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Infectious Disease and Neurocognition
acute viral encephalitis or meningitis, whereas their specicity in MS has not been
elucidated (Brändle et al., 2016).
John Cunningham virus (JCV), which causes progressive multifocal
leukoencephalopathy (PML), a disease with high mortality, became alarmingly relevant for MS patients as a side eect of natalizumab treatment during the rst clinical trials of the drug (Keeley et al., 2005). Natalizumab (Tysabri) is a monoclonal
antibody targeting integrin α4β1, inhibiting the migration of activated autoreactive
lymphocytes into the CNS, but also impairing immunosurveillance of the brain.
PML is an opportunistic disease previously known to aect patients with acquired
immunodeciency syndrome (AIDS). In 2020, over 800 PML cases were identied
among 200,000 natalizumab- treated patients worldwide, with a 24 percent mortality
rate (Kartau et al., 2019). However, precautions, including limiting the treatment to
JCV- seronegative MS patients and minimizing total treatment duration, have reduced the incidence of PML. JCV infection might be cleared by stopping the treatment and allowing antiviral immune cells to re- enter the CNS (Carruthers & Berger,
2014). A complication of this inux of immune cells following treatment cessation
is acute severe destruction by the autoreactive lymphocytes while gaining control of
the JCV infection. is is known as an “immune reconstitution inammatory syndrome” (IRIS) (Cliord et al., 2010).
An interesting example of a disease rst diagnosed as MS, but later classied as
a distinct diagnosis, is the human T- cell lymphotropic virus type 1 (HTLV- 1)- associated myelopathy tropical spastic paraparesis (HAM/ TSP), which is primarily
restricted to HTLV- 1 endemic areas (Ishak et al., 2020). is disease is characterized by slowly progressive spastic paraparesis, which can also be present in MS
(Puccioni- Sohler et al., 2007). e strongest biomarker for HAM/ TSP is high intrathecal proviral load and anti- HTLV- 1 antibodies, although the latter can also occur
in MS patients with coincident infection of the virus.
Each of these diseases can cause CNS demyelination to varying degrees but are
distinct from MS in symptoms and severity, or if not, the alternative diagnosis can
be supported by diagnostic tests of viral antigens and antiviral antibodies. In MS, no
single viral agent has been identied as the causative agent in the acute stages of the
disease. at does not exclude viruses as triggers, and some suggestions of how that
might be possible can be found in the animal models of the disease.
Animal models of multiple sclerosis
ere are several animal models of MS, some of which are induced by viral infection. However, in the most widely used model, experimental autoimmune encephalitis, the disease is induced by injecting myelin, myelin proteins, or peptides
from myelin proteins, together with adjuvants. is model has been instrumental
in understanding and treating autoimmunity against myelin and developing antiinammatory drugs, although it has not contributed to elucidating the triggering
Multiple Sclerosis 319
factors of the disease. Injecting myelin without adjuvants is not enough to cause
disease. Similarly, skull traumas, which expose myelin to the peripheral immune
system, have not been associated with an increased risk for MS (Peger et al., 2009).
Other animal models show that a virus can mediate this adjuvant eect.
eiler’s murine encephalomyelitis virus (TMEV) infection of the SJL/ J mice
strain when infected intracerebrally causes acute encephalitis and subsequent
demyelinating disease during the chronic phase of the infection (Lipton, 1975).
In this biphasic model, the viral load decreases during the chronic demyelinating
phase, but lymphocytes persist in the white matter. Unlike in the acute phase, no
virus can be found in the neurons, although they are not completely cleared from
oligodendrocytes, astrocytes, and microglia (DePaula- Silva et al., 2017). is model
is interesting because it demonstrates that one virus can trigger dierent diseases
depending on the host’s genetic susceptibility. TMEV induces epilepsy if another
mouse strain (C57BL/ 6J) is infected, which is an analogy to what we have found
for HHV- 6A and HHV- 6B in MS and epilepsy (Dunn et al., 2020). A signicant
dierence between the mice strains is the much stronger innate antiviral response
in C57BL/ 6J mice, mediated by interferons, that helps to clear the virus, whereas
the SJL/ J have more T regulatory cells suppressing the antiviral immune response
(DePaula- Silva et al., 2017; Rodriguez et al., 1995).
Another model that supports viruses as etiological agent for MS- like symptoms
despite failure to isolate the agent at the phase of myelination is the intrathecal injection of the mouse hepatitis virus (MHV) (Hosking & Lane, 2009). e model is biphasic, i- phasic, with the rst phase of acute viral infection leading to replication of
the virus in neurons and subsequent clearing by the immune system over a few days
of acute encephalomyelitis (Bender & Weiss, 2010). In the second phase, a chronic
fulminant demyelinating disease develops, and no replicating virus can be detected
by plaque assay. However, viral antigen and RNA might persist within the CNS for
up to a year and are presumably responsible for continued T- cell, B- cell, and macrophage inltration into the CNS, causing demyelination. Even though MHV was
given intrathecally in this model, a range of dierent MHVs exist in mice, causing
diverse symptoms ranging from hepatitic and respiratory to neurological with or
without chronic demyelination.
Patients with MS tend to have a more gradual onset than can be mimicked in
animal models. As the fertile eld hypothesis postulates, several events might be
needed to trigger MS, with both childhood and additional factors later in life contributing to disease breakthrough in adulthood (von Herrath et al., 2003). us,
common viral infections colonizing children at a young age with only rare occasions
of severe disease might contribute to the fertile eld, increasing the susceptibility.
ese events t well with the migration data described for MS risk. ey also t well
with the infection of common viruses like herpesviruses during childhood and with
the life- long latencies and subsequent reactivation these viruses cause later in life.
An interesting example of an animal model of viruses known to be neurotropic
in humans is the macaque infected with HHV- 6A and HHV- 6B (Leibovitch et al.,
Infectious Disease and Neurocognition
2018). ese apes naturally express the complement inhibitory cell surface protein CD46, a known receptor for HHV- 6A/ B. Depending on the route of inoculation, the symptoms vary. Intravenously, HHV- 6A, but not HHV- 6B, can
give spinal cord pathologies and symptoms. Intranasally, the most likely route
of natural infection, HHV- 6A results in asymptomatic infection, although subsequent studies showed that it signicantly accelerated experimental autoimmune encephalitis if induced 2 months aer the HHV- 6A infection (Leibovitch
et al., 2018). Although these studies need to be followed up to improve our understanding of the molecular mechanisms behind CNS involvement, the herpesviruses are interesting contributing triggering factors where several associations
with MS have been reported.
Association of herpesviruses with multiple sclerosis
Of the long list of viruses claimed to be associated with MS, both HHV- 6A and EBV
have recently reemerged as possible candidates. HHV- 6A and HHV- 6B have a broad
tropism, with T cells as an optimal target, but also some neurotropism. HHV- 6B
causes exanthem subitum, whereas the primary disease for HHV- 6A is unknown.
EBV has a strict tropism for B cells, causing their immortalization through transformation. It is associated with several forms of cancer and autoimmune diseases,
including MS (Soldan & Lieberman, 2022).
A recent study of a United States military cohort conrmed an association between MS and EBV aer following 10 million young adults, 955 of whom were
diagnosed with MS during their military service. e timing of EBV seroconversion was established using longitudinal blood samples (Bjornevik et al., 2022).
e researchers showed anti- EBV seroconversion increased the risk of MS, with
all but one of the 25 MS cases found to be anti- EBV antibody positive before their
MS diagnosis. is translated to being 32 times more likely to develop MS when
anti- EBV antibody- positive than expected. Lanz and colleagues identied a crossreactivity with CNS protein GlialCAM, showing that molecular mimicry might be
one mechanism explaining the association (Lanz et al., 2022). Several studies show
similar cross- reactivity between viral and human proteins, indicating that viruses
might trigger autoimmunity due to sharing similar epitopes (Wucherpfennig &
Strominger, 1995).
However, these similarities with host mimicking only a few amino acids can be
questioned, given the probability of any virus sharing as few as four amino acid
sequences with any human protein is high, as there only are 20 amino acids available
to choose from (Wucherpfennig, 2001). One additional limitation of the molecular
mimicry hypothesis is the lack of explanation for the homing of the lymphocytes to
the target organ since it is missing the necessary indications for where the lymphocytes should egress the blood vessels. At sites of inammation, the tissue- resident
macrophages or tissue damage need to guide the activated lymphocytes to the correct
Multiple Sclerosis 321
location by presenting the right antigen and upregulating integrins and selectins on
the blood vessels (Bleriot et al., 2020; Madri & Graesser, 2000).
EBV infection has been shown to be a risk factor for MS only aer age 18, whereas
HHV- 6A infection is a risk factor across the lifespan (Biström et al., 2021). One interpretation of these ndings is that autoimmunity might be triggered by one virus
that directs the specicity to the target organ in combination with an EBV infection
that creates chronicity by immortalizing the autoreactive B cells, meaning both are
needed to cause disease. is chronicity fueling capacity might explain how EBV can
be associated with several autoimmune diseases.
e detection of HHV- 6A/ B in MS brain was rst described using an unbiased
method of representational dierence analysis to subtract blood deoxyribonucleic
acid (DNA) from brain DNA (Challoner et al., 1995) and later conrmed by laser
dissection (Cermelli et al., 2003). An association could be conrmed by serology
(Soldan et al., 1997), and aer several years of conicting results due to the inability
to serologically separate HHV- 6A from HHV- 6B, it was nally conrmed for HHV6A (Engdahl et al., 2019).
Taken together, one single viral infection as a hypothetical candidate for a triggering factor for MS is not likely. Rather our bodies should be viewed as ecosystems
of several viruses competing for their optimal niche, with extensive manipulation of
our immune system. For example, cytomegalovirus (CMV) infection, when measured as a serological response, is protective against MS (Comabella et al., 2022;
Vanheusden et al., 2015), indicating that it might manipulate the immune system
so that EBV and HHV- 6A have reduced capacity to colonize and reactivate in the
body. A working hypothesis would be to view these common herpesviruses as competing for the human niche, having strategies to favor their own reproduction at the
expense of others. us, the timing of initial infection in relation to the other herpesviruses, highly dependent on a mother’s transferred immunity over the placenta
(Pou et al., 2019), is essential to investigate further to gain a better understanding of
the dynamic fertile ground leading to autoimmunity.
Incorporation hypothesis
An alternative explanation to molecular mimicry for how viruses can cause autoimmunity can be deduced from how large, enveloped viruses, like the herpesviruses,
form their envelopes. ese are stolen from the host cells while the virus is egressing
through the cell membrane or into cytosolic vesicles induced in the infected cell.
Although these lipid membranes contain the spikes encoded by the virus, they also
contain several host cell- encoded proteins.
e hypothesis was rst described for CMV as a mechanism by which reactivation
of the virus could cause gra- versus- host disease (GVHD) aer bone marrow transplantation (Soderberg et al., 1996). As CMV infection was associated with GVHD
in CMV- negative recipients receiving bone marrow from a CMV- positive donor,
Infectious Disease and Neurocognition
the cells in the bone marrow harboring the virus were searched to remove these before transplantation. Infected cells were identied as CD13 positive, and, surprisingly, also the viral envelope was shown to contain human CD13 (Giugni et al., 1996;
Soderberg et al., 1993). e authors subsequently demonstrated that CMV induced
CD13- specic autoimmunity and that these antibodies contributed to the tissue
damage in chronic GVHD (Soderberg et al., 1996). Moreover, bone marrow transplantation patients treated with antiviral drugs had decreased GVHD (Giugni et al.,
1996). Further studies could conrm that CMV incorporates over 70 dierent host
cell proteins (Varnum et al., 2004), and it was clear from these studies that this phenomenon could be a more general mechanism explaining the specic tissue destruction in autoimmune diseases.
An additional example is human immunodeciency virus (HIV), which incorporates HLA and CD4 (Arthur et al., 1992), resulting in an infected person’s sexual
partner developing antibodies against the specic HLA haplotype to the virus carried by the infected person. ere are interesting cases now in the era of eective
antiviral treatment of HIV where the viral count is down, but the recovery of CD4
cells does not occur, indicating that an anti- CD4 autoimmunity induced by the same
mechanisms might have occurred.
Another example is the vesicular stomatitis virus, which incorporates myelin
basic protein, one of the target proteins in MS (Lodish & Porter, 1980; Rott et al.,
1994). Details of these viruses showed incorporation of a subset of the 10– 15 cell
surface host proteins, which are present in 10– 80 copies per virion and exposed to
the surface of the virion. e specicity was shown to depend on submembrane viral
proteins since these could be mutated to change the composition of the incorporated
host cell proteins (Lodish & Porter, 1980).
Our studies have shown that levels of CD46, the receptor of HHV- 6A/ B, were elevated in its soluble form in MS patients. is elevation correlated with polymerase
chain reaction positivity of HHV- 6A/ B (universal primers for A and B). By purifying
serum from MS patients through a CD46 column, eluates were identied as HHV6A immediate early gene positive with polymerase chain reaction (Cassiani- Ingoni
et al., 2005). us, the CD46 was incorporated in the viral particle, which could be
conrmed with anti- CD46 gold staining with electron microscopy, iodixanol purication, and western blot staining of viral culture supernatant (Hammarstedt et al.,
2007). ese studies also showed that several other proteins were incorporated into
the viral particle. However, since the viral particles were cultivated in T cells, it does
not elucidate further information about MS- associated autoimmunity. To connect
host cell protein incorporation to MS, the virus must be cultivated in the target cell of
the disease, the oligodendrocyte. ese cells express the CD46 receptor for the virus
and are, therefore, permissive to infection (Cassiani- Ingoni et al., 2005).
Incorporation of CD46 into HHV- 6A may not be directly connected to MSspecic pathology, but it seems to be an interesting more general phenomenon.
Several viruses incorporate complement inhibitory proteins such as CD46, CD55,
and CD59 as a survival advantage for the virus (Monteori et al., 1994; Spear et al.,
Multiple Sclerosis 323
1995; Spiller et al., 1997). By incorporating complement proteins into the viral envelope, a virus can evade virolysis by the complement system (Saifuddin et al., 1994;
Vanderplasschen et al., 1998). Furthermore, incorporation might cause B- cell activation, triggering the production of anti- CD46 and anti- CD59 antibodies in MS
(Pintér et al., 2000). Up to 80 percent of relapsing– remitting MS patients were shown
to have high levels of anti- CD46 antibodies in the acute phase of the disease. MS
sera were also found to compete with the binding of anti- CD46 and anti- CD59,
further indicating that CD59 also is incorporated into the viral particle. However,
anti- CD46 antibodies may not cause organ- specic autoimmunity, but the crosslinking of CD46 on T cells and dendritic cells seems to shi the immunity toward
interleukin- 10 secretion and a more anti- inammatory state as an additional survival advantage for the virus (Martinez- Forero et al., 2008).
With the incorporation hypothesis, it is evident that searching for a single virus
causing a specic autoimmune disease will be fruitless. On the contrary, one must
identify all possible viruses capable of infecting the target cell of the autoimmunity.
In MS, oligodendrocytes would need to be characterized at the protein level to be
able to delineate precisely what epitopes the immune system reacts against. Further
research is required to investigate the role of the incorporation hypothesis in other
viral- induced autoimmune diseases.
Consequences of the incorporation hypothesis
for autoimmunity
ree fundamental principles arise from the incorporation hypothesis, which diers
from the commonly cited molecular mimicry hypothesis of how viruses may trigger
autoimmunity:
1. All large, enveloped viruses will trigger some degree of autoimmunity. Naturally
occurring autoantibodies might spring from these infections and may even have
an essential function in clearing cellular debris from the circulation. Here a distinction needs to be made between autoimmunity and autoimmune disease,
where the latter is the combination of destroying the target cells and not being able
to regenerate cells with the same function. is will be the case with terminally differentiated cells such as oligodendrocytes or pancreatic island cells in diabetes.
2. Dierent viruses can give the same disease if they replicate in the same host cell.
A good example is HHV- 6A/ B in thyroid tissue, one of several viruses identied in this tissue as single or multiple infections associated with autoimmune
thyroid disease (Weider et al., 2022).
3. e same virus can give dierent autoimmune diseases depending on what host
cell they replicated in. Again HHV- 6A/ B can be found in several organs, like
thyroid tissue (Seyyedi et al., 2019), liver (Potenza et al., 2008), and brain (Dunn
et al., 2020), possibly contributing to autoimmunity against these organs.
Infectious Disease and Neurocognition
Moreover, the hypothesis or mechanism envisioned as the etiological agent
of viral- induced autoimmunity matters. Given systemic infections would not be
enough to cause the disease, as would be the case for molecular mimicry, the virus
must reach and replicate in the target organ. is unusual event is in line with the
concept that prevalent viruses might cause autoimmune disease in rare, genetically
susceptible individuals. It is also important to consider this alternative hypothesis
when planning to treat MS with specic antiviral drugs, as these then would need
to pass the blood– brain barrier to be ecient. Nevertheless, there are already some
treatments for MS that also work as antiviral on a systemic level.
Treatments of multiple sclerosis indirectly
targeting viral infections
Treatments of MS are generally immunomodulating, but interferon beta and
rituximab treatment can also be regarded as having an antiviral mode of action
(Sedaghat & Etemadifar, 2022). Interferon beta was the rst drug approved for MS,
although the exact mechanism of action in MS is still unclear. Interferons are the
primary early antiviral response of the immune system and are produced within an
hour of the viral infections. Signaling through the interferon receptor induces a profound upregulation of over 1000 genes, putting both the infected and uninfected
cells in an “antiviral” state and acting as an alarmin that will kick- start the immune
system (Hesse et al., 2009). Like cytokines in general, the function of interferons is to
activate the immune response quickly in the acute phase. On the other hand, chronic
administration will induce a negative feedback mechanism that will dampen the
immune response to protect against overreaction. It is probably this dampening effect of chronically administered interferon beta that downregulates the activity of
autoreactive immune cells and leads to a reduced number of relapses in MS. At the
same time, it will still give a broad antiviral eect, and MS patients treated with interferon beta have a lower risk of infections compared to other MS treatments (Luna
et al., 2020).
Since rituximab depletes CD20- positive B cells, the reservoir for EBV, it is not
impossible that the drug also simultaneously reduces the viral burden of EBV
as it targets the autoreactive B cells (Cencioni et al., 2021; Dreyfus, 2011). is
strategy has been used to treat EBV- related hepatitis (Ohta et al., 2006), posttransplant lymphoproliferative disorder (Styczynski et al., 2009), and lymphomatoid
granulomatosis aer renal transplantation (Castrale et al., 2011).
Future directions
MS is considered an autoimmune disease; however, the exact etiology remains to be
elucidated. Yet, viruses continue to be seen as the most plausible triggers, and, as we
Multiple Sclerosis 325
have given examples of in this chapter, the hit- and- run principle can leave traces of
autoimmunity even long aer the viral infection has been cleared. Moreover, the vast
abundance of viruses in the human population (Virgin, 2014), whether reactivating
from latency or as opportunistic infections, will profoundly impact the immune
system. It is, therefore, hard to consider any immune reactions without taking viruses into account (Schönrich et al., 2022; Virgin et al., 2009). Learning more about
the viral composition of our natural biota and the impact of colonization of common
viruses on our immune system will lead us to a better understanding of plausible
detrimental eects this might have. To explore these aspects of the human body, it
would be benecial to include infected cells in the Protein Atlas, a fantastic resource
that maps protein expression of normal and cancer cells and tissues. However, this
is a daunting project requiring many skillful researchers and substantial economic
support at a basic research level.
If indeed it turns out that common viruses are causing autoimmunity in a subset
of the infected individuals, should we then develop a vaccine against them? Several
of these eorts are already on their way (Cohen, 2018), but many questions are le
to understand before one can eciently utilize vaccines without causing unintended
side eects. Most associations with autoimmune diseases have been established
through serology, showing an increase of antiviral antibodies directed against intracellular viral proteins, like EBNA1 for EBV or immediate early protein (IE) for
HHV- 6A. e question is whether it is “good” or “bad” to have antibodies against
intracellular viral proteins. Antibodies directed against non- structural intracellular
proteins will not be neutralizing in the sense that they would stop propagation and
dissemination of the virus and would, therefore, not protect against either infection
or reactivation. ese antibodies could potentially be considered a pseudo- marker
for increased viral infection, as they have to be formed when lysed cells are leaking
out their intracellular content and should therefore be proportional to the number of
virus- infected cells killed. e function of these antibodies might be to clear the cell
debris from the circulation and may, therefore, be benecial for our health. Although
this function may be enhanced by vaccination, it might be better to target the infection early in infancy or by enhancement of the mother’s immunity by increasing
neutralizing antibodies passing over the placenta.
Given that herpesviruses are well established in the human population, an evolutionary advantage must be hidden here. One example was illustrated in the
chronic, but not the acute, herpesvirus infection of mice that protected the animals
from lethal bacterial infection. e explanation might be that the immune system
was already slightly activated and, therefore, better prepared to ght other pathogens (Barton et al., 2007). us, eradicating these common viruses might leave a
niche open for other pathogens that we are less well adapted to. Nevertheless, the
role infections play in modifying our immune system is an essential aspect of MS
and other autoimmune diseases, and it also might shed some light on neuropsychiatric and neurocognitive impairments where similar mechanisms could be explored
(Alexopoulos & Dalakas, 2019).
Infectious Disease and Neurocognition
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