Chapter 4 Receptor Interactions, Tropism, and Mechanisms Involved in Morbillivirus‐Induced Immunomodulation

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Abstract

Induction of immunomodulation and ‐suppression is a common feature of morbilliviruses such as measles virus (MV), rinderpest virus (RPV), and canine distemper virus (CDV) in their respective hosts. As major uptake receptor, signaling lymphocytic activation molecule (SLAM, CD150) essentially determines their tropism for immune cells, which is of considerable importance with regard to immunosuppression and the systemic spread to organs including secondary lymphoid organs, the skin, the respiratory tract, and the brain. Independent of their ability to enhance virus uptake in specialized host cells, other cell surface receptors such as the substance P receptor, DC‐SIGN, Toll‐like receptors (TLR), Fc‐gamma receptor II (FcγRII), CD46, and additional uncharacterized receptors exert a variety of immunomodulatory effects as reflected by activation of or interference with viability, differentiation, trafficking, or acquisition of effector functions of specialized immune cells. In this review, we discuss receptor interactions, tropism, and mechanisms involved in the severe, transient immunosuppression induced by MV and other morbilliviruses.

Introduction

Morbilliviruses are members of the paramyxoviridae which have a negative‐stranded RNA genome encoding for six structural and two nonstructural proteins (Fig. 1). Functionally, morbilliviral structural proteins can be grouped into those essential for replication of the genome [the nucleocapsid (N) protein and the polymerase complex consisting of the large polymerase protein (L) and its cofactor, the phosphoprotein (P)] forming the ribonucleoprotein particle (RNP) complex, and those associated with the viral lipid bilayer membrane [the fusion (F) and hemagglutinin (H) glycoproteins and the basic matrix (M) protein] forming the envelope. Viral entry relies on the interaction of the H protein with receptor molecules on the host cell surface (see below) followed by a pH‐independent conformational change of the F protein, which inserts its fusogenic domain into the target cell membrane thereby initiating the membrane fusion process required for uptake of the viral core complex into the host cell cytoplasm. When expressed at the cell membrane of infected cells, the glycoprotein complex also causes fusion with adjacent uninfected cells (provided these express H‐protein receptors) thereby giving rise to typical syncytia in tissue culture and in vivo. Apparently, the fusion activity of the F/H glycoprotein complex is negatively regulated by the M protein, which physically and functionally interacts with the cytoplasmic domains of F and H (Cathomen et al., 1998a, Cathomen et al., 1998b). In addition to controlling fusogenicity, the M protein is also a driving force in promoting viral budding, but also acts as a negative regulator of morbilliviral transcription by as yet unknown mechanisms (Pohl et al., 2007, Reuter et al., 2006).

In contrast to the strictly human pathogen, their type species measles virus (MV), the other morbilliviruses, rinderpest virus (RPV), canine and phocine distemper viruses (CDV and PDV), peste des petits ruminants virus (PPRV), and the cetacean dolphin and porpoise morbilliviruses (DMV and PMV) are animal viruses, which, in common with MV, are highly contagious and cause systemic infections which can result in similar devastating diseases in their respective hosts (Barrett, 1999, Barrett and Rossiter, 1999, Katz, 1995). Following entry via the respiratory tract, they commonly cause fever, cough, and conjunctivitis, but also a severe transient immunosuppression favoring acquisition and aggravation of secondary infections which may follow a lethal course. In humans, immunosuppression induced during the acute infection is actually the major cause of MV‐associated infant mortality worldwide. Despite implementation of the efficient vaccine, more than 30 million cases of acute measles are still reported annually with ∼345,000 fatalities (WHO, 2007), the majority of which develops in Third World countries as a consequence of immunosuppression (Katz, 1995). Especially virulent strains of RPV, infecting large ruminants and also pigs, reach death rates of up to 100% in cattle and wildlife such as buffalos (Syncerus caffer). In contrast to MV and RPV, CDV has a broader host range infecting many carnivores including dogs, lions, seals, and ferrets. CDV strains substantially differ in virulence. Because of the considerable worldwide socioeconomical impact of their infections, the WHO thus proclaimed and started eradication programs against MV and RPV. Most of the present knowledge about morbillivirus‐induced immunosuppression has been achieved from patients infected with measles or experimental approaches in tissue culture and animal models using MV. Therefore, MV will take the biggest part of this review serving as a model virus for the other morbilliviruses.

Measles is a well‐defined clinical entity normally contracted by children and young adults. While a long lasting virus‐specific immunity is efficiently induced in the course of acute measles and after vaccination, there is a generalized transient suppression of immune responses to other infections lasting for several weeks. Characteristically, a marked leukopenia and a loss of delayed‐type hypersensitivity (DTH) reactions are observed. Lymphopenia affects both the B and the T cell compartment (Okada et al., 2000). It was long before its isolation and molecular characterization that MV was recognized as the first immunosuppressive pathogen. The term “’anergy” was coined by von Pirquet in 1908 (von Pirquet, 1908) to describe the loss of DTH reactions to tuberculin in MV‐infected individuals. In addition to the marked lymphopenia, proliferative responses of lymphocytes to polyclonal and antigen‐specific stimulation ex vivo are highly impaired (Borrow and Oldstone, 1995, Griffin, 1995, Schneider‐Schaulies et al., 2001). This can be documented for several weeks after acute measles, and also, albeit to a moderate extent, after vaccination (Hussey et al., 1996). Infiltration of mononuclear cells into local areas of virus replication and the appearance of antiviral antibodies and virus‐specific T cells in the blood mark the onset of virus‐specific immune responses. Activation of virus‐specific T cells is reflected by soluble CD4, CD8, IL‐2R, and β2 microglobulin in serum, and a Th1 cytokine profile which switches to a Th2 type as indicated by a rise in IL‐4 plasma levels (reviewed in Griffin, 1995).

Natural MV infections may also occur in primates such as macaques, in which they are accompanied by immunosuppression, secondary infections, and reactivation of persistent viral infections (Choi et al., 1999). The diseases caused by other morbilliviruses in their specific hosts are also associated with immunosuppression (Barrett, 1999, Barrett and Rossiter, 1999). The clinical course observed after experimental infection of ferrets with a virulent CDV strain strongly resembles that seen with MV in humans: After intranasal infection with 104 TCID50, the ferrets developed a rash beginning at day 6, which was accompanied by a severe leukopenia. Signs of disease included severe dehydration caused by diarrhea, sometimes accompanied by pneumonia and conjunctivitis. One week after infection, the DTH response to tetanus toxoid was completely suppressed, the proliferative capacity of T cells in response to phytohemagglutinin (PHA) was strongly reduced, and all animals had to be euthanized between 12 and 16 days post infection (von Messling et al., 2003). When gene functions of the envelope genes (M, F, and H) and the RNP complex genes (N, P, and L) of a recombinant virulent and an attenuated strain were compared using recombinant viruses for experimental infection, virulence‐relevant mutations were found distributed throughout the genome suggesting that both the activity of the core replication complex and viral functions determining attachment, cell targeting, and spread, contribute to pathogenicity (von Messling et al., 2003).

Initial infection with morbilliviruses and subsequent spread are mainly determined by the presence of specific host cell receptors. Though MV infection doubtlessly occurs via the respiratory tract, primary target cells are, however, not yet clearly identified. Epithelial cells are susceptible to infection with certain MV strains in vitro (see below), yet do not express the receptor for MV wild‐type strains, CD150, which is restricted to the hematopoetic system (see below). Possibly, MV is rather acquired by tissue resident macrophages or dendritic cells (DCs) within the epithelium and transported to local lymphatic tissues (Ingrid Allen, personal communication; Fig. 2). In fact, MV‐infected MHC class II positive cells with DC morphology have recently been detected in peripheral mucosal tissues and isolated from skin explants of macaques experimentally infected with a eGFP‐tagged recombinant wild‐type MV (de Swart et al., 2007). This study impressively confirmed the pronounced tropism of MV for the lymphatic system including lymph nodes, where the virus is believed to infect B cells, T cells, and monocytes, which subsequently mediate systemic spread by a cell‐associated viremia. Thus, MV can be reisolated from human peripheral blood lymphocytes (which is greatly enhanced by mitogen stimulation) and MV‐specific RNA and proteins are detectable in a small proportion of peripheral lymphocytes and monocytes during and for few days after the rash (Esolen et al., 1993, Forthal et al., 1992, Schneider‐Schaulies et al., 1991). Though figures vary depending on the method used for detection, the overall percentage of infected peripheral blood mononuclear cells does not exceed 2% at any stage of infection, and similar frequencies were recently determined in experimentally infected macaques (de Swart et al., 2007). In CDV‐infected ferrets, a high percentage of lymphocytes and monocytes was found to be infected in the thymus and secondary lymphoid organs as revealed by histology. Interestingly, in contrast to MV, CDV‐infection leads to a high percentage of infection of peripheral blood lymphocytes (up to 40% of T cells and 60% of B cells) already at day 7 post infection (von Messling et al., 2004).

The first MV receptor identified was CD46 (membrane cofactor protein, MCP), a member of the complement regulatory proteins which is ubiquitously expressed on human nucleated cells (Dörig et al., 1993, Naniche et al., 1993) (Table I). High affinity binding to CD46 is, however, confined to attenuated virus strains and isolates adapted to growth on Vero cells. As a consequence of surface interaction and infection with the H protein, CD46 is downregulated from the cell surface and this, in agreement with the natural function of this molecule, has been associated with an enhanced sensitivity to complement‐mediated lysis (Schneider‐Schaulies et al., 1995b, Schnorr et al., 1995).

In contrast to this special property of attenuated MV strains, all MV strains (including lymphotropic wild‐type viruses and attenuated viruses) use CD150 (signaling lymphocyte activation molecule, SLAM), a member of the CD2 subset of the immunoglobulin (Ig) superfamily, as entry receptor (Erlenhoefer et al., 2001, Hsu et al., 2001, Ono et al., 2001b, Tatsuo et al., 2000, Tatsuo et al., 2001, Yanagi et al., 2006). The basis for the restriction of particularly wild‐type MV H proteins to functional interaction with this molecule has recently been directly documented by resolution of the H‐protein structure (Hashiguchi et al., 2007). Corroborating their similarity in cell tropism and pathogenicity, other morbilliviruses such as CDV and RPV also use the species‐specific orthologues of CD150 as major uptake receptors (Baron, 2005, Tatsuo and Yanagi, 2002). CD150 is expressed on activated B cells, activated and memory T cells including activated regulatory T cells (Browning et al., 2004), and immature thymocytes (Aversa et al., 1997). In line with this expression pattern, CD150+ B cells represented the prime target cell population in human tonsillar tissue material infected with MV wild‐type strains in vitro (Condack et al., 2007). Within the T cell compartment, MV infection clearly segregated with CD45RO+ memory cells that also expressed CD150. Interestingly, these, though less frequently infected than B cells, appeared to be preferentially depleted from the infected tissue. Though its basis is unclear as yet, preferential infection‐mediated depletion of T cells in secondary lymphoid tissues might well contribute to peripheral T cell lymphopenia (see below). The preferential tropism of wild‐type MV for B cells (both in lymphoid tissues and in peripheral blood) was also confirmed in eGFP‐MV‐infected macaques (de Swart et al., 2007), where expression of the marker transgene clearly segregated with that of CD150 on the individual cell compartments analyzed. If at all and to what extent monocytes (tissue resident or peripheral) are infected is unclear. Though believed to serve as MV carriers in humans (Esolen et al., 1993), peripheral blood monocytes were found essentially uninfected in macaques. This is in agreement with the absence of detectable levels of CD150 on these cells, as also seen for freshly isolated human primary monocytes and monocytic cell lines (Minagawa et al., 2001). CD150 expression is, however, inducible on monocytes and on maturing DCs, particularly in response to inflammatory signals (Kruse et al., 2001, Minagawa et al., 2001).

In addition to supporting entry of morbilliviruses into hematopoetic cells, interaction with this molecule may also contribute to immunomodulation independently of infection. As described for CD46 after interaction with attenuated MV, CD150 is downregulated from the cell surface by wild‐type MV contact or infection, with functional consequences being unknown as yet (Erlenhoefer et al., 2001, Welstead et al., 2004). As revealed by ligation with specific antibodies, CD150 can favor CD95‐mediated apoptosis in some B and T cell lines (Mikhalp et al., 1999), but also costimulate T cells by promoting enhanced IFN‐γ production and thereby a Th1 response (Cocks et al., 1995, Engel et al., 2003, Sidorenko and Clark, 2003). Strikingly, studies using T cells from CD150‐deficient mice fail to support a critical role of this molecule in IFN‐γ production, but rather indicate that CD150 enhances TCR‐stimulated IL‐4 release. This study also provided evidence that CD150 may modulate Toll‐like receptor (TLR) 4 but not TLR2 or TLR9 signaling in macrophages. Thus, LPS‐stimulated production of IL‐12, TNF‐a, and NO were diminished and that of IL‐6 was enhanced in the absence of CD150 (Wang et al., 2004). In DCs, consequences of CD150 ligation either by antibodies or MV have not yet been addressed.

The tropism of MV during natural infection predominantly, but not completely, segregates with its usage of CD150 as virus entry receptor. Given the importance of CD150 as a receptor for infection with presumably all morbilliviruses, it is unclear how these viruses access CD150 negative cells in vivo such as epithelial cells, endothelial cells, and in brain infections neurons, oligodendrocytes, and astrocytes. Moreover, in vitro infection of primary endothelial cells (Andres et al., 2003), small airway epithelial cells (Takeuchi et al., 2003), and a lung carcinoma epithelial cell line (Takeda et al., 2007) by wild‐type MV clearly occurred independently of CD150. With the help of the latter cell line (H358), which is highly susceptible to wild‐type MV forming large syncytia in the absence of CD150 and independently of CD46, a novel receptor‐binding site on the viral H protein could be identified (Takeda et al., 2007). In addition to these known and unknown uptake receptors, a variety of cell surface receptors have been identified that interact with MV, but do not act as uptake receptors. They may support receptor‐mediated virus uptake, such as the cytoskeletal protein moesin and DC‐SIGN (CD209), or fusion, such as the substance P receptor (neurokinin‐1), or may induce intracellular signaling, such as TLR2, and the Fc‐gamma receptor II (FcγRII; see below).

Section snippets

Leukopenia Associated with Morbillivirus Infections

Measles is associated with a pronounced leukopenia affecting B cells, monocytes, neutrophils, as well as CD4+ and CD8+ T cells, the extent of which seems to be related to the age‐dependent severity of the disease (Okada et al., 2000, Okada et al., 2001). In contrast to B cell frequencies, which can still be below control levels for up to six weeks, numbers of T cells return to normal after 10 days and the CD4/CD8 ratio remains constant over time (Arneborn and Biberfeld, 1983, Okada et al., 2001

Mechanisms and Consequences of T Cell Silencing in Morbillivirus Infections

The ability of MV to cause cell cycle arrest in infected cells including T cells is well known. In addition, infection‐dependent alterations of differentiating effector functions, but not those already established, have been intensively studied (Borrow and Oldstone, 1995, Casali et al., 1984). However, the vast majority of T cells isolated from patients or experimentally infected animals is uninfected, yet in spite of this resists mitogenic activation signals in terms of proliferation.

Receptors and Signaling Involved in Suppression of Cell Functions

Interestingly, transmission of the MV glycoprotein‐induced inhibitory signal does not rely on CD46 or CD150, since (1) murine T cells, which do not express functional uptake receptors, are also effectively arrested, (2) CD46‐ or CD150‐specific antibodies do not prevent silencing of human T cells (Erlenhoefer et al., 2001, Schlender et al., 1996), and (3) both receptors can modulate CD3 signals upon coligation in vitro, act, however, costimulatory rather than inhibitory (Astier et al., 2000,

Virus interference with DC functions in animal models

Because of their unique role in initiating and shaping immune responses, DCs are regarded as central to the understanding of both, induction of a virus‐specific immune response, and key aspects of the virus‐induced immunosuppression. Association of MV with follicular DCs has been documented in macaques (McChesney et al., 1997), yet it is unknown whether these cells can be considered as long‐term repositories for MV. Infection of macaques with a recombinant wild‐type MV expressing enhanced green

Conclusions and Perspectives

Many specific aspects of the morbillivirus‐induced disease and profound immunosuppression appear to be based on the tropism mediated by usage of CD150 as entry receptor on activated cells of the immune system. Selecting monocytes and DCs in the respiratory epithelium as first target cells which transport the viral load to draining lymph nodes, morbilliviruses find their way right into the center of the immune system. Considering the role of DCs to induce and shape immune responses, it is

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