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The human parvovirus B19 and its interactions in vivo
Pathol Biol 2002 ; 50 : 283, 284 2002 Éditions scientifiques et médicales Elsevier SAS. Tous droits réservés S0369-8114(02)00304-8/EDI
Editorial
The human parvovirus B19 and its interactions in vivo Frédéric Morinet ∗ Service de microbiologie, hôpital Saint-Louis, 1, avenue Claude Vellefaux, 75475 Paris cedex 10, France
parvovirus B19 / immune system / environmental factors
The human parvovirus B19 was discovered in 1975 by Yvonne Cossart at the Public Health Laboratory in London. As for each viral infection, some questions must be advocated. First, are we all susceptible to a B19 infection? Is our genetic background able to avoid this infection? This point was resolved by Kevin Brown who published in 1993 that the viral receptor is the P blood group antigen and in 1994 that some minorities might not be infected by B19 since their cells do not express constitutively P antigen. Srivastava in this issue on B19 tries to define the possible existence of a coreceptor with the help of recombinant human parvovirus B19 vector. Effectively, the P receptor antigen is present in many types of cells in vivo but only viral entry and gene expression occur in erythroid cells. Secondly, are we infected by one strain or by a viral population with some degree of heterogeneity? No clear data are available to resolve this point but, as mentioned by Nunoue (this issue), in patients who have B19 protracted infection multiple strains may be detected in a same individual. Do they exist at an indetectable level in primary infected patients and, only in a context of persistent infection they will replicate at a sufficient high level to be no longer ignored? Nunoue expounds clearly the differences between the host and the virus dominant models. In the latter the phenotype, i.e. the clinical manifestations correlate with the virus genome type whereas in the former it is the reverse, the host factors determine the type of viral infection. Preliminary data show that, in B19 infections, host dominant model seems a priori involved; the possible link between the association of the genotype V and B19 encephalopathy remains controversial [1]. Occurrence of synonymous rather non synonymous muta-
∗ Correspondence and reprints.
E-mail address: [email protected] (F. Morinet).
tions in parvovirus evolution was reported by Lukashov [2]. This rule must be evaluated in the detection of two scarse variants V9 and K71 which differ around 10% from B19 (Söderlund-Venermo, this issue). Their association to B19 specific clinical situations were not reported. In addition, the K71 variant was detected in skin biopsy from healthy patients; its virological status was not defined at present, i.e. competent or defective for replication. The third question which deserves to be brought up by this data is the following: does the skin represent a reservoir for B19 persistence? Söderlund-Venermo suggests in fact that in addition to this tissue, at least bone marrow and synovial cells may harbour B19 latent genomic DNA. Arthropathy may be a stigma of primary infection in adults as described by White in 1985 and this is clearly accepted. More difficult is to reconciliate the responsability of B19 in rheumatoid arthritis; we must rather considered that B19 persistent in synovial tissues is amplified by inflammatory cytokines. Clinical manifestations due to B19 human parvovirus infection may involve a role more or less marked of the immune system. This role is highly probable in erythema infectiosum (fifth disease) linked to a primary B19 infection in children by Mary Anderson in 1983, where immune complexes are involved and for arthropathy, where in addition to immune complex deposition, exacerbation of interleukin 6 synthesis by one of the five viral proteins, the non structural NS1, is detected. This data was reported by Moffatt in 1996. Synthesis of B19 IgG antibody to viral capsid protein involves TCD4+ -B cell cooperation, as suggested by persistent B19 anaemia in children with X-linked hyper IgM syndrome but IgM specific production seems T independent explaining their high level of B19 specific IgM [3]. Such an IgM response T indepen-
284
F. Morinet
dent was mentionned for an animal parvovirus, the minute virus of mice [4]. The signification of humoral response against the NS1 protein is evaluated by Modrow (this issue). Macrophage activation syndrome involves probably an amplified cytotoxic TCD8+ response against epitopes of NS1 B19 protein which is depicted by Klenerman in this issue. The role of the immune system is just advocated to explain some cases of B19 myocarditis, perhaps by molecular mimicry between viral protein and cardiac tissue. In fact, the majority of fetal, neonatal and infant myocarditis and the acute erythroblastopenia observed in patient with sickle cell disease described by John Pattison in 1981 seem to result of a direct effect of B19 virus on precursors of erythroid cells. In such cells, Mortimer and Young have showed in 1983–1984 that B19 replicates fully; the death of infected proerythroblasts involves at least apoptosis in vitro and in vivo as summed up in the first chapter of this issue. Others mecanisms of death were advocated and must be considered. An inhibition of erythroid colony formation by empty viral capsid and necrosis of infected erythroid cells might to coexist in addition to apoptosis. Once more the viral protein implicated in apoptosis is the NS1; if the four other viral proteins are involved in the programmed cell death remains to determine. The high level of plasmatic viraemia which results of infection of erythroid cells may be detected by the polymerase chain reaction as summarised by Zerbini (this issue). The question is, how relevant is the quantitative viral DNA detection by gene amplification in regard to the infectious potential of the number of DNA copies detected? This crucial point is tackled by Laub (this issue) aptness of the risk of B19 transmission by blood products. Yet, Joan Pehta [5] in a meeting concerning parvovirus
B19 and transfusion medicine suggested that below 104 genome copies per ml, no viral infection occurred in recipients of “B19 DNA” contamined plasma pools. Finally, is there a possibility to find a common physiological trunck to explain the responsability of B19 in erythroblastopenia in sickle cell patients, arthropathy, fetal death, its selective amplification in bone marrow and possible involvement in vasculitis? All these situations are characterised by a low oxygen tension level: patients with sickle cell disease are in chronic hypoxia, the placenta develops during the first trimester in hypoxic conditions, inflammatory clinical conditions are associated with anemia and from a physiological point of view, the oxygen tension in bone marrow is low, under 3%. The possible upregulation of B19 gene expression by relative hypoxia merits further investigations [6].
REFERENCES 1 Yoto Y, Kudoh T, Haseyama K, Tsutsumi H. Human parvovirus B19 and meningoencephalitis. Lancet 2001; 358: 2168. 2 Lukashov V, Goudsmit J. Evolutionary relationship among parvoviruses: virus–host coevolution among autonomous primate parvoviruses and links between adeno-associated and avian parvoviruses. J Virol 2001; 75: 2729-40. 3 Seyama K, Kobayashi R, Hasle H, Apter AJ, Rutledge JC, Rosen D, Ochs H. Parvovirus B19-induced anemia as the presenting manifestation of X-linked hyper-IgM syndrome. J Infect Dis 1998; 178: 318-24. 4 Bachmann MF, Zinkernagel RM. The influence of virus structure on antibody responses and virus serotype formation. Immunol Today 1996; 17: 553-8. 5 Brown KE, Young NS, Barbosa LH. Parvovirus B19: implications for transfusion medicine. Summary of a workshop. Transfusion 2001; 41: 130-5. 6 Ebbesen P, Zachar V. Oxygen tension and virus replication. Acta Virologica 1998; 42: 417-21.
Editorial
The human parvovirus B19 and its interactions in vivo Frédéric Morinet ∗ Service de microbiologie, hôpital Saint-Louis, 1, avenue Claude Vellefaux, 75475 Paris cedex 10, France
parvovirus B19 / immune system / environmental factors
The human parvovirus B19 was discovered in 1975 by Yvonne Cossart at the Public Health Laboratory in London. As for each viral infection, some questions must be advocated. First, are we all susceptible to a B19 infection? Is our genetic background able to avoid this infection? This point was resolved by Kevin Brown who published in 1993 that the viral receptor is the P blood group antigen and in 1994 that some minorities might not be infected by B19 since their cells do not express constitutively P antigen. Srivastava in this issue on B19 tries to define the possible existence of a coreceptor with the help of recombinant human parvovirus B19 vector. Effectively, the P receptor antigen is present in many types of cells in vivo but only viral entry and gene expression occur in erythroid cells. Secondly, are we infected by one strain or by a viral population with some degree of heterogeneity? No clear data are available to resolve this point but, as mentioned by Nunoue (this issue), in patients who have B19 protracted infection multiple strains may be detected in a same individual. Do they exist at an indetectable level in primary infected patients and, only in a context of persistent infection they will replicate at a sufficient high level to be no longer ignored? Nunoue expounds clearly the differences between the host and the virus dominant models. In the latter the phenotype, i.e. the clinical manifestations correlate with the virus genome type whereas in the former it is the reverse, the host factors determine the type of viral infection. Preliminary data show that, in B19 infections, host dominant model seems a priori involved; the possible link between the association of the genotype V and B19 encephalopathy remains controversial [1]. Occurrence of synonymous rather non synonymous muta-
∗ Correspondence and reprints.
E-mail address: [email protected] (F. Morinet).
tions in parvovirus evolution was reported by Lukashov [2]. This rule must be evaluated in the detection of two scarse variants V9 and K71 which differ around 10% from B19 (Söderlund-Venermo, this issue). Their association to B19 specific clinical situations were not reported. In addition, the K71 variant was detected in skin biopsy from healthy patients; its virological status was not defined at present, i.e. competent or defective for replication. The third question which deserves to be brought up by this data is the following: does the skin represent a reservoir for B19 persistence? Söderlund-Venermo suggests in fact that in addition to this tissue, at least bone marrow and synovial cells may harbour B19 latent genomic DNA. Arthropathy may be a stigma of primary infection in adults as described by White in 1985 and this is clearly accepted. More difficult is to reconciliate the responsability of B19 in rheumatoid arthritis; we must rather considered that B19 persistent in synovial tissues is amplified by inflammatory cytokines. Clinical manifestations due to B19 human parvovirus infection may involve a role more or less marked of the immune system. This role is highly probable in erythema infectiosum (fifth disease) linked to a primary B19 infection in children by Mary Anderson in 1983, where immune complexes are involved and for arthropathy, where in addition to immune complex deposition, exacerbation of interleukin 6 synthesis by one of the five viral proteins, the non structural NS1, is detected. This data was reported by Moffatt in 1996. Synthesis of B19 IgG antibody to viral capsid protein involves TCD4+ -B cell cooperation, as suggested by persistent B19 anaemia in children with X-linked hyper IgM syndrome but IgM specific production seems T independent explaining their high level of B19 specific IgM [3]. Such an IgM response T indepen-
284
F. Morinet
dent was mentionned for an animal parvovirus, the minute virus of mice [4]. The signification of humoral response against the NS1 protein is evaluated by Modrow (this issue). Macrophage activation syndrome involves probably an amplified cytotoxic TCD8+ response against epitopes of NS1 B19 protein which is depicted by Klenerman in this issue. The role of the immune system is just advocated to explain some cases of B19 myocarditis, perhaps by molecular mimicry between viral protein and cardiac tissue. In fact, the majority of fetal, neonatal and infant myocarditis and the acute erythroblastopenia observed in patient with sickle cell disease described by John Pattison in 1981 seem to result of a direct effect of B19 virus on precursors of erythroid cells. In such cells, Mortimer and Young have showed in 1983–1984 that B19 replicates fully; the death of infected proerythroblasts involves at least apoptosis in vitro and in vivo as summed up in the first chapter of this issue. Others mecanisms of death were advocated and must be considered. An inhibition of erythroid colony formation by empty viral capsid and necrosis of infected erythroid cells might to coexist in addition to apoptosis. Once more the viral protein implicated in apoptosis is the NS1; if the four other viral proteins are involved in the programmed cell death remains to determine. The high level of plasmatic viraemia which results of infection of erythroid cells may be detected by the polymerase chain reaction as summarised by Zerbini (this issue). The question is, how relevant is the quantitative viral DNA detection by gene amplification in regard to the infectious potential of the number of DNA copies detected? This crucial point is tackled by Laub (this issue) aptness of the risk of B19 transmission by blood products. Yet, Joan Pehta [5] in a meeting concerning parvovirus
B19 and transfusion medicine suggested that below 104 genome copies per ml, no viral infection occurred in recipients of “B19 DNA” contamined plasma pools. Finally, is there a possibility to find a common physiological trunck to explain the responsability of B19 in erythroblastopenia in sickle cell patients, arthropathy, fetal death, its selective amplification in bone marrow and possible involvement in vasculitis? All these situations are characterised by a low oxygen tension level: patients with sickle cell disease are in chronic hypoxia, the placenta develops during the first trimester in hypoxic conditions, inflammatory clinical conditions are associated with anemia and from a physiological point of view, the oxygen tension in bone marrow is low, under 3%. The possible upregulation of B19 gene expression by relative hypoxia merits further investigations [6].
REFERENCES 1 Yoto Y, Kudoh T, Haseyama K, Tsutsumi H. Human parvovirus B19 and meningoencephalitis. Lancet 2001; 358: 2168. 2 Lukashov V, Goudsmit J. Evolutionary relationship among parvoviruses: virus–host coevolution among autonomous primate parvoviruses and links between adeno-associated and avian parvoviruses. J Virol 2001; 75: 2729-40. 3 Seyama K, Kobayashi R, Hasle H, Apter AJ, Rutledge JC, Rosen D, Ochs H. Parvovirus B19-induced anemia as the presenting manifestation of X-linked hyper-IgM syndrome. J Infect Dis 1998; 178: 318-24. 4 Bachmann MF, Zinkernagel RM. The influence of virus structure on antibody responses and virus serotype formation. Immunol Today 1996; 17: 553-8. 5 Brown KE, Young NS, Barbosa LH. Parvovirus B19: implications for transfusion medicine. Summary of a workshop. Transfusion 2001; 41: 130-5. 6 Ebbesen P, Zachar V. Oxygen tension and virus replication. Acta Virologica 1998; 42: 417-21.