In the past rodents have been linked as the vectors for transmission of
enteroviruses causing myocarditis in the human population. Based on this
observation Niklasson et al studied the small rodent Clethrionomys
glareolus with the intent of isolating new picornaviruses that have the
potential ability to cause myocarditis in humans. Niklasson et al
isolated a new picornavirus prototype, which they subsequently named
Ljungan virus after the Ljungan River in Sweden where the rodents carrying
the virus were trapped. Three strains of this virus were isolated and
named Ljungan 87-012, Ljungan 174F and Ljungan 145SL. The molecular data
of these newly isolated viruses confirmed that they were indeed
picornaviruses. Sequencing of the Ljungan virus revealed a 52% homology
in the 5* noncoding region of the genome with the Mengo virus of the
cardiovirus genus. This similarity may reflect the ability of the virus
to replicate in rodents. In addition, the capsid proteins of the newly
isolated virus are 70% homologous with the capsid proteins of the human
pathogen echovirus 22. This homology may also reflect the potential
ability of Ljungan virus to infect humans. The Ljungan virus produces no
apparent disease in Clethrionomys glareolus, which suggests that the
rodent may be a reservoir for the virus
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While enteroviruses have long been believed to be the most common agent
of
myocarditis this link is not fully supported because of the lack of
evidence that localizes the virus to dying or inflamed heart cells. In a
study done by Li et al., a direct link between the enterovirus infection
and a percentage of myocarditis and dilated cardiomyopathy (DCM) cases was
made using an improved immunohistochemical technique. This technique uses
an enterovirus group-specific monoclonal antibody (mAb) that reacts with
a nonneutralizing epitope on the capsid protein VP1 of enteroviruses.
Uses of this technique allow enteroviral antigen to be detected in
myocardial samples. In this study myocardial samples were obtained from
patients with myocarditis or DCM. Enteroviral capsid protein was found in
81.8% of patients with myocarditis and in 75% of patients with DCM while
no capsid proteins were found in the controls. In addition, RT-NPCR
testing revealed that 54.5% of myocarditis patients and 37.5% of DCM
patients had viral RNA in their tissues. The imunohistochemistry
technique localized infected cells adjacent to dying or dead myocytes,
which indicates a direct relationship between the enterovirus infection
and pathological changes in the myocardium.
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While nutrition has long been believed to increase the susceptibility to
viral infection because of its ability to compromise the immune system, in
a recent study, researcher Melinda Beck found that a deficient diet can
help select for mutations in the viral genome so as to increase virulence.
Beck focused specifically on the effects of selenium deficiency on the
pathogenicity of the picornavirus coxsackievirus B3/0 (CVB3/0), which is a
benign strain of the myocarditis causing CVB3.
In this study Beck infected Se-adequate mice with CVB3/0 and
Se-deficient mice with the same strain. Se-adequate mice infected with the
CVB3/0 did not develop myocarditis while the Se-deficient mice developed
mild myocarditis. In addition, it was also found that Se-deficient mice
had increased virus titres in the body when compared to Se-adequate mice.
Beck concluded that there are two reasons why the benign strain turned
virulent in the Se-deficient mice. First, it is possible that the
deficiency compromised the immune system, which then allowed the virus to
replicate at high titres in the heart. A second explanation is that a
deficiency may have lead to a mutation in the virus making it virulent.
Virus that was isolated from the Se-deficient mice revealed six nucleotide
changes in the genomic sequence. These six changes were found to exist in
other virulent strains of CVB3 and it was also found that once these
mutations had occurred even mice that were Se-adequate became susceptible
to myocarditis when infected with this virus. In the body Se acts as an
antioxidant thus lack of Se leads to oxidative stress on the body. Thus it
is believed that the oxidative stress lead to the genomic changes. Hence
Beck concludes that malnutrition can lead to increased oxidative stress
which not only compromises the immunity but can also alter the viral
genome and thus lead to increased viral susceptibility.
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Enterovirus infection has been suspected as a causative agent of ALS, a
motor neuron disease that leads to degeneration of motor neurons in the
brain stem leading to paralysis and death. In order to correlate
persistent enterovirus infection wit h the development of ALS, Berger et
al. Used RT-PCR and RT-IS-PCR on formaldehyde-fixed spinal cord samples
from 17 patients with ALS and 29 spinal cord samples from control
patients. The RT-PCR analysis revealed that in 88.3% of ALS patients
enterovirus nucleic acid was evident. Using the RT-IS-PCR analysis,
nucleic acid was also found in 76.4% of ALS. The neuronal cells positive
for viral genome were localized to the gray matter of spinal cord patients
with ALS. The detected enterovirus nucleic acid was sequenced and in the
5* noncoding region there was an 86-94% homology between the PCR products
and the enterovirus echovirus 7. This evidence suggests a strong
relationship between the presence of enteroviral genomic sequences in
neurons and the development of ALS. However, the evidence does not
elucidate the mechanism that leads to the destruction of motor neurons nor
does it suggest that echovirus 7 is specifically the cause of ALS.
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On June 17, 1999 the ACIP recommended to change the routine
poliomyelitis vaccination schedule in the U.S. from the sequential
schedule of inactivated poliovirus vaccine (IPV) followed by live oral
poliovirus vaccine (OPV) which was started in 1997, to an all IPV
schedule. Starting January 1, 2000, all children will receive four doses
of IPV at ages 2, 4, and 16-18 months, as well as at age 4-6 years. The
reason for the change is in order to eliminate the risk for
vaccine-associated paralytic polio (VAPP). Since 1979, the only cases of
indigenous poliomyelitis reported in the U.S. have been associated with
OPV. VAPP is associated with OPV with a risk of one case per 2.4 million
doses distributed. In the U.S., OPV will only be used for special
circumstances such as: 1) in mass vaccination campaigns to control
outbreaks of paralytic polio, 2) in the case of unvaccinated children who
will be traveling in less than 4 weeks to polio endemic areas, and 3) in
cases where parents do not accept the recommended number of vaccine
injections for their children. While soon OPV will have limited
availability in the U.S., OPV will continue to be used in other areas
where polio is endemic, as its use will help facilitate the global polio
eradication initiative.
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The crystal structure of coxsackievirus A9 has been solved to 2.9
Angstrom resolution! What is useful about this is that the structure along
the five-fold axis provides new information about the uncoating mechanism
of enteroviruses. It has been found that Coxsackievirus A9 may bind a
larger natural pocket factor than other picornaviruses. This observation
may prove helpful in the design of new antiviral compounds for
enteroviruses.
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AG7088 has been found by protein structure-based design methodologies,
to be a potent and irreversible inhibitor of human rhinovirus 3C protease.
Thus AG7088 is a promising candidate for a rhinovirus antiviral agent.
The reason why a protease inhibitor can act as an antiviral agent is that
viral proteases are needed for cleavage of viral precursor polyproteins
into structural and enzymatic proteins which are essential for viral
replication. In addition to acting as a protease inhibitor for
rhinoviruses, this agent has also been shown to reduce the replication of
other picornaviruses such as Coxsackie A21 and B7, Enterovirus 70, and
echovirus 11. Because of these findings, AG7088 is a very promising
antiviral candidate, and is currently undergoing phase I clinical trials
in humans.
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The structure of poliovirus I complexing with its extracellular
receptor, the 3-domain CD155, has been determined to 22 Angstrom
resolution! CD155 binds in the poliovirus "canyon" in a similar way that
ICAM-1 binds to the "canyon" of human rhinovirus. However the orientation
of the long, slender CD155 molecule relative to the poliovirus surface is
different from the orientation of ICAM-1 to rhinovirus. Binding in the
"canyon" may be a trigger for initiation of subsequent uncoating steps
required for viral infection.
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A new technique has been developed for detecting enteroviruses and
rhinoviruses: reverse transcription-polymerase chain reaction (RT-PCR).
This new technique is more rapid and sensitive than the traditional
methods of virus isolation. It makes use of panthanide chelate labeled
probes and time-resolved fluorometry in order to amplify and detect the
presence of enteroviruses and rhinoviruses simultaneously. This new
technique may soon be a routine diagnostic technique for enteroviral and
rhinoviral infections.
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Lobert, Pierre-Emmanuel et al. "A coding RNA sequence acts as a replication signal in cardioviruses." Proc. Natl. Acad. Sci, Spet 1999, 96: 11560-11565.
Researchers discovered a 130 nucleotide sequence in the VP-2 region of the cardioviruses Theiler*s virus and Mengo*s virus that was found to serve as a cis-acting signal for genomic replication. These signal regions could be exchanged between the two viruses and it was found that the replication function was conserved. This 130-nt sequence was found to control only the initiation of replication and not the translational efficiency. While the 130 nucleotide sequence is conserved in both viruses it is believed that only a smaller 62 nucleotide sequence acts as the actual signal for replication, and point mutations affecting an even smaller region (9 nucleotides) inhibits replication.
topBeck, Melinda. "Selenium and host defense towards viruses." Proceedings of the Nutrition Society, 1999, 58: 707-711.
Berger, M.M, et al. "Detection and cellular localization of enterovirus RNA sequences in spinal cord of patients with ALS." Neurology, Jan 2000, 54: 20-25.
Hendry, E. et. al., "The crystal structure of coxsackievirus A9: new insights into the uncoating mechanisms of enteroviruses," Structure Fold des, 1999 Dec 15, 7(12):1527-38
Li, Y. et al. "Enteroviral Capsid Proteins VP1 Is Present in Myocardial Tissues From Some Patients With Myocarditis or Dilated Cardiomyopathy." Circulation, 2000 Jan 25, 101 (3): 231-4.
Lobert, Pierre-Emmanuel et al. "A coding RNA sequence acts as a replication signal in cardioviruses." Proc. Natl. Acad. Sci, Spet 1999, 96: 11560-11565.
Lonnrot, Salminen, et. al., "Diagnosis of enterovirus and rhinovirus infections by RT-PCR and time-resolved fluorometry with lanthanide chelate labeled probes," Journal of Medical Virology, 1999, Nov,59(3):378-84
Niklasson, B. et al. "A New Picornavirus isolated from Bank Voles (Clethrionomys glareolus)." Virology, 1999 Mar 1, 255(1): 86-93.
"Notice to Readers: Recommendations of the Advisory Committee on Immunization Practices: Revised Recommendations for Routine Poliomyelitis Vaccination," MMWR Weekly July 16, 1999/48(27);590
Patrick and Binford, et. al., "In Vitro Antiviral Activity of AG7088, a Potent Inhibitor of Human Rhinovirus 3C Protease," Antimicrobial Agents and Chemotherapy, Oct. 1999, Vol 43, No 10: 2444-2450
Yongning, Bowman, et. al., "Interaction of the poliovirus receptor with poliovirus," Journal of Neurophysiology, Vol 97, No 1:79-84, January 4, 2000
