The basic steps of the infectious cycle of any pathogen—entry into, spread within, and exit from the host—offer crucial insights into how pathogens cause disease. As a result, a full understanding of the stages of a microorganism's life cycle may inform the rational design of therapeutics to prevent or ameliorate consequent disease.
Measles virus (MV) is one of the most transmissible microorganisms known; it continues to result in hundreds of thousands of infections annually throughout the world, many of which have serious pathogenic consequences that can result in death. Despite the tremendous progress that has been made in deciphering the basis of MV pathogenesis and in the creation of effective attenuated vaccines, how MV causes disease—including rare, but serious, central nervous system (CNS) complications--remains poorly understood. It is our view that defining the pathogenesis of MV in the CNS necessitates an understanding of the interaction of the virus with the host in trafficking to and spreading within the CNS. This is the focus of this review.
1.1 Measles virus: genome and proteins
MV is a member of the Paramyxoviridae, within the Morbillivirus genus. Its genome consists of ~16,000 bases of non-segmented, single-stranded negative sense RNA, meaning that the viral genome is transcribed immediately upon entry into the cell. Virions are spherical and enveloped, and the envelope is derived from the host cell as the viral particle buds from the plasma membrane. The viral genome encodes 8 proteins, the function of which are briefly noted below. Inserted into the envelope of the virion are the two MV glycoproteins, hemagglutinin (H) and fusion (F). These proteins mediate attachment to cellular receptors and fusion of the virion with the target cell or fusion of an infected cell with an adjacent uninfected cell. The matrix protein (M) lies immediately underneath the virion envelope and serves in virus assembly and budding. The two polymerase proteins, large (L) and phosphoprotein (P), are closely associated with the genome, which is encapsidated by the nucleocapsid (N) protein. The nonstructural proteins V and C, encoded within the P cistron, are also packaged within the virion; these proteins have recently been shown to play a role in counteracting host antiviral immune responses (reviewed in Griffin, 2001).
1.2 Measles virus pathogenesis
MV is a human-restricted pathogen that spreads among individuals by release of aerosol droplets. An infected individual will undergo a latent period of 10 to 14 days followed by a few days of fever, cough, coryza, and rash. Primary infection occurs in the upper respiratory tract, but MV will secondarily infect lymphoid cells (reviewed in Griffin, 2001; Rall, 2003; Schneider-Schaulies et al., 2003; Sips et al., 2007). Although the immunological response made by most infected, immunocompetent individuals is sufficient to clear the virus and provide life-long protection, a period of transient immunosuppression is a notorious characteristic of MV infection, and is likely the basis of most of the complications and the subsequent fatalities following acute infection (reviewed in Dhib-Jalbut and Johnson, 1994; Griffin et al., 2008; Rall, 2003). Additional consequences of acute infection include diarrhea, pneumonia, and encephalitis.
Immunosuppression following MV infection can last for weeks, extending beyond the classical MV symptoms. The chief risk of immunosuppression is that it renders infected individuals more susceptible to secondary infections, though precisely how this occurs is not fully understood. In humans, MV-induced immunosuppression is characterized by a loss of delayed type hypersensitivity responses to recall antigens [e.g., tuberculin (Tamashiro et al., 1987)], a limited response of lymphocytes to mitogens when cultured ex vivo (Hirsch et al., 1984), and impaired responses to new antigens (Coovadia et al., 1978). To date, a number of mechanisms have been proposed based on animal and cell culture studies, all of which could be pertinent in the natural infection. For example, Griffin and colleagues showed that MV infection of antigen-presenting cells suppresses interleukin-12 (IL-12) production, which then in turn skews the CD4+ T cell response toward a Th2 profile (Karp et al., 1996). This altered CD4+ T cell response leads to inappropriate priming of T cells and a failure of T cells to proliferate following interaction with MV-infected dendritic cells (Fugier-Vivier et al., 1997; Servet-Delprat et al., 2000). These studies correlate well with serum profiles in MV-infected macaques and humans that also show a skewing toward Th2-like cytokines (Atabani et al., 2001; Moss et al., 2002; Polack et al., 2000). In addition to influencing the Th1/Th2 balance, acute MV infection may precipitate immunosuppression by causing an overall lymphopenia, due to effects on T cell proliferation and progression through the cell cycle (Naniche et al., 1999; Niewiesk et al., 2000; Niewiesk et al., 1999; Schnorr et al., 1997), as well as specifically inhibiting immune function via the production of unidentified, immunosuppressive molecules from infected T cells (Sun, et al., 1998). A detailed discussion of MV-induced immunosuppression can be found in other chapters within this volume.
1.2.2 CNS Complications following Acute MV Infection
Approximately 1 in 100,000 acutely infected individuals later go on to develop CNS complications. These diseases differ in terms of immune status of the affected host, onset of symptoms, presence of MV within the CNS, host survival rate, and neuropathological findings. These are briefly discussed below.
22.214.171.124 Subacute sclerosing panencephalitis (SSPE)
is a slow, progressive disease that is invariably fatal, and can occur from 1 to 15 years following acute MV infection (Dubois-Dalcq et al., 1974). Children are far more likely to develop this complication than adults (reviewed in Johnson, 1998). The disease initially manifests as subtle cognitive losses, progressing to more overt cognitive dysfunction, followed by motor loss, seizures and eventual organ failure in virtually all affected individuals. The rate of SSPE occurrence ranges from 1 in 10,000-300,000 acute MV infections (reviewed in Rima and Duprex, 2005; Takasu et al., 2003). Neurons are predominantly infected, though at late times of infection, oligodendrocytes, astrocytes, and endothelial cells may also be involved (reviewed in Rima and Duprex, 2005). SSPE affects both gray and white matter and is histologically characterized by the presence of cellular inclusion bodies, inflammation, glial activation, loss of blood-brain barrier integrity, and neuronal loss (reviewed in Dhib-Jalbut and Johnson, 1994; Rall, 2003). A serologic hallmark of SSPE, as compared to the other CNS complications, is the elevation of measles-specific antibodies in the blood and cerebrospinal fluid (CSF)(Dubois-Dalcq et al., 1974).
Importantly, evidence from brain biopsies of SSPE patients indicates that infected neurons do not release budding virus (Paula-Barbosa and Cruz, 1981). Based on extensive sequencing studies of MV from these specimens and from cells persistently infected with MV isolates from SSPE patients, it has been proposed that the failure of infected neurons to produce complete extracellular virus may be due to defects in protein expression caused by extensive point mutations in the envelope associated genes, H, F and M (Cattaneo et al., 1988; reviewed in Dhib-Jalbut and Johnson, 1994; Rima and Duprex, 2005), though what role these viral proteins play in neuronal spread of MV—and how mutations may affect MV biology in infected neurons--are not known.
126.96.36.199 Post-infectious encephalomyelitis (PIE)
occurs more frequently than SSPE, affecting ~1 in 1,000 infected individuals. Symptoms of PIE normally appear 5 to 14 days after the characteristic MV rash but can predate the rash (reviewed in Johnson, 1998). This complication is thought to be an autoimmune reaction, perhaps to myelin basic protein (Johnson, et al., 1984). MV antigen and nucleic acids have not been detected in PIE brain biopsies by immunohistochemistry or in situ hybridization (Johnson, et al., 1984; reviewed in Dhib-Jalbut and Johnson, 1994; Norrby and Kristensson, 1997) supporting the notion that this is an autoimmune disease. Additional hallmarks of PIE include perivascular inflammation and demyelination (reviewed in Norrby and Kristensson, 1997). Unlike SSPE, intrathecal production of MV antibodies has only been found in a few cases of PIE. Affected individuals present with seizures, deafness, ataxia, and movement disorders. There is a ~25% mortality rate associated with PIE, and survivors are likely to suffer from frequent neurologic sequelae.
188.8.131.52 Measles inclusion body encephalitis (MIBE)
a rare CNS complication following acute MV infection, has been described in children and adults receiving immunosuppressive drugs and therefore is thought to chiefly affect immunocompromised hosts. The neurologic disease appears 3 to 6 months after the acute MV rash (reviewed in Dhib-Jalbut and Johnson, 1994; Johnson, 1998). As the name suggests, MIBE is characterized by inclusion bodies in both neurons and glia, with accompanying neuronal loss but an overall lack of inflammation (reviewed in Dhib-Jalbut and Johnson, 1994; Johnson, 1998; Norrby and Kristensson, 1997; Rall, 2003). Measles antigen is present in the brain, and virus has been isolated directly from the brains of affected individuals (Johnson, 1998). MIBE differs from SSPE in the absence of elevated serum and cerebrospinal fluid neutralizing antibodies (reviewed in Dhib-Jalbut and Johnson, 1994; Rima and Duprex, 2005). The disease course is relatively short, lasting from days to weeks, causing seizures, motor deficits, and stupor, often leading to coma and death (reviewed in Johnson, 1998).
Importantly, despite the fact that only a small percentage of acute MV infections will go on to develop CNS complications, a few studies have detected MV RNA in various organs, including brain, upon autopsy of elderly individuals who died of nonviral and non-CNS causes (Katayama et al., 1998; Katayama et al., 1995). These findings suggest that MV may persist in the brains (and other organs) of healthy individuals, and that the frequency with which MV invades the CNS cannot be determined by summing the occurrence of the above described CNS complications.