Peptide motif analysis predicts lymphocytic choriomeningitis virus as trigger for multiple sclerosis

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Highlights

Abstract

The etiology of multiple sclerosis (MS) involves both genetic and environmental factors. Genetically, the strongest link is with HLA DRB1*1501, but the environmental trigger, probably a virus, remains uncertain. This investigation scans a panel of proteins from encephalitogenic viruses for peptides homologous to the primary autoantigen from myelin basic protein (MBP), then evaluates candidate peptides against a motif required for T cell cross-reactivity and compares viral prevalence patterns to epidemiological characteristics of MS. The only peptide meeting criteria for cross-reactivity with MBP was one from lymphocytic choriomeningitis virus (LCMV), a zoonotic agent. In contrast to current candidates such as Epstein–Barr virus, the distribution of LCMV is consistent with epidemiological features of MS, including concentration in the temperate zone, higher prevalence farther from the equator, and increased prevalence in proximity to regions of peak MS incidence, while lack of person-to-person transmission is consistent with low MS concordance across monozygotic twins. Further, LCMV blocks induction of type I interferon (IFN). Hypothetically this would dysregulate immune processes in favor of proinflammatory pathways as well as upregulating HLA class II and providing more binding sites for autoantigen. The combination of molecular mimicry with virally-induced immune dysregulation has the potential to explain aspects of autoimmunity not addressed by either mechanism alone.

Introduction

Multiple sclerosis (MS) is a chronic immune-mediated neurological disease that affects approximately 1.3 million people worldwide. It is generally accepted that both genetic and environmental factors are involved, but disease etiology remains poorly understood after decades of research. Recent advances have identified a number of genetic risk factors, with HLA DRB1*1501 haplotype continuing to provide the strongest association (Gourraud et al., 2012, Wu et al., 2010, Qiu et al., 2011, Link et al., 2012, Nolan et al., 2012). Yet, with approximately 9% of the world’s population carrying this allele (Solberg et al., 2008) and a global MS prevalence of 0.03% (World Health Organization, 2008), the proportion of DRB1*1501-positive individuals who develop MS is low, on the order of 0.3%. Among environmental factors, a viral agent has been postulated to instigate immune recognition of self-antigens (Fujinami, 2001), hypothetically by means of a mechanism termed “molecular mimicry” (Olson et al., 2001). Under this model, structural similarities between a viral peptide and a self-peptide cause activation of autoreactive T cells. Although a range of viruses has been considered over the past 50 years, including poliovirus, measles, rabies, herpes family viruses, mumps, canine distemper, and retroviruses (Kakalacheva et al., 2011), the identity of a causative virus remains elusive.

A popular candidate for an etiologic role in MS is Epstein–Barr virus (EBV), as antibodies against its nuclear antigen-1 (EBNA1) have been found in MS patients (Kakalacheva et al., 2011). However, the distribution of EBV worldwide does not provide a good fit to the epidemiology of MS. MS is concentrated in the temperate zone, with highest prevalence in Europe, Canada, the United States, and Australia (World Health Organization, 2008). Within the temperate zone, MS shows a gradient of prevalence that increases with latitude (Simpson et al., 2011) and is interspersed with regional pockets of exceptionally high prevalence. Although some of these differences can be explained by genetic factors, MS concordance across monozygotic twin pairs is low, ranging from 13% to 31%, based on studies in Canada, the United States, the British Isles, Finland, and Italy (Willer et al., 2003, Islam et al., 2006, Mumford et al., 1994, Kuusisto et al., 2008, Ristori et al., 2006, Sadovnick et al., 1993). This suggests that the environmental trigger for MS in genetically susceptible individuals is somewhat uncommon or has low infectivity. In contrast, the EBV seropositivity rate in adults is in excess of 90% (Kakalacheva et al., 2011). Further, exposure to EBV occurs earlier in life among children in developing countries, with universal seroconversion by age 3–4, whereas infection in developed countries often is delayed until adolescence (Hjalgrim et al., 2007). The high seroprevalence of antibodies against EBV, together with earlier exposure in countries with lower MS prevalence, are not fully consistent with the latitudinal gradient and low twin concordance rates seen for MS. In fact, some researchers suggest that EBV is a marker of chronic brain inflammation rather than causative per se (Castellazi et al., 2014).

The ideal candidate for an infectious trigger interacting with DRB1*1501 under the molecular mimicry hypothesis would satisfy both molecular biological and epidemiological criteria. The infectious agent would contain a peptide that binds to HLA in a similar way as the self-antigen and lies in a similar configuration. The bound peptide would activate the same T cell clones as those that recognize the self-antigen. The infectious agent would be somewhat uncommon or have low infectivity in order to explain the low MS concordance across monozygotic twin pairs. The agent would be most prevalent in the temperate geographic zone. Its distribution would be consistent with the latitudinal gradient observed for MS. It would show higher prevalence or infectivity in regions that report elevated incidence or prevalence of MS.

The aim of this investigation was to predict the viral peptide most closely matching these criteria. A set of proteins from viruses capable of causing encephalitis was scanned for regions of sequence similarity to myelin basic protein (MBP) residues 85–99. The peptides with highest sequence homology were then compared to MBP 85–99 on five scales representing characteristics predictive of protein binding and configuration. The highest scoring viral peptides were evaluated for similarity to a binding motif that has been determined experimentally to activate MBP-reactive T cell clones from MS patients with DRB1*1501 haplotype. Finally, the plausibility of the top predicted virus was evaluated through a review of its epidemiology and a comparison to the prevalence patterns observed for MS.

Section snippets

General

All computations were done with custom programs written in the R language (Hornik, 2014).

Viral proteins

A list of viruses capable of causing encephalitis was generated from review of medical reference texts. Encephalitogenic viruses endemic to equatorial regions were excluded as unlikely to be causative, since MS is most prevalent in the temperate zone. Protein sequences derived from the viral capsid or envelope or previously observed to be antigenic were selected for testing. Protein sequences were obtained

Viral peptide homology search

Ten viruses that have the potential to cause encephalitis in regions with a temperate climate were identified from a review of medical reference texts. From these 10 viruses, sequences for 17 proteins were obtained from the UniProt database and searched for regions of homology with MBP 85–99 using overlapping windows of varying lengths. These proteins are listed in Table 1.

Virtually all encephalitogenic viral proteins in the test set showed some degree of homology with MBP 85–99. The highest

Epidemiological evaluation

LCMV is a zoonotic agent of the family Arenaviridae. Its primary host is the common house mouse, Mus musculus (Lehmann-Grube, 1971), although other rodents, including pets, may become infected (Biggar et al., 1975). The virus persists in asymptomatic carrier mice and is discharged in nasal secretions, saliva, milk, blood, and urine (Lehmann-Grube, 1971, Traub, 1938, Childs et al., 1992). The distribution of LCMV-seropositive mice is uneven and locally clustered within a mouse population,

Discussion

While rapid advances have been made in identifying genetic factors associated with MS, the identity of an infective agent triggering the disease in genetically susceptible individuals remains uncertain. Many agents have been proposed, based primarily on their correlation with disease exacerbation or their isolation from CSF or brain tissue (Kakalacheva et al., 2011). Yet none of these have been linked to a specific causative mechanism, nor do they explain the prevalence patterns long observed

Acknowledgments

The author thanks Elizabeth A. Holly of the University of California – San Francisco, Brad Efron and Susan Holmes of Stanford University, Betz Halloran of the Fred Hutchinson Cancer Research Center, and Norm Breslow of the University of Washington for helpful comments and suggestions. Acknowledgments also go to the many biologists, physicians, epidemiologists, virologists, and other scientists whose meticulous work provided the foundation for this analysis, and to the patients, whose cause

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