UTMB Department of Pathology

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Arenavirus Pathogenesis

Arenaviruses are single-stranded RNA viruses with bipartitite ambisense genomes; the small RNA segment (S) encodes viral glycoproteins and nucleoprotein, and the large RNA segment (L) encodes the RNA-dependent RNA polymerase and a small zinc binding protein of uncertain function. Arenaviruses are the causative agents of a group of rodent-borne human hemorrhagic fevers, including Lassa fever, Argentine hemorrhagic fever, Bolivian hemorrhagic fever, Venezuelan hemorrhagic fever, and likely other as yet undefined diseases. Very little is known about the mechanisms by which these viruses cause severe disease in humans. In order to study pathogenesis of arenavirus disease, my laboratory has been using the Pichinde (PIC) virus-guinea pig model for Lassa fever, which represents the safest, most convenient, and most accurate animal model for any viral hemorrhagic fever.

This model is based on the New World arenavirus Pichinde (PIC), which is non-pathogenic for humans, but becomes extremely pathogenic in guinea pigs after serial passage in that host. The passaged, virulent Pichinde virus variant (P18) possesses virologic and pathologic features that are strikingly similar to those described in the West African human hemorrhagic fever, Lassa fever. We have been using the low passage, attenuated virus (P2) in concert with the virulent P18 to delineate protective vs. pathogenic mechanisms in vivo, as well as viral molecular determinants of virulence. Viral sequence analysis and reassortment genetics indicate that genes othe viral S segment (envelope glycoprotein precursor and nucleoprotein genes) are critical for guinea pig virulence and an expanded pattern of tropism characteristic of experimental P18 infection. Current and future studies will concentrate on effects of specific envelope glycoprotein mutations on viral binding and entry into host cells, and on cell-cell spread of virus.

Because pro-inflammatory cytokines such as tumor necrosis factor and interleukin-8 are likely to play an important role in the pathogenesis of arenavirus hemorrhagic fevers, we are strategically targeting the transcription factors NFB and AP-1 as a means to modulate cytokine expression and diminish pathology in the PIC model. In a major multidisciplinary research collaboration between virologists, molecular biologists, and structural biologists, dithio-substituted oligonucleotide aptamers which can specifically bind and block activation of NF-kB or AP-1 family transcription factors are being selected from combinatorial libraries. After in vitro characterization of their specificity and binding properties, candidate aptamers are being tested in the guinea pig Pichinde model for their ability to ameliorate arenavirus disease.

A candidate anti-AP-1 thioaptamer is showing particular promise in this model. This thioaptamer binds specific AP-1 family dimers which function as inhibitors of transcription. When administered to guinea pigs soon after infection, this aptamer reduces mortality by 50% in P18 infected guinea pigs in the absence of specific antiviral therapy. This improved survival is accompanied by early boosting of TNF- expression in peripheral blood leukocytes of treated animals. Further studies are ongoing to optimize this promising agent, improve delivery methods, and test in BSL-4 animal models of Lassa fever and potentially other hemorrhagic fevers. This work has been done in collaboration with Norbert Herzog, David Gorenstein, the late Robert Shope, and others.

In concert with these studies, we have recently developed real-time RT-PCR assays for a panel of guinea pig cytokines, including several macrophage-derived cytokines involved in innate immunity. Detailed characterization of cytokine responses in tissues from infected animals and cell culture infections with attenuated vs. virulent Pichinde variants is ongoing. Results from these studies will provide important information with regard to early protective and pathogenic mechanisms in arenavirus hemorrhagic fevers.

1. Granwehr BP, Lillibridge KM, Higgs, S, Mason PW, ARONSON JF, Campbell GA, Barrett ADT. West Nile virus: Where are we now? The Lancet Infectious Diseases 4: 1-10 (2004)
2. Paessler S, Aguilar P, Anishchenko M, Want HQ, ARONSON J, Campbell G, Cararra A, and Weaver SC. The golden hamster as an animal model for eastern equine encephalitis virus-induced vasculitis/encephalitis and its use in studies of virus entrance into the brain. Journal of Infectious Diseases 189(11): 2072-6 (2004)
3. Smith MB, Molina CM, Schnadig VJ, Boyars MC, ARONSON J. Pathologic Features Of Mycobacterium Kansasii Infection In Patients With The Acquired Immune Deficiency Syndrome (AIDS) Arch Pathol Lab Med 127:554-560 (2003)
4. Gonzalez-Salazar D, Estrada-Franco JG, ARONSON JF, Weaver SC. Equine Amplification And Virulence Of Subtype IE Venezuelan Equine Encephalitis Viruses Isolated During The 1993 And 1996 Mexican Epizootics. Emerging Infectious Diseases 9(2): 161-8 (2003)
5. Yang XB, Li X, Prow TW, Reece LM, Bassett SE, Luxon BA, Herzog NK, ARONSON J, Shope RE, Leary JF, and Gorenstein DG. Immunofluorescence assay and flow-cytometry selection of bead-bound aptamers. Nucl Acids Res 31(10): E54 (2003)
6. Fennewald SM, ARONSON JF, Zhang L, Herzog NK. Alterations in NF-B and RBP-J by arenavirus infection of macrophages in vitro and in vivo. J Virol, 76(3):1154-1162 (2002)
7. Lele SM, Milazzo ML, Graves K, ARONSON JF, West AB, Fulhorst CF. Pathology of Whitewater Arroyo viral infection in Neotoma albigula (white-throated woodrat). Journal of Comparative Pathology, 128(4): 289-92 (2002.)
8. Zhang L, Marriott KA, Harnish DG, ARONSON JF. Reassortant analysis of guinea pig virulence of Pichinde virus variants. Virology, 290(1): 30-38 (2001)
9. ARONSON JF, Grieder FB, Davis NL, Charles PC, Knott T, Brown K, Johnston RE. A single-site mutant and revertants arising in vivo define early steps in the pathogenesis of Venezuelan equine encephalitis virus. Virology 270:111-123, 2000
10. Ahmed AE, ARONSON J, Jacob S: Induction of oxidative stress and TNF-alpha secretion by dichloracetonitrile; a water disinfectant by-product, as possible mediators of apoptosis or necrosis in a murine macrophage cell line (RAW). Toxicol in vitro. 14(3):199-210, 2000
11. Atchison CR, West, AB, Balakumaran A, Hargus SJ, Pohl LR, Daiker DH, ARONSON JF, Hoffman WE, Shipp BK, and Moslen MT. Drug-enterocyte adducts: Possible causal factor for diclofenac enteropathy in rats. Gastroenterology 119:1537-1547 (2000)
12. Yang X-B, Fennewald S, Luxon BA, ARONSON JF, Herzog NK and Gorenstein DG. Aptamers containing thymidine 3’-0-phosphorodithioates: Synthesis and Binding to Nuclear Factor–B. Bioorg Med Chem Lett 9:3357-3362, 1999
13. Zhang L, Marriott K, ARONSON JF. Sequence analysis of the small RNA segment of guinea-pig passaged Pichinde virus variants. Am J Trop Med Hyg 61: 220-225, 1999
14. Trgovich J, ARONSON JF, Eldridge JC, Johnston RE. TNF, interferon and stress response induction as a function of age-related susceptibility to fatal Sindbis virus infection of mice. Virology 263:339-48, 1999
15. Wolf DA, ARONSON JF, Rajaraman S, Veasey SP. Wischnewski ulcers and acute pancreatitis in two hospitalized patients with cirrhosis, portal vein thrombosis, and hypothermia. J Forensic Sci 44:1082-5, 1999
16. Haubold EM, ARONSON JF, Cowan DF, McGinnis MR, Cooper Jr.CR. Isolation of fungal rDNA from bottlenose dolphin skin infected with Loboa loboi. Med Mycol 36:263-7, 1998
17. Trgovcich J, Ryman K, Extrom P, Eldridge JC, ARONSON JF, Johnston RE. Sindbis virus infection of neonatal mice results in a severe stress response. Virology 227:234-238, 1997
18. Kaphalia BS, Khan MF, Carroll RM, ARONSON, JF, Ansari GAS. Subchronic toxicity of 2-chloroethanol and 2-bromoethanol in rats. Res Comm Pharmacol Toxicol, 1:173-186, 1996
19. Trgovcich J, ARONSON JF, Johnston RE. Fatal Sindbis virus infection of neonatal mice in the absence of encephalitis. Virology 224:73-83, 1996
20. ARONSON JF, Herzog NK, Jerrells TR. Tumor necrosis factor plays a role in the pathogenesis of guinea pig arenavirus disease. Am J Trop Med Hyg 52:262-269, 1995
21. Grieder FB, Davis NL, ARONSON JF, Charles PC, Sellon DC, Suzuki K, Johnston RE. Specific restrictions in the progression of Venezuelan equine encephalitis virus induced disease resulting from single amino acid changes in the glycoproteins. J Virol 206:994-1006, 1995
22. ARONSON JF, Herzog NK, Jerrells TR. Pathological and virological features of arenavirus disease in guinea pigs: Comparison of two Pichinde virus strains. Am J Pathol 145: 228 235, 1994
23. Dumler JS, Brouqui P, ARONSON JF, Taylor J, Walker DH. Identification of Ehrlichia in human tissue. NEJM 325:1109-1110, 1991
24. Richards R, ARONSON JF, Schoenbechler M, Diggs C, Alving, C. Antibodies reactive with liposomal phospholipids are produced during experimental Trypanosoma rhodesiense infection in rabbit. J Immunol 130:1390, 1983.

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