Arenavirus

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J Med Virol. Author manuscript; available in PMC 2008 October 7.
Published in final edited form as: J Med Virol. 2004 March ; 72(3): 424–435. doi:10.1002/jmv.20000.

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Mucosal Arenavirus Infection of Primates Can Protect Them From Lethal Hemorrhagic Fever
Juan D. Rodas, Igor S.Lukashevich, Juan C. Zapata, Cristiana Cairo, Ilia Tikhonov, Mahmoud Djavani, C. David Pauza, and Maria S. Salvato* Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, Maryland

Abstract
Arenaviruses are transmitted from rodents to human beings by blood or mucosal exposure. The most devastating arenavirus in terms of human disease is Lassa fever virus, causingup to 300,000 annual infections in West Africa. We used a model for Lassa fever in which Rhesus macaques were infected with a related virus, lymphocytic choriomeningitis virus (LCMV). Our goals were to determine the outcome of infection after mucosal inoculation and later lethal challenge, to characterize protective immune responses, and to test cross-protection between a virulent (LCMV-WE) and anavirulent (LCMV-ARM) strain of virus. Although intravenous infections in the monkey model were uniformly lethal, intragastric infections recapitulated the spectrum of clinical outcomes seen in human exposure to Lassa fever virus: death, recovery from disease, and most often, subclinical infection. Plaque neutralization, ELISA, lymphocyte proliferation, and chromium-release assays were used tomonitor humoral and cellular immune responses. Cross protection between the two strains was observed. The three out of seven monkeys that experienced protection were also the three with the strongest cellmediated immunity.

Keywords arenavirus; mucosal infection; primates; hemorrhagic fever; immunity

INTRODUCTION
Arenaviruses are rodent-borne pathogens that can cause lethal disease in guineapigs, primates, and human beings [Oldstone, 2002]. Numerous murine studies of viral persistence and cellmediated immunity feature the prototype arenavirus, lymphocytic choriomeningitis virus (LCMV) [Zinkernagel and Doherty, 1974; Ahmed et al., 1984; Salvato et al., 1991; Oldstone, 2002]. In contrast to murine LCMV infections, LCMV infection of Rhesus macaques can resemble Lassa hemorrhagic fever inhuman beings [Jahrling et al., 1980; Peters et al., 1987; Lukashevich et al., 2002, 2003]. This study describes the consequences of intragastric inoculation of Rhesus macaques with LCMV. Mucosal exposure accounts for a significant proportion of natural Lassa fever virus infections. Every year Lassa fever virus (LAS) infects approximately 300,000 human beings with 30% morbidity and 16% mortality[Jahrling et al., 1985; McCormick et al., 1986a, 1987; McCormick, 1990; McCormick and Fisher-Hoch, 2002]. The natural reservoir for LAS is the rat Mastomys natalensis, and the acquisition, preparation, and consumption of rodent meat is a major risk factor for rodent-to-human transmission [ter Meulen et al., 1996]. Another

*Correspondence to: Maria S. Salvato, Institute of Human Virology,University of Maryland Biotechnology Institute, 725 West Lombard St., Baltimore, MD 21201. E-mail: salvato@umbi.umd.edu.

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indication that ingestion of arenaviruses can lead to disease is that some hepatitis outbreaks in zoo-kept tamarinds and marmosets were traced to feeding with LCMV-infected mice [Montali et al., 1993, 1995]. Our experimental studies showed that mucosalinoculation leads to attenuated LCMV infection in mice [Rai et al., 1996, 1997] and in macaques [Lukashevich et al., 2002, 2003] in comparison with same-dose inoculations by the intravenous route. The WE strain of LCMV used in the present study is hepatotropic in mice, guinea pigs, and primates [Riviere et al., 1985; Zinkernagel et al., 1986; Lukashevich et al., 2002, 2003]. When inoculated...