Pathology of Experimental Machupo Virus Infection, Chicava Strain, in Cynomolgus Macaques (Macaca fascicularis) by Intramuscular and Aerosol Exposure

Abstract

Machupo virus, the causative agent of Bolivian hemorrhagic fever (BHF), is a highly lethal viral hemorrhagic fever of which little is known and for which no Food and Drug Administration-approved vaccines or therapeutics are available. This study evaluated the cynomolgus macaque as an animal model using the Machupo virus, Chicava strain, via intramuscular and aerosol challenge. The incubation period was 6 to 10 days with initial signs of depression, anorexia, diarrhea, mild fever, and a petechial skin rash. These were often followed by neurologic signs and death within an average of 18 days. Complete blood counts revealed leukopenia as well as marked thrombocytopenia. Serum chemistry values identified a decrease in total protein, marked increases in alanine aminotransferase and aspartate aminotransferase, and moderate increases in alkaline phosphatase. Gross pathology findings included a macular rash extending across the axillary and inguinal regions beginning at approximately 10 days postexposure as well as enlarged lymph nodes and spleen, enlarged and friable liver, and sporadic hemorrhages along the gastrointestinal mucosa and serosa. Histologic lesions consisted of foci of degeneration and necrosis/apoptosis in the haired skin, liver, pancreas, adrenal glands, lymph nodes, tongue, esophagus, salivary glands, stomach, small intestine, and large intestine. Lymphohistiocytic interstitial pneumonia was also present. Inflammation within the central nervous system (nonsuppurative encephalitis) was histologically apparent approximately 16 days postexposure and was generally progressive. This study provides insight into the course of Machupo virus infection in cynomolgus macaques and supports the usefulness of cynomolgus macaques as a viable model of human Machupo virus infection.

Pathogenesis of Bolivian Hemorrhagic Fever in Guinea Pigs

“…The pattern of infection, subsequent inflammation, and resultant clinical signs of MACV infection in guinea pigs is very similar to the disease course previously reported in macaques. 3 Given the reported progression of clinical signs and symptoms in humans, 22 we believe that the course of disease is very similar in humans, guinea pigs in this study, and macaques in previous studies. In patients with MACV infection, initial signs include fever, lethargy, and anorexia, and these initial signs of infection are also observed in the guinea pig model.…”

“…Appearance of neurologic signs correlates temporally with lesion development; the progression from initial illness to neurologic disease in guinea pigs mirrors the disease course seen in nonhuman primates and humans. 3,22 Guinea pigs that were exposed parenterally or via aerosol had clinical signs of respiratory difficulty, and this was in contrast to nonhuman primates, with only those aerosol exposed having noticeable respiratory distress. 3 These observations were subjective and performed in the challenging biosafety level 4 environment, so future studies should continue to assess these clinical findings for corroborative evidence.…”

“…Further studies with this animal model could be used under the Food and Drug Administration's Animal Rule to develop countermeasures against BHF resulting from outbreaks, laboratory accidents, or intentional exposure as a biowarfare or biothreat agent. Approval of medical countermeasures against diseases that must use the Food and Drug Administration's Animal Rule may be required to demonstrate proof of efficacy in more than 1 animal model, and this model, in combination with the nonhuman primate model, 3 is a platform for such testing. Previous MACV studies performed at the USAMRIID and elsewhere used the Caravallo strain.…”

“…Similar findings have been reported in both human and macaque cases in the literature. 3,8,28 In situ hybridization was not performed but would be useful as a confirmatory test to rule out confounding factors such as background/nonspecific staining and to identify infected cell types with an even higher degree of confidence. It appears that the MACV causes destruction of some select lymphoid cells in the cortex with a concomitant hyperplastic response in paracortical regions in guinea pigs.…”

“…9). 3 From day 13 postexposure, there was also lymphohistiocytic inflammation in the heart, which remained generally minimal to mild throughout the course of the study. The inflammation occasionally involved the endocardium, myocardium, pericardium, or a combination of the 3 with multifocal mild myocardial degeneration and necrosis.…”