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Ebola virus disease (EVD) is a serious global health concern because case fatality rates are approximately 50% due to recent widespread outbreaks in Africa. Well-defined nonhuman primate (NHP) models for different routes of Ebola virus exposure are needed to test the efficacy of candidate countermeasures. In this natural history study, four rhesus macaques were challenged via aerosol with a target titer of 1000 plaque-forming units per milliliter of Ebola virus. The course of disease was split into the following stages for descriptive purposes: subclinical, clinical, and decompensated. During the subclinical stage, high levels of venous partial pressure of carbon dioxide led to respiratory acidemia in three of four of the NHPs, and all developed lymphopenia. During the clinical stage, all animals had fever, viremia, and respiratory alkalosis. The decompensatory stage involved coagulopathy, cytokine storm, and liver and renal injury. These events were followed by hypotension, elevated lactate, metabolic acidemia, shock and mortality similar to historic intramuscular challenge studies. Viral loads in the lungs of aerosol-exposed animals were not distinctly different compared to previous intramuscularly challenged studies. Differences in the aerosol model, compared to intramuscular model, include an extended subclinical stage, shortened clinical stage, and general decompensated stage. Therefore, the shortened timeframe for clinical detection of the aerosol-induced disease can impair timely therapeutic administration. In summary, this nonhuman primate model of aerosol-induced EVD characterizes early disease markers and additional details to enable countermeasure development.

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) 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.

Burkholderia mallei is a Gram-negative bacillus that causes a pneumonic disease known as glanders in equids and humans, and a lymphatic infection known as farcy, primarily in equids. With the potential to infect humans by the respiratory route, aerosol exposure can result in severe, occasionally fatal, pneumonia. Today, glanders infections in humans are rare, likely due to less frequent contact with infected equids than in the past. Acutely ill humans often have non-specific clinical signs and in order to diagnose cases, especially in scenarios of multiple cases in an unexpected setting, rapid diagnostics for B. mallei may be critical. The pathogenesis of acute glanders in the rhesus macaque (Macaca mulatta) was studied as an initial effort to improve diagnostic methods. In the study described here, the diagnostic techniques of PCR, culture and histopathology were compared. The results indicated that PCR may provide rapid, non-invasive diagnosis of glanders in some cases. As expected, PCR results were positive in lung tissue in 11/12 acutely infected rhesus macaques, but more importantly in terms of diagnostic algorithm development, PCR results were frequently positive in non-invasive samples such as broncho-alveolar lavage or nasal swabs (7/12) and occasionally in blood (3/12). However, conventional bacterial culture failed to recover bacteria in many of these samples. The study showed that the clinical presentation of aerosol-exposed rhesus macaques is similar to descriptions of human glanders and that PCR has potential for rapid diagnosis of outbreaks, if not individual cases.

Burkholderia 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 aerosolized B. pseudomallei 1026b. 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.