SUMMARY:Cynomolgus monkeys (Macaca fascicularis) were exposed by fine-particle aerosol to lethal doses of monkeypox virus, Zaire strain. Death, attributable to fibrinonecrotic bronchopneumonia, occurred 9 to 17 days postexposure. Lower airway epithelium served as the principal target for primary infection. The relative degree of involvement among lymphoid tissues suggested that tonsil, mediastinal, and mandibular lymph nodes were also infected early in the course of the disease, and may have served as additional, although subordinate, sites of primary replication. The distribution of lesions was consistent with lymphatogenous spread to the mediastinal lymph nodes and systemic dissemination of the virus through a monocytic cell-associated viremia. This resulted in lesions affecting other lymph nodes, the thymus, spleen, skin, oral mucosa, gastrointestinal tract, and reproductive system. The mononuclear phagocyte/dendritic cell system was the principal target within lymphoid tissues and may also have provided the means of entry into other systemic sites. Hepatic involvement was uncommon. Lesions at all affected sites were characterized morphologically as necrotizing. Terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining of select lesions suggested that cell death within lymphoid and epithelial tissues was due in large part to apoptosis. Skin and mucosal surfaces of the respiratory and gastrointestinal tracts also exhibited variable proliferation of epithelial cells and subjacent fibroblasts. Epithelial intracytoplasmic inclusion bodies, consistent with Guarnieri bodies, were usually inconspicuous by light microscopy, but when present, were most readily apparent in the stratified squamous epithelium of the oral mucosa and epidermis. Multinucleated syncytial cells were also occasionally observed in the stratified squamous epithelium of the tongue, tonsil, and skin, and in the intestinal mucosa. Monkeypox virus antigen was readily demonstrated by immunohistochemistry using anti-vaccinia mouse polyclonal antibodies as well as anti-monkeypox rabbit polyclonal antibodies. Detectable poxviral antigen was limited to sites exhibiting obvious morphologic involvement and was most prominent within epithelial cells, macrophages, dendritic cells, and fibroblasts of affected tissues. The presence of poxviral antigen, as determined by immunohistochemistry, correlated with ultrastructural identification of replicating virus. Concurrent bacterial septicemia, present in one monkey, was associated with increased dissemination of the virus to the liver, spleen, and bone marrow and resulted in a more rapidly fatal clinical course. (Lab Invest 2001, 81:1581-1600.

A passive immunization strategy for treating Ebola virus infections was evaluated using BALB/ c mice, strain 13 guinea pigs, and cynomolgus monkeys. Guinea pigs were completely protected by injection of hyperimmune equine IgG when treatment was initiated early but not after viremia had developed. In contrast, mice were incompletely protected even when treatment was initiated on day 0, the day of virus inoculation. In monkeys treated with one dose of IgG on day 0, onset of illness and viremia was delayed, but all treated animals died. A second dose of IgG on day 5 had no additional beneficial effect. Pretreatment of monkeys delayed onset of viremia and delayed death several additional days. Interferon-alpha2b (2 x 10(7) IU/kg/day) had a similar effect in monkeys, delaying viremia and death by only several days. Effective treatment of Ebola infections may require a combination of drugs that inhibit viral replication in monocyte/macrophage-like cells while reversing the pathologic effects (e.g., coagulopathy) consequent to this replication.

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The survival of 7 of 8 patients with Ebola virus (EBOV) infection after transfusions of convalescent-phase blood during a 1995 outbreak of EBOV infection is frequently cited as evidence that passive immunotherapy is a viable treatment option. To test whether whole-blood transfusions were more efficacious than passively administered immunoglobulins or monoclonal antibodies, we transfused convalescent-phase blood from EBOV-immune monkeys into naive animals shortly after challenge with EBOV. Although passively acquired antibody titers comparable to those associated with effective vaccination were obtained, all monkeys that had received transfusions succumbed to infection concurrently with control monkeys. These data cast further doubt on the value of passive immunotherapy for the treatment of EBOV infection.

A complex biological system is often required to study the myriad of host-pathogen interactions associated with infectious diseases, especially since the current basis of biology has reached the molecular level. The use of animal models is important for understanding the very complex temporal relationships that occur in infectious disease involving the body, its neuroendocrine and immune systems and the infectious organism. Because of these complex interactions, the choice of animal model must be a thoughtful and clearly defined process in order to provide relevant, translatable scientific data and to ensure the most beneficial use of the animals. While many animals respond similarly to humans from physiological, pathological, and therapeutic perspectives, there are also significant species-by-species differences. A well- of animal models available to researchers. In certain cases, such as for new or emerging diseases for which human data are not available, the animal model is crucial for understanding the pathogenesis of the disease before the development of vaccines or therapeutics can even be considered. Beyond that, a well-designed animal model provides a sound basis for supporting good science and ensuring the most beneficial use of both animal and human resources. Animal models play an especially important role in infectious disease research because in many cases, the resultant disease is potentially lethal or permanently disabling and therefore does not readily lend itself to research using human subjects. Animal models are essential for scientific advancement in many areas of human health, but if they are not well characterized and understood, erroneous conclusions may be drawn, hindering scientific advancement and resulting in a waste of animal life. A well-designed animal model requires a thorough understanding of similarities and differences in theThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

A mouse lacking CD28, a T-cell costimulatory molecule, and STAT6, a transcription factor that mediates interleukin-4 (IL-4) signaling, was developed from parental CD28-and STAT6-deficient mice. STAT6/CD28 ؊/؊ BALB/c mice that were 8 weeks old had a normal phenotype, and IL-4 production was induced following infection with nematode parasites. Unexpectedly, when they were between 4 and 8 months old, all mice examined spontaneously developed severe chronic dermatitis associated with pronounced numbers of Demodex ectoparasites. In addition, pronounced CD4 and CD8 T-cell infiltrates in the dermis and subcutaneous fat, increased serum immunoglobulin G2a levels, and lymphadenopathy associated with increased gamma interferon and IL-12 expression were observed. Single-knockout siblings lacking either CD28 or STAT6 had a phenotype similar to that of BALB/c wild-type controls. To distinguish whether the ectoparasite Demodex or the Th1 immunity was the proximal cause of the inflammatory skin disease, STAT6/CD28 ؊/؊ mice were treated with a miticide that eliminated the ectoparasites. This treatment markedly reduced the severity of the dermatitis and the associated lymphoid infiltrates. These findings suggest that ubiquitous ectoparasites, which are generally considered to be commensal, may contribute to disease when specific molecules required for an effective Th2 response are blocked.

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