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Measles virus breaks through epithelial cell barriers to achieve transmission
Makoto Takeda
Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Address correspondence to: Makoto Takeda, Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan. Phone: 81-92-642-6138; Fax: 81-92-642-6140; E-mail: mtakeda@virology.med.kyushu-u.ac.jp.
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Published June 20, 2008 - More info
J Clin Invest. 2008;118(7):2386–2389. https://doi.org/10.1172/JCI36251.
© 2008 The American Society for Clinical Investigation
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Abstract
The current model of measles virus (MV) pathogenesis implies that apical infection of airway epithelial cells precedes systemic spread. An alternative model suggests that primarily infected lymphatic cells carry MV to the basolateral surface of epithelial cells, supporting MV shedding into the airway lumen and contagion. This model predicts that a mutant MV, unable to enter cells through the unidentified epithelial cell receptor (EpR), would remain virulent but not be shed. To test this model, we identified residues of the MV attachment protein sustaining EpR-mediated cell fusion. These nonpolar or uncharged polar residues defined an area located near the binding site of the signaling lymphocytic activation molecule (SLAM), the receptor for MV on lymphatic cells. We then generated an EpR-blind virus maintaining SLAM-dependent cell entry and inoculated rhesus monkeys intranasally. Hosts infected with the selectively EpR-blind MV developed rash and anorexia while averaging slightly lower viremia than hosts infected with wild-type MV but did not shed virus in the airways. The mechanism restricting shedding was characterized using primary well-differentiated human airway epithelial cells. Wild-type MV infected columnar epithelial cells bearing tight junctions only when applied basolaterally, while the EpR-blind virus did not infect these cells. Thus, EpR is probably a basolateral protein, and infection of the airway epithelium is not essential for systemic spread and virulence of MV.
Authors
Vincent H.J. Leonard, Patrick L. Sinn, Gregory Hodge, Tanner Miest, Patricia Devaux, Numan Oezguen, Werner Braun, Paul B. McCray Jr., Michael B. McChesney, Roberto Cattaneo
Measles is an acute, viral infectious disease characterized by high fever, cough, and a maculopapular rash. Measles causes temporary and severe immunosuppression in patients, and secondary bacterial infections are a major cause of measles-related deaths (1). Studies have clearly shown that measles virus (MV), the causative agent, mainly replicates in lymphoid organs and causes devastating damage to the immune system of infected individuals (1). Despite the availability of effective vaccines, measles is still responsible for about 4% of deaths among children under 5 years of age worldwide (2). Importantly, the disease is transmitted via respiratory aerosols and is highly contagious in nature (1). In this issue of the JCI, Leonard et al. (3) report their detailed analyses of the interaction of MV with human host cells, in addition to data regarding MV pathogenesis in a rhesus monkey model. Their studies have revealed an elegant strategy by which MV propagates in patients and is transmitted to other target individuals and provide a good explanation for the highly contagious nature of measles.
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MV targets the host immune system
MV is an enveloped virus possessing a nonsegmented negative-strand RNA genome and is classified into the Morbillivirus genus of the Paramyxoviridae family (1). The virus has two types of glycoprotein spikes, designated hemagglutinin (H) and fusion (F) proteins, on the virus envelope (Figure 1). The H protein binds to specific molecules (receptors) on target cells, while the F protein mediates membrane fusion between the virus envelope and the host cell plasma membrane by cooperating with the H protein (1). The H protein is a key determinant of MV cell tropism, since its binding to receptors is critical for MV to initiate its infectious cycle (4). In 2000, signaling lymphocytic activation molecule (SLAM; also known as CD150) was identified as a receptor for MV (5). SLAM is expressed on cells of the immune system, such as activated lymphocytes and dendritic cells (6). These findings could explain the lymphotropism and immunosuppressive properties of MV (4). Although the ubiquitously expressed CD46 molecule has been identified as an MV receptor, this molecule only functions as a receptor for laboratory-adapted vaccine strains of MV, and clinical MV strains do not use this molecule as a receptor (4). The use of SLAM as a receptor has been shown to be common among species of the Morbillivirus genus (7). Canine distemper virus (CDV) is a member of the Morbillivirus genus and causes a disease similar to measles in dogs. By generating a recombinant CDV that lacks the ability to bind SLAM, von Messling et al. (8) previously demonstrated that the ability to bind this receptor is crucial for CDV spread and virulence in vivo. Recombinant MVs engineered to express enhanced GFP are powerful tools for monitoring MV infection of cultured cells and animals (9). Using such viruses in a monkey model, de Swart et al. (10) reported that SLAM-positive lymphocytes and dendritic cells are the predominant cell types infected by MV in vivo. The data regarding recombinant viruses along with classic observations of MV pathology (11) clearly indicate that MV, by using SLAM as a receptor, primarily targets cells of the immune system to spread efficiently throughout the body of infected humans (Figure 2).
Figure 1Schema of the MV particle and its receptor-binding H protein. MV is an enveloped virus and possesses 2 types of glycoprotein spikes, designated H and F proteins. The F protein mediates membrane fusion between the viral envelope and the host cell plasma membrane, while the H protein that forms homodimers on the viral envelope is responsible for binding of virus to receptors on target cells. The head domain of the H protein exhibits a six-bladed β-propeller fold. Residues important for using SLAM as a receptor map to a localized area of the β5 sheet, forming a putative SLAM-binding site (shown in blue). On the other hand, relevant residues for epithelial cell infection map to a small area in the β5 and β4 sheets, forming another putative receptor-binding site (yellow) that is essentially distinct from the SLAM-binding site.
Figure 2The time course of MV infection and receptor usage. (A) MV enters humans through the respiratory route and initiates its infectious cycle in lymphoid organs in the upper respiratory tract by using SLAM as a receptor. (B) MV-infected lymphocytes enter the bloodstream, and MV propagates in lymphoid organs throughout the body. (C) MV-infected immune cells appear to transmit MV to epithelial cells in various organs (e.g., airway, intestine, bladder). A putative epithelial cell receptor appears to play an important role in MV infection of epithelial cells. (D) MV then replicates in epithelial cells and actively releases progeny viruses into the airway. Consequently, respiratory aerosols of patients contain large amounts of MV particles.
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MV emerges by breaking through epithelial barriers
MV infection has long been thought to begin in the respiratory epithelium and then spread to lymphoid tissue. By intranasally inoculating monkeys with a recombinant mutant MV that retains the ability to use SLAM but lacks the ability to infect epithelial cells, Leonard et al. (3) demonstrated that the ability to infect epithelial cells is not required for MV to enter and spread in the host. Thus, their data support the idea that respiratory epithelial cells are not initial targets of MV (4, 17). Then what is the relevance of MV infection of epithelial cells in measles pathogenesis? Several tight junction or other cell junction molecules have been shown to be involved in the entry processes of various viruses, such as hepatitis C virus (18), reovirus (19), and herpes simplex virus (20). Leonard et al. (3) demonstrated that MV enters primary cultures of well-differentiated airway epithelial cells basolaterally and buds exclusively from the apical (luminal) side (Figure 3). Since the external surfaces of organs or tissues are composed of polarized epithelial cell layers, the ability of MV to infect these cells and bud from the apical side may facilitate virus shedding. Indeed, Leonard et al. (3) demonstrated in their rhesus monkey model that the mutant MV that cannot infect epithelial cells is not shed into the airway. MV therefore seems to infect epithelial cells in order to release progeny particles by breaking through the epithelial barrier (Figures 2 and 3). This active virus shedding into the airway may explain why MV is transmitted efficiently via respiratory aerosols, whereas human immunodeficiency virus, which shares with MV a similar tropism for immune cells, requires sexual contact or direct infusion into blood for transmission.
Figure 3Model of MV shedding into the external surface of epithelium. (A) As Leonard et al. report in their current study (3), wild-type MV can be transmitted from infected immune cells (red) to epithelial cells via an epithelial cell receptor located on the basolateral surface of the latter. Mutant MV (yellow) that lacks the ability to use epithelial cell receptors fails to infect epithelial cells. The unidentified receptor may be a molecule related to tight junctions. (B) Progeny MV particles bud exclusively from the apical surface of the epithelium and are thus actively released into the airway.
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