Arenavirus-mediated liver pathology: acute lymphocytic choriomeningitis virus infection of rhesus macaques is characterized by high-level interleukin-6 expression and hepatocyte proliferation.
Lymphocytic choriomeningitis virus (LCMV) and Lassa virus can cause hemorrhagic fever and liver disease in primates. The WE strain of LCMV (LCMV-WE) causes a fatal Lassa fever-like disease in rhesus macaques and provides a model for arenavirus pathogenesis in humans. LCMV-WE delivered intravenously or intragastrically to rhesus macaques targets hepatocytes and induces high levels of liver enzymes, interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), and soluble tumor necrosis factor receptors (sTNFRI and -II) in plasma during acute infection. Proinflammatory cytokines TNF-alpha and IL-1beta were not detected in plasma of infected animals, but increased plasma gamma interferon was noted in fatally infected animals. Immunohistochemistry of acute liver biopsies revealed that 25 to 40% of nuclei were positive for proliferation antigen Ki-67. The increases in IL-6, sIL-6R, sTNFR, and proliferation antigen that we observe are similar to the profile of incipient liver regeneration after surgical or toxic injury (N. Fausto, Am. J. Physiol. 277:G917-G921, 1999). Although IL-6 was not directly induced by virus infection in vitro, peripheral blood mononuclear cells from acutely infected monkeys produced higher levels of IL-6 upon lipopolysaccharide stimulation than did healthy controls. Our data confirm that acute infection is associated with weak inflammatory responses in tissues and initiates a program of liver regeneration in primates.
Lukashevich
Igor S
IS
Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201, USA. lukashev@umbi.umd.edu
Tikhonov
Ilia
I
Rodas
Juan D
JD
Zapata
Juan C
JC
Yang
Yida
Y
Djavani
Mahmoud
M
Salvato
Maria S
MS
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology* / Q000473:pathology*; D002455:Cell Division; D002522:Chlorocebus aethiops; D022781:Hepatocytes / Q000473:pathology* / Q000821:virology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000097:blood; D016209:Interleukin-8 / Q000096:biosynthesis; D019394:Ki-67 Antigen / Q000032:analysis; D008217:Lymphocytic choriomeningitis virus; D008253:Macaca mulatta; D019947:Receptors, Interleukin-6 / Q000097:blood; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014709:Vero Cells
D015850:Interleukin-6; D016209:Interleukin-8; D019394:Ki-67 Antigen; D019947:Receptors, Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000410:Alanine Transaminase