Lassa virus (LASV) causes a severe, often fatal hemorrhagic disease in regions in Africa where the disease is endemic, and approximately 30% of patients develop sudden-onset sensorineural hearing loss after recovering from acute disease. The causal mechanism of hearing loss in LASV-infected patients remains elusive. Here, we report findings after closely examining the chronic disease experienced by surviving macaques assigned to LASV exposure control groups in two different studies. All nonhuman primates (NHPs) developed typical signs and symptoms of Lassa fever, and seven succumbed during the acute phase of disease. Three NHPs survived beyond the acute phase and became chronically ill but survived to the study endpoint, 45 days postexposure. All three of these survivors displayed continuous disease symptoms, and apparent hearing loss was observed using daily subjective measurements, including response to auditory stimulation and tuning fork tests. Objective measurements of profound unilateral or bilateral sensorineural hearing loss were confirmed for two of the survivors by brainstem auditory evoked response (BAER) analysis. Histologic examination of inner ear structures and other tissues revealed the presence of severe vascular lesions consistent with systemic vasculitides. These systemic immune-mediated vascular disorders have been associated with sudden hearing loss. Other vascular-specific damage was also observed to be present in many of the sampled tissues, and we were able to identify persistent virus in the perivascular tissues in the brain tissue of survivors. Serological analyses of two of the three survivors revealed the presence of autoimmune disease markers. Our findings point toward an immune-mediated etiology for Lassa fever-associated sudden-onset hearing loss and lay the foundation for developing potential therapies to prevent and/or cure Lassa fever-associated sudden-onset hearing loss. IMPORTANCE Lassa virus is one of the most common causes of viral hemorrhagic fever. A frequent, but as yet unexplained, consequence of infection with Lassa virus is acute, sudden-onset sensorineural hearing loss in one or both ears. Deafness is observed in approximately 30% of surviving Lassa fever patients, an attack rate that is approximately 300% higher than mumps virus infection, which was previously thought to be the most common cause of virus-induced deafness. Here, we provide evidence from Lassa virus-infected cynomolgus macaques implicating an immune-mediated vasculitis syndrome underlying the pathology of Lassa fever-associated deafness. These findings could change the way human Lassa fever patients are medically managed in order to prevent deafness by including diagnostic monitoring of human survivors for onset of vasculitides via available imaging methods and/or other diagnostic markers of immune-mediated vascular disease.

Lassa virus (LASV) is an ambisense RNA virus in the Arenaviridae family and is the etiological agent of Lassa fever, a severe hemorrhagic disease endemic to West and Central Africa.1,2 There are no US Food and Drug Administration (FDA)-licensed vaccines available to prevent Lassa fever.1,2 in our previous studies, we developed a gene-optimized DNA vaccine that encodes the glycoprotein precursor gene of LASV (Josiah strain) and demonstrated that 3 vaccinations accompanied by dermal electroporation protected guinea pigs from LASV-associated illness and death. Here, we describe an initial efficacy experiment in cynomolgus macaque nonhuman primates (NHPs) in which we followed an identical 3-dose vaccine schedule that was successful in guinea pigs, and a follow-on experiment in which we used an accelerated vaccination strategy consisting of 2 administrations, spaced 4 weeks apart. In both studies, all of the LASV DNA-vaccinated NHPs survived challenge and none of them had measureable, sustained viremia or displayed weight loss or other disease signs post-exposure. Three of 10 mock-vaccinates survived exposure to LASV, but all of them became acutely ill post-exposure and remained chronically ill to the study end point (45 d post-exposure). Two of the 3 survivors experienced sensorineural hearing loss (described elsewhere). These results clearly demonstrate that the LASV DNA vaccine combined with dermal electroporation is a highly effective candidate for eventual use in humans.

ABSTRACTBurkholderia pseudomallei, the causative agent of melioidosis, is recognized as a serious health threat due to its involvement in septic and pulmonary infections in areas of endemicity and is recognized by the Centers for Disease Control and Prevention as a category B biothreat agent. An animal model is desirable to evaluate the pathogenesis of melioidosis and medical countermeasures. A model system that represents human melioidosis infections is essential in this process. A group of 10 rhesus macaques (RMs) and 10 African green monkeys (AGMs) was exposed to aerosolizedB. pseudomallei1026b. The first clinical signs were fever developing 24 to 40 h postexposure followed by leukocytosis resulting from a high percentage of neutrophils. Dyspnea manifested 2 to 4 days postexposure. In the AGMs, an increase in interleukin 1β (IL-1β), IL-6, IL-8, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α) was observed. In the RMs, IL-1β, IL-6, and TNF-α increased. All the RMs and AGMs had various degrees of bronchopneumonia, with inflammation consisting of numerous neutrophils and a moderate number of macrophages. Both the RMs and the AGMs appear to develop a melioidosis infection that closely resembles that seen in acute human melioidosis. However, for an evaluation of medical countermeasures, AGMs appear to be a more appropriate model.

Abstract. Feline peripheral nerve sheath tumors are uncommonly reported, and their clinical behavior has not been well documented. Fifty-nine peripheral nerve sheath tumors were collected from 53 cats. All of the tumors involved skin, subcutis, skeletal muscle, and/or mucous membranes. Histologically, the tumors were composed of compact to loosely arranged streams and fascicles of spindled cells with eosinophilic, often wavy cytoplasmic processes; small to occasionally moderate amounts of collagenous to myxoid matrix; and nuclear palisading. Immunohistochemically, all tumors were positive for vimentin and S-100 protein, 44 of 59 were positive for glial fibrillary acidic protein (GFAP), and all were negative for muscle specific actin. The tumors fell into 3 histologic categories: 34 benign tumors with Antoni A areas that were S-100 protein and GFAP positive, 9 benign tumors that lacked Antoni A areas and were S-100 protein positive and GFAP negative, and 16 tumors with features of malignancy. Seventy-five percent of these cases involved the head, neck, or limbs. Recurrent tumors were submitted or tumors were reported to have recurred in 9 cases. Tumor recurrence was reported for all 3 of the histologic subtypes. None was documented as having metastasized.

A 7-year-old warmblood mare was referred because of a respiratory tract disorder; pulmonary granular cell tumor was diagnosed. Pulmonary granular cell tumor is a locally invasive but rare type of tumor with low metastatic potential. The entire right lung was resected to ensure removal of all neoplastic tissue. The horse recovered well and has minimal difficulties functioning with one lung. Most of these tumors are diagnosed during postmortem examination. To our knowledge, this is the first report of pulmonary granular cell tumor treated by complete lung resection in a horse.