Ebola virus (EBOV) causes Ebola virus disease (EVD), marked by severe hemorrhagic fever; however, the mechanisms underlying the disease remain unclear. To assess the molecular basis of EVD across time, we performed RNA sequencing on 17 tissues from a natural history study of 21 rhesus monkeys, developing new methods to characterize host-pathogen dynamics. We identified alterations in host gene expression with previously unknown tissue-specific changes, including downregulation of genes related to tissue connectivity. EBOV was widely disseminated throughout the body; using a new, broadly applicable deconvolution method, we found that viral load correlated with increased monocyte presence. Patterns of viral variation between tissues differentiated primary infections from compartmentalized infections, and several variants impacted viral fitness in a EBOV/Kikwit minigenome system, suggesting that functionally significant variants can emerge during early infection. This comprehensive portrait of host-pathogen dynamics in EVD illuminates new features of pathogenesis and establishes resources to study other emerging pathogens.

Cardiovascular disease is a major cause of morbidity in aging and in HIV-infected individuals despite efficacy of cART, and furthermore, is associated with macrophage activation and inflammation. Nonhuman primates simulate human disease, and we previously reported that distinct macrophage populations play different roles in the pathogenesis of disease during SIV infection in rhesus macaques. For example, in the lung, short-lived macrophages were more readily destroyed by SIV and contributed to AIDS pathogenesis. Long-lived alveolar macrophages on the other hand were not easily destroyed by virus and thus may contribute to a long-term virus reservoir that also promotes chronic inflammation. The present studies extend this work to characterize macrophages in heart and skeletal muscles affecting cardiomyopathy observed during SIV/HIV infection as well as in heart tissues of uninfected younger and older macaques. The results demonstrated that macrophages are distributed uniformly throughout the heart tissues in animals of all age groups. Increased percentages of macrophages, however, were observed in hearts of aged macaques with similar increased percentages of macrophages in SIV-infected younger adult macaques. Interestingly, the increased macrophages of both aged uninfected and younger SIV-infected macaques was not due to increases in the absolute numbers of macrophages but rather to decreased heart muscle cellularity. This suggested that cardiovascular disease observed in aged as well as HIV-infected individuals may be due to similar mechanisms of decreased number of heart muscle cells and dysfunctional inflammatory long-lived macrophages of the heart.

Marburg virus (MARV) is a filovirus related to Ebola virus (EBOV) associated with human hemorrhagic disease. Outbreaks are sporadic and severe, with a reported case mortality rate of upward of 88%. There is currently no antiviral or vaccine available. Given the sporadic nature of outbreaks, vaccines provide the best approach for long-term control of MARV in regions of endemicity. We have developed an inactivated rabies virus-vectored MARV vaccine (FILORAB3) to protect against Marburg virus disease. Immunogenicity studies in our labs have shown that a Th1-biased seroconversion to both rabies virus and MARV glycoproteins (GPs) is beneficial for protection in a preclinical murine model. As such, we adjuvanted FILORAB3 with glucopyranosyl lipid adjuvant (GLA), a Toll-like receptor 4 agonist, in a squalene-in-water emulsion. Across two different BALB/c mouse challenge models, we achieved 92% protection against murine-adapted Marburg virus (ma-MARV). Although our vaccine elicited strong MARV GP antibodies, it did not strongly induce neutralizing antibodies. Through both in vitro and in vivo approaches, we elucidated a critical role for NK cell-dependent antibody-mediated cellular cytotoxicity (ADCC) in vaccine-induced protection. Overall, these findings demonstrate that FILORAB3 is a promising vaccine candidate for Marburg virus disease. IMPORTANCE Marburg virus (MARV) is a virus similar to Ebola virus and also causes a hemorrhagic disease which is highly lethal. In contrast to EBOV, only a few vaccines have been developed against MARV, and researchers do not understand what kind of immune responses are required to protect from MARV. Here we show that antibodies directed against MARV after application of our vaccine protect in an animal system but fail to neutralize the virus in a widely used virus neutralization assay against MARV. This newly discovered activity needs to be considered more when analyzing MARV vaccines or infections.