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Paramyxoviruses and their role in disease
Paramyxoviruses
and Their Role in Disease By Bert K. Rima
M
EMBERS OF THE family Parunz)?uo\~il?‘due are RNA viruses that probably are responsible for more virus-related mortality than any other family of viruses.’ This article emphasizes their potential role in long-term persistent infection of the host, especially in Paget’s disease. Viruses of all three genera into which the family has been subdivided have been implicated in its etiology. Paramyxoviruses replicate primarily in the upper respiratory tract. and most infections are limited to this site. Systemic infection is rare except in the case of measles and mumps virus. Their propensity to establish persistent infection in cultured cells, as well as in infected hosts, has led these viruses to be suggested as causative agents for a number of human and animal diseases with characteristics of slow virus infections. In the virion, the nucleocapsid containing the negative sense RNA genome of 15.500 (-~400) nucleotides’ is surrounded by a lipid bilayer membrane from which viral glycoprotein spikes protrude. The spikes mediate attachment of the virus to host cell receptors and fusion of the viral membrane with that of the host cell to achieve infection. The paramyxoviruses are called negative strand viruses because the genomic RNA present in the virus particles is not capable of being translated directly into viral protein but must be transcribed before it can be translated. At no time during the life cycle of the paramyxoviruses is a DNA copy of the virus genome generated. Thus, these viruses cannot integrate their genomic information in the host DNA like other viruses which are involved in long-term infections. Because the half-life of these nucleocapsids is very short compared with DNA, persistent infections by paramyxoviruses require a constant low level of expression and
From the School of Biolo~
arzd Bw&mr.w-\,
The Qurcw ‘(
Universig of Belfast, Be(fust N Iwlurrd Address reprint requests to Bet? K. Rima, Ir PhD. Dilxsrotl o/ Genetic Engineering, School of Bioloa Queen k University qf Belfast.
and Biochernistr~, The
Medical
B&log,
Lishum Rd. Belfast BT9 7BL. N Ireland Copyright z’ 1994 by W. B. Saundws C’ompat~~ 0049.017219412304-0009$5.0011)
230
Cut/w.
97
replication of the virus. and this process muat occur without triggering the immune system. DISEASES ASSOCIATED PARAMYXOVIRUS
WITH
PERSISTENCE
‘I’hc best-described example of ;I long-rerm persistent infection of a paramyxovirus is supplied by subacute sclcrosing panencephalitix (SSPE).’ Between X and 10 years after primap measles, I in 300,000 children dies of this invariably lethal encephalitis, caused h> rampant replication of measles virus (MV) in the brain. Detailed histology showed the presence of inclusion bodies typical of paramyxoviruse\ in central nervous system (CNS) tissue from SSPE patients. but virus isolation experiments tailed at first. The finding that SSPE patients had \cr! high MV titers in both strum and CNS then confirmed the etiology. Later cocultivation 01’ brain and lymph node tissues with susceptible cell lines led to isolations of MV. The presence of MV antigen in the neurons of affected patients can bc demonstrated in all cases h! immunocytochemistry. The presence of MV RNA scqucnccs in the tissues has now been demonstrated directly by cloning and nucleotide sequencing. using nucleic acid probes ~‘oIdetection of viral RNA in in situ or northern blot hybridization. Finally. polymerasc chain reaction (PCR) also has been used to contirm the presence of MV in the brain of all patient>. Nevertheless. details of the pathogcnesia ot SSPE remain largely unknown. Persistent paramyxovirus infection has bccrl suggested to plav ;I role in a number (11‘othcl diseases (Table -1 ). In all cases. evidence cjhtained by in situ hybridization needs t’urthel. confirmation with other tcchniqucs. \uch ;i\ PCR. The primal-) cvidencc that led to the \uggc+ tion of involvcmcnt of ~~aramyxoviruac~ 111 Paget’s disease stems from observations that In certain focal lesions. ostcoclasts of patients contain tubular nuclear and cytoplasmic inclusion bodies characteristic of paramyxovirus.i Evidence for the prcsencc of viral antigens. but not virus isolation. has been obtained for SV5. parainfluenza virus type 3. respiratory s!;nc!,tial
Seminars ,n Art/w//sandf?heumat/sm,
Vol 23, No 4 (February),
1994:
pp 230-231
231
PARAMYXOVIRUSES
Table 1: Diseases With Potential Link to Persistent Paramyxovirus Evidence for Virus Implicated
Virus Isolation
Virus Antigen
Virus RNA by ISH
Virus RNA by PCR or Blotting
Serology
Epidemiology
SSPE
MV
+
+
+
+
+
MIBE
MV
+
+
+
+
+
+ -
ODE
CDV
+
+
MV
+ -
+
AICAH
+
+
+
+ -
MS
MV
?*
+
sv5
+
+ -
-
+
-
Disease
Crohn’s
MV
?* -
Paget’s
PIV3
-
+
sv5
-
+
MV
-
+
RSV
-
+
CDV
-
Abbreviations:
+
_
+
+ -
+
-
-
+
-
?* ?*
+
ISH, in situ hybridization; PCR, polymerase chain reaction: SSPE, subacute sclerosing panencephalitis; MV, measles
virus; MISE, measles inclusion body encephalitis; ODE, old dog encephalitis; CDV, canine distemper virus; AICAH, autoimmune chronically active hepatitis; MS, multiple sclerosis: SV5, simian virus 5; PIV3, parainfluenza virus 3; RSV, respiratory syncytial virus. *Ambiguous evidence or nonconfirmed reports.
virus, and MV.5,6 In one case, antigens of the last two viruses were present simultaneously.6 One study using in situ hybridization described the presence of MV nucleic acid in osteoclasts of Paget’s patients, but the virus was also found in osteoblasts7 This lack of specificity may reduce the importance of the findings. Recently, positive in situ hybridization with a canine distemper virus probe has been described for osteoclasts, osteocytes, and osteoblasts in 41% of Paget’s patients, but no other techniques were used.8 Seroepidemiological evidence for and against a link of this and other viruses to Paget’s disease has been presented. In conclusion, in situ hybridization has given
support for the presence of a number of paramyxoviruses in bone cells of affected patients. The lack of specificity could indicate that their presence may be an epiphenomenon in the life cycle of the osteoclast, and the role of this persistent infection in the disease remains to be defined. An animal model system would be beneficial for further analysis, and the use of canine distemper virus in one of its many natural hosts may be useful.
ACKNOWLEDGMENT The author thanks Drs Cosby and Wakefield for communicating unpublished findings on Crohn’s disease.
REFERENCES 1. Pringle CR: Paramyxoviruses and disease, in Russell WC, Almond JW (eds): Molecular Basis of Viral Disease. London, Cambridge University, 1987, pp 51-90 2. Galinski MS, Wechsler SL: The molecular biology of the paramyxovirus genus, in Kingsbury DW (ed): The Paramyxoviruses. New York, NY, Plenum, 1991, pp 41-82 3. Billeter MA, Cattaneo R: Molecular biology of defective measles viruses persisting in the human central nervous system, in Kingsbury DW (ed): The Paramyxoviruses. New York, NY, Plenum Press, 1991, pp 323-34.5 4. Mills BG, Singer FR: Nuclear inclusions in Paget’s disease of bone. Science 194:201-202,1976 5. Basle MF, Russell WC, Goswami KKK, et al: Para-
myxovirus antigens in osteoclasts from Paget’s disease bone tissue detected by monoclonal antibodies. J Gen Virol 66:2102-2110,1985 6. Mills BG, Singer FR, Werner LP, et al: Evidence for both respiratory syncytial virus and measles virus antigens in the osteoclasts of patients with Paget’s disease of bone. Clin Orthopaed Rel Res 183:303-311,1984 7. Basle MF, Fournier JG, Rozenblatt S, et al: Measles virus RNA detected in Paget’s bone tissue by in situ hybridisation. J Gen Virol67:907-913,1986 8. Gordon MT, Anderson DC, Sharpe PT: Canine distemper virus localised in bone cells of patients with Paget’s disease. Bone 12~195201,199l
and Their Role in Disease By Bert K. Rima
M
EMBERS OF THE family Parunz)?uo\~il?‘due are RNA viruses that probably are responsible for more virus-related mortality than any other family of viruses.’ This article emphasizes their potential role in long-term persistent infection of the host, especially in Paget’s disease. Viruses of all three genera into which the family has been subdivided have been implicated in its etiology. Paramyxoviruses replicate primarily in the upper respiratory tract. and most infections are limited to this site. Systemic infection is rare except in the case of measles and mumps virus. Their propensity to establish persistent infection in cultured cells, as well as in infected hosts, has led these viruses to be suggested as causative agents for a number of human and animal diseases with characteristics of slow virus infections. In the virion, the nucleocapsid containing the negative sense RNA genome of 15.500 (-~400) nucleotides’ is surrounded by a lipid bilayer membrane from which viral glycoprotein spikes protrude. The spikes mediate attachment of the virus to host cell receptors and fusion of the viral membrane with that of the host cell to achieve infection. The paramyxoviruses are called negative strand viruses because the genomic RNA present in the virus particles is not capable of being translated directly into viral protein but must be transcribed before it can be translated. At no time during the life cycle of the paramyxoviruses is a DNA copy of the virus genome generated. Thus, these viruses cannot integrate their genomic information in the host DNA like other viruses which are involved in long-term infections. Because the half-life of these nucleocapsids is very short compared with DNA, persistent infections by paramyxoviruses require a constant low level of expression and
From the School of Biolo~
arzd Bw&mr.w-\,
The Qurcw ‘(
Universig of Belfast, Be(fust N Iwlurrd Address reprint requests to Bet? K. Rima, Ir PhD. Dilxsrotl o/ Genetic Engineering, School of Bioloa Queen k University qf Belfast.
and Biochernistr~, The
Medical
B&log,
Lishum Rd. Belfast BT9 7BL. N Ireland Copyright z’ 1994 by W. B. Saundws C’ompat~~ 0049.017219412304-0009$5.0011)
230
Cut/w.
97
replication of the virus. and this process muat occur without triggering the immune system. DISEASES ASSOCIATED PARAMYXOVIRUS
WITH
PERSISTENCE
‘I’hc best-described example of ;I long-rerm persistent infection of a paramyxovirus is supplied by subacute sclcrosing panencephalitix (SSPE).’ Between X and 10 years after primap measles, I in 300,000 children dies of this invariably lethal encephalitis, caused h> rampant replication of measles virus (MV) in the brain. Detailed histology showed the presence of inclusion bodies typical of paramyxoviruse\ in central nervous system (CNS) tissue from SSPE patients. but virus isolation experiments tailed at first. The finding that SSPE patients had \cr! high MV titers in both strum and CNS then confirmed the etiology. Later cocultivation 01’ brain and lymph node tissues with susceptible cell lines led to isolations of MV. The presence of MV antigen in the neurons of affected patients can bc demonstrated in all cases h! immunocytochemistry. The presence of MV RNA scqucnccs in the tissues has now been demonstrated directly by cloning and nucleotide sequencing. using nucleic acid probes ~‘oIdetection of viral RNA in in situ or northern blot hybridization. Finally. polymerasc chain reaction (PCR) also has been used to contirm the presence of MV in the brain of all patient>. Nevertheless. details of the pathogcnesia ot SSPE remain largely unknown. Persistent paramyxovirus infection has bccrl suggested to plav ;I role in a number (11‘othcl diseases (Table -1 ). In all cases. evidence cjhtained by in situ hybridization needs t’urthel. confirmation with other tcchniqucs. \uch ;i\ PCR. The primal-) cvidencc that led to the \uggc+ tion of involvcmcnt of ~~aramyxoviruac~ 111 Paget’s disease stems from observations that In certain focal lesions. ostcoclasts of patients contain tubular nuclear and cytoplasmic inclusion bodies characteristic of paramyxovirus.i Evidence for the prcsencc of viral antigens. but not virus isolation. has been obtained for SV5. parainfluenza virus type 3. respiratory s!;nc!,tial
Seminars ,n Art/w//sandf?heumat/sm,
Vol 23, No 4 (February),
1994:
pp 230-231
231
PARAMYXOVIRUSES
Table 1: Diseases With Potential Link to Persistent Paramyxovirus Evidence for Virus Implicated
Virus Isolation
Virus Antigen
Virus RNA by ISH
Virus RNA by PCR or Blotting
Serology
Epidemiology
SSPE
MV
+
+
+
+
+
MIBE
MV
+
+
+
+
+
+ -
ODE
CDV
+
+
MV
+ -
+
AICAH
+
+
+
+ -
MS
MV
?*
+
sv5
+
+ -
-
+
-
Disease
Crohn’s
MV
?* -
Paget’s
PIV3
-
+
sv5
-
+
MV
-
+
RSV
-
+
CDV
-
Abbreviations:
+
_
+
+ -
+
-
-
+
-
?* ?*
+
ISH, in situ hybridization; PCR, polymerase chain reaction: SSPE, subacute sclerosing panencephalitis; MV, measles
virus; MISE, measles inclusion body encephalitis; ODE, old dog encephalitis; CDV, canine distemper virus; AICAH, autoimmune chronically active hepatitis; MS, multiple sclerosis: SV5, simian virus 5; PIV3, parainfluenza virus 3; RSV, respiratory syncytial virus. *Ambiguous evidence or nonconfirmed reports.
virus, and MV.5,6 In one case, antigens of the last two viruses were present simultaneously.6 One study using in situ hybridization described the presence of MV nucleic acid in osteoclasts of Paget’s patients, but the virus was also found in osteoblasts7 This lack of specificity may reduce the importance of the findings. Recently, positive in situ hybridization with a canine distemper virus probe has been described for osteoclasts, osteocytes, and osteoblasts in 41% of Paget’s patients, but no other techniques were used.8 Seroepidemiological evidence for and against a link of this and other viruses to Paget’s disease has been presented. In conclusion, in situ hybridization has given
support for the presence of a number of paramyxoviruses in bone cells of affected patients. The lack of specificity could indicate that their presence may be an epiphenomenon in the life cycle of the osteoclast, and the role of this persistent infection in the disease remains to be defined. An animal model system would be beneficial for further analysis, and the use of canine distemper virus in one of its many natural hosts may be useful.
ACKNOWLEDGMENT The author thanks Drs Cosby and Wakefield for communicating unpublished findings on Crohn’s disease.
REFERENCES 1. Pringle CR: Paramyxoviruses and disease, in Russell WC, Almond JW (eds): Molecular Basis of Viral Disease. London, Cambridge University, 1987, pp 51-90 2. Galinski MS, Wechsler SL: The molecular biology of the paramyxovirus genus, in Kingsbury DW (ed): The Paramyxoviruses. New York, NY, Plenum, 1991, pp 41-82 3. Billeter MA, Cattaneo R: Molecular biology of defective measles viruses persisting in the human central nervous system, in Kingsbury DW (ed): The Paramyxoviruses. New York, NY, Plenum Press, 1991, pp 323-34.5 4. Mills BG, Singer FR: Nuclear inclusions in Paget’s disease of bone. Science 194:201-202,1976 5. Basle MF, Russell WC, Goswami KKK, et al: Para-
myxovirus antigens in osteoclasts from Paget’s disease bone tissue detected by monoclonal antibodies. J Gen Virol 66:2102-2110,1985 6. Mills BG, Singer FR, Werner LP, et al: Evidence for both respiratory syncytial virus and measles virus antigens in the osteoclasts of patients with Paget’s disease of bone. Clin Orthopaed Rel Res 183:303-311,1984 7. Basle MF, Fournier JG, Rozenblatt S, et al: Measles virus RNA detected in Paget’s bone tissue by in situ hybridisation. J Gen Virol67:907-913,1986 8. Gordon MT, Anderson DC, Sharpe PT: Canine distemper virus localised in bone cells of patients with Paget’s disease. Bone 12~195201,199l