbinder D, Urken ML. Ameloblastic fibrosarcoma of the mandible: a case report and a review of the literature. J Oral Maxillofac Surg 2015 Aug;73(8):1661.e1-7. Epub 2015 Apr 10. DOI: 1016/j.joms.2015.03.066 PMID: 25921823
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