Measles Virus Spread and Pathogenesis in Genetically Modified Mice

B Mrkic

J Pavlovic

T Rülicke

P Volpe

Institut für Molekularbiologie Abt. I,^{Institut für Medizinische Virologie,}^{Biologisches Zentrallabor,}^{and Institut für Neuropathologie,}^{Universität Zürich, Zürich, Switzerland, and Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110}⁴

^{Corresponding author. Mailing address: Institut für Molekularbiologie Abt. I, Universität Zürich, Winterthurerstr. 190, 55-L-34a, 8057 Zürich, Switzerland. Phone: 41-1-633 31 17. Fax: 41-1-635 68 64. E-mail:}hc.hzinu.1oiblom@oenattac.

Received 1998 Mar 2; Accepted 1998 Jun 8.

Abstract

Attenuated Edmonston measles virus (MV-Edm) is not pathogenic in standard mice. We show here that MV-Edm inoculated via the natural respiratory route has a limited propagation in the lungs of mice with a targeted mutation inactivating the alpha/beta interferon receptor. A high dose of MV-Edm administered intracerebrally is lethal for about half of these mice. To study the consequences of the availability of a high-affinity receptor for MV propagation, we generated alpha/beta interferon-defective mice expressing human CD46 with human-like tissue specificity. Intranasal infection of these mice with MV-Edm resulted in enhanced spread to the lungs and more prominent inflammatory response. Virus replication was also detected in peripheral blood mononuclear cells, the spleen, and the liver. Moreover, intracerebral inoculation of adult animals with low MV-Edm doses caused encephalitis with almost inevitably lethal outcome. We conclude that in mice alpha/beta interferon controls MV infection and that a high-affinity receptor facilitates, but is not strictly required for, MV spread and pathogenesis.

Abstract

Measles remains one of the leading causes of infant death in developing countries (40) and, in rare cases, persistent measles virus (MV) infection induces the lethal neurodegenerative disease subacute sclerosing panencephalitis (SSPE) (10, 55). Direct studies of early MV replication in humans are lacking, but experimental studies in monkeys (32, 58) and histopathological observations in humans (33) suggest local replication in the respiratory mucosa a few days after infection. MV may then spread, possibly carried in pulmonary macrophages, to draining lymph nodes and from there enter the bloodstream carried in leukocytes, disseminating first to lymphoid tissues and then to tissues throughout the body (40).

MV infection of adult rodents is restricted to brain-adapted strains inoculated intracerebrally (29). These strains have substantial changes in the sequence of the receptor binding protein hemagglutinin (H) (30), alterations which may permit more efficient MV entry into rodent cells. MV entry into mouse cells is also more efficient with expression of CD46, the receptor for the MV vaccine strain Edmonston (MV-Edm) (13, 36) and probably for several wild-type strains (51, 52, 57). However, transgenic rodents expressing CD46 are not susceptible to MV infection when inoculated by the natural respiratory route (17, 39, 56). Nevertheless, MV-Edm intracerebral inoculation of neonatal transgenic mice expressing one form of CD46 in neurons resulted in disease and death (46).

To obtain mice in which MV spread can be studied, we operated at two levels. First, knowing that alpha/beta interferon controls MV infection in cultured cells (6, 28) and may do so in patients with SSPE (15, 60), we tested whether mice with a targeted mutation inactivating the alpha/beta interferon receptor (Ifnar^{strain) (}35) are susceptible to infection with the attenuated strain MV-Edm. Indeed we observed limited MV spread after intranasal inoculation and 50% lethality after high-dose intracerebral inoculation. Second, we produced the new transgenic line CD46Ge (Ge for genomic), which, unlike previous lines (17, 46, 56), expresses CD46 with human-like tissue specificity (34, 42), and crossed it with Ifnar^{mice to obtain an Ifnar}^{-CD46Ge line. Respiratory inoculation of these mice with MV-Edm resulted in enhanced virus spread and more prominent lung tissue inflammation, and intracerebral infection was lethal at low virus doses.}

ACKNOWLEDGMENTS

We thank Lluis Montoliu for guidance in YAC transgenesis, Ulrike Müller and Michel Aguet for the Ifnar^{mice, Stefan Niewiesk for MV CAM/RBH, Pius Spielhofer for MV-P-CAT, Gudrun Christiansen and Marianne König for excellent technical assistance, Bernhard Odermatt for consultation, Adriano Fontana for comments on the manuscript, Walter Bossart and Toni Cathomen for support, and Martin Billeter for continuous support and guidance.}

This research was supported by grants from the Swiss National Science Foundation to R.C., J.P., and A. A. The salary of B.M. was contributed by the Swiss Serum and Vaccine Institute.

ACKNOWLEDGMENTS

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