Histol Histopathol (1998) 13: 181 -199 Histology and 001: 10.14670/HH-13.181 Histopathology http://www.hh.um.es From Cell Biology to Tissue Engineering Invited Review Morphological analysis of mouse hepatitis virus AS9-induced pathology with regard to viral receptor expression C. Godfraind1 and J.P. Coutelier2 1 Laboratory of Pathology, St-Luc Hospital , 2Unit of Experimental Medicine, International Institute for Cellular and Molecular Pathology, Catholic University of Louvain, Louvain, Bruxelles, Belgium Summary. Mouse hepatitis virus, strain A59 (MHV­ Introduction: viral tropism and cellular receptors A59), is a coronavirus that triggers in susceptible mice a wide vari ety of pathologies, including hepatitis, thymus T he pathogenicity induced by viral in fections results in volution, B lymphocyte po lyclonal acti vatio n a nd , from several facto rs tha t are some times diffic ult to after intra-cerebral inocul ation, transient de myelination. distinguish. Some of these factors depend on th e viral One receptor that mediates ent ry of the virus into ta rget genome. It is well documented that v irus strains th at cell s has been ide nti fied: it is a g lycoprote in of the di ffer in one of their proteins, and often only by a few or carcinoembryonic a ntigen fa mily, call ed Bgpl a. The even by a s ing le amino acid , have w ide ly di ffe re nt avail abilit y of a ntibo dies recogniz ing th is mo lecul e abilities to trigger diseases in a n infected host. In permits the analysis of its cellular expression and of the addition, factors in the host itself may de termine the relationship between receptor expression and pathology o utcome of a n infectio n. Some host facto rs c learl y induced by the vi rus. Bgpl a is fo und on epitheli al and de te rmine the efficiency of th e immune respo nse to e ndoth e li a l ce ll s as we ll as o n B ly mphocytes a nd eliminate the invading microorgani sm. Others affect the macrophages. In the li ver, Bgpla expression correlates in iti al interacti ons between th e virus and the host, and we ll with in fection of hepatocytes and endothelial cells, parti cularly, the ability of th e virus to infect host cell s. leading to the development of hepatitis. However, other A lthough considerable work remains to be done in order cells ex pressing this molecul e, such as central nervous to elucid ate the mechanisms that affect the host-v irus system endoth elial cell s, are not in fected by the virus. relationship, it is clear that viral tropism, whic h is the T hi s o bservati on m ay expla in how the blood-brain ability of a virus to in fec t partic ular cell types, is a barri er prevents d isseminati on of M HV- AS9 fro m the critical factor in viral pathogenicity. general circulati on into th e brain. Thymic atrophy results Although the encounter of a potential host cell by a fro m a poptosis of imma ture doubl e-positi ve T virus remai ns regul ated by c ha nce, the first event that ly m phocy tes w hic h mig ht be caused ind irectly by w ill determine the tropism of this v irus is usuall y its in fection of a small proportion of thymus epitheli al cells binding onto the cell. T herefore, many reports point to th at express Bgp I a rath er th an by in fection of T cells the expression of specific recepto rs, and even of co­ th at do no t express the receptor. Finall y, po lyclo nal receptors as key factors that explain at least partl y the acti va ti o n of B lym phocytes, lead ing to inc reased pathogenicit y of a pa rticular virus. However, in some secreti on of anti bodies of the IgG2a isotype, involves a c irc ums tances, v iruses m ay infect cell s tha t do no t cascade of events, including cy tokine secreti on, that may ex press recepto rs s pecificall y recognized by v iral result from the interaction of MHV-A59 with B cells and proteins. For instance, in fection of a cell that expresses macrophages th at express Bgpla. Therefore, aft er v iral no specific virus receptor may result from close contact in fec ti o n , cellul a r expressio n of Bg p la m ay have of an in fected cell with another cell type (Gall agher et d iffere nt results: ce ll lys is; a lt e ra ti o n of cellula r al. , 1992). Several viruses, w hen coated w ith anti-viral functi ons th at may lead to indirect death of other cell antibodies (Halstead and O'Rourke, 1977; Cafruny and ty pes, or resistance to in fecti on. Pl agemann, 1982; Inada and Mims, 1985; Ochiai et al. , 1988; Ro binson e t a I. , 1989) a nd/ o r comple me nt Key words: Vi ral receptor, Mouse hepatitis virus, Viral (Mo nt efio ri et al. , 1990), can infect phagocytic cells by path ogenicit y, Bili ary glycoprotein, Carcinoembryoni c binding of the antibody- or complement-coated virus to ant igen Fc receptors or to receptors to complement components on these cell s (reviewed by Halstead, 1994). However, Offprint requests to: C. Godfraind . Laboratory of Path ology, St Lu c the usual way for a virus to in fect a cell is via binding to Hospital. UCL. Av. Hippocrate 10, B-1200 Bruxelles. Belgium a specific compone nt of the cell membrane via one or 182 Mouse hepatitis virus receptor expression more viral structural proteins. (VCAM-1) for encephalomyocarditis v irus (Huber, Based on their biochemical nature, two types of virus 1994), and an as yet unidentified 34 kD molecule for receptors can be distinguished. Some of them are Theiler's virus (Kilpatrick and Lipton, 1991). Cellular carbohydrate residues and others are proteins. Examples expression of membrane cofactor protein (MCP or of carbohydrate receptors are the heparan sulfate-I ike CD46), a receptor for measles virus, is correlated with glycosaminoglycans initially bound by herpes viruses susceptibility to infection by this virus (Dbrig et £II. , including herpes simplex virus and human cyto­ 1993, 1994; Naniche et £II., 1993). Antigens of the major megalovirus (WuDunn and Spear, 1989; Kari and Gehrz, histocompatibility complex (MHC) have been 1992; Cooper, 1994), and sialic acid residues that are implicated in cellular binding of Semliki Forest virus recognized by the hemagglutinin glycoprotein of and lactate dehydrogenase-elevating virus (Helen ius et influenza viruses and by parvoviruses (Paulson et aI., aI., 1978; Inada and Mims, 1984, ] 985), although this 1979; Weis et aI., 1988). Although carbohydrate has not yet been conclusively proven (Oldstone et aI. , moieties with virus receptor activity are expressed on 1980; Buxton et aI., 1988). Alphaviruses, including many cell types and could therefore allow for a Sindbis virus and Venezuelan equine encephalitis virus widespread dissemination of the virus, some restriction apparently recognize several different receptors, one of in viral tropism results from conformational differences which is the high-affinity laminin receptor (Ubol and in the saccharidic residues or from modifications of the Griffin, 1991; Wang et £II., 1992; Strauss et aI., 1994). viral attachment protein by proteolytic cleavage, which Human coronavirus HCV-229E and transmissible is sometimes required for viral infectivity (Naeve et aI., gastroenteritis virus of swine can bind their target cells 1984; Skehel et aI., 1994; Tashiro and Rott, J 996). after recognition of amino-peptidase N (Delmas et £II. , Most viral receptors identified so far are membrane 1992; Yeager et £II., 1992, Holmes and Dveksler, 1994). proteins or glycoproteins. Interestingly, many of these Therefore, on one hand a virus may use more than viral receptors are adhesion molecules belonging to the one cellular receptor. On the other hand, some molecules immunoglobulin superfamily or to the integrin family, may act as receptors for viru ses belonging to very that are also either responsible for physiological different families. Other factors, in addition to the recognition of various cell types, or receptors for expression of a receptor expressed on the surface of funct ionally important soluble molecules of the host. potential target cells, also influence the tropism of a The restriction of the expression of specific receptors to virus. Expression of molecules in addition to the specific particular cell subpopulations may thus be an important virus receptor may be required for virus entry into the dete rminant of virus tropism. For example, human cell. Several proteins have been identified as cofactors, immunodeficiency virus (HIV-1) can infect T helper including chemokine receptors. Such cofactors also lymphocytes, monocytes and brain cells that harbour the affect the cellular tropism observed for diverse HIV-1 CD4 molecule, recognized by the viral gp120 envelope isolates (Choe et aI., 1996, Doranz et at. , 1996, Feng et glycoprotein (Dalgleish et aI., 1984; Klatzmann et aI., £II., 1996). Similarly the lymphocyte homing receptor 1984; Maddon et aI., 1986; Harrison, 1994). Other types CD44 may possibly interact with PVR to promote of membrane proteins, including transporter molecules binding of poliovirus onto cells and therefore modulate and low-density lipoprotein receptor-related proteins, viral tropism (Shepley, 1994; Shepley and Racaniello, can serve as receptors for diverse retroviruses 1994). In addition to virus receptors and co-factors, (Cunningham and Kim, 1994; Weiss, 1994; Young et aI., intracellular host factors and the immune response may 1994).