Pathogenesis of Bolivian Hemorrhagic Fever in Guinea Pigs

Abstract

Machupo virus, the cause of Bolivian hemorrhagic fever, is a highly lethal viral hemorrhagic fever with no Food and Drug Administration-approved vaccines or therapeutics. This study evaluated the guinea pig as a model using the Machupo virusChicava strain administered via aerosol challenge. Guinea pigs (Cavia porcellus) were serially sampled to evaluate the temporal progression of infection, gross and histologic lesions, and sequential changes in serum chemistry and hematology. The incubation period was 5 to 12 days, and complete blood counts revealed leukopenia with lymphopenia and thrombocytopenia. Gross pathologic findings included congestion and hemorrhage of the gastrointestinal mucosa and serosa, noncollapsing lungs with fluid exudation, enlarged lymph nodes, and progressive pallor and friability of the liver. Histologic lesions consisted of foci of degeneration and cell death in the haired skin, liver, pancreas, adrenal glands, lymph nodes, tongue, esophagus, salivary glands, renal pelvis, small intestine, and large intestine. Lymphohistiocytic interstitial pneumonia was also present. Inflammation within the central nervous system, interpreted as nonsuppurative encephalitis, was histologically apparent approximately 16 days postexposure and was generally progressive. Macrophages in the tracheobronchial lymph node, on day 5 postexposure, were the first cells to demonstrate visible viral antigen. Viral antigen was detected throughout the lymphoid system by day 9 postexposure, followed by prominent spread within epithelial tissues and then brain. This study provides insight into the course of Machupo virus infection and supports the utility of guinea pigs as an additional animal model for vaccine and therapeutic development.

Glycoprotein-Specific Antibodies Produced by DNA Vaccination Protect Guinea Pigs from Lethal Argentine and Venezuelan Hemorrhagic Fever

“…Studies are under way to determine the cause of the attenuation. Recent studies have identified another strain of MACV, strain Chicava, to be 100% lethal in Hartley guinea pigs (55). Ongoing studies are examining the protective effect of DNA vaccinederived antibodies against strain Chicava.…”

Machupo Virus Expressing GPC of the Candid#1 Vaccine Strain of Junin Virus Is Highly Attenuated and Immunogenic

“…Our animal experiments involved the use of IFN-␣␤/␥ R Ϫ/Ϫ mice. A study in animals with an intact interferon pathway, such as guinea pigs or NHPs, as recently described (28,29), is required for the development of a safe and efficacious vaccine against MACV infection. Our study also highlights the feasibility of attenuating other highly pathogenic New World arenaviruses, such as Guanarito virus, following the same approach by introducing the GPC gene from the Cd#1 vaccine strain of JUNV.…”

Differential Immune Responses to Hemorrhagic Fever-Causing Arenaviruses

“…Neurological symptoms are common during NW arenavirus infection. This correlates with robust viral replication in neurological tissues as evidenced by high viral titers in the brains of infected animals [52,102]. MACV antigen can also be preferentially detected within neurons [52].…”

“…This correlates with robust viral replication in neurological tissues as evidenced by high viral titers in the brains of infected animals [52,102]. MACV antigen can also be preferentially detected within neurons [52]. Interestingly, treatment of AHF and BHF with convalescent serum increases the likelihood of developing a long-term neurologic syndrome [43,103].…”

“…In contrast, neutralizing antibodies that develop early in infection are critical for clearance of JUNV infection of guinea pigs [50]. MACV infection also induces a potent IFN response in NHPs [51] and guinea pigs [52]. In addition, as demonstrated during human cases of AHF, immune plasma is an effective treatment for AHF in NHPs [53].…”