Posts Tagged ‘parvovirus’

Virus logistics – vimentin is required for parvovirus infection

Thursday, July 11th, 2013

Cytoskeleton Parvoviruses have always been a bit of a mystery because they are very fussy about the types of cell they will grow in. Mostly, that has been explained as needing actively-dividing cells which are passing through S phase of the cell cycle so that the virus can replicate its DNA genome along with that of the host cell. But maybe that’s not the full story.

The cytoskeleton – a network of cellular scaffolding – is more complicated than you might think. Although it just seems like just a bunch of microscopic fibres, it has multiple important tasks, giving cells their shape, allowing them to move and acting as the transport network of the cell, shifting “stuff” (technical term there) from one place to another. the reason it is able to perform these varied jobs is because it consists of not just one but a variety of different types of filaments – actin, lamins, etc. One of the so-called intermediate filaments is vimentin, which has an important transport role in the cytoplasm.

Working with a mouse parvovirus (MVM) often used for laboratory studies of this virus group, a new paper in Virology shows that disrupting the vimentin part of the cytoskeleton inhibits virus replication. This seems to be because the virus is affected just after it has escaped from endosomes shortly after uptake into host cells, but also because new virus particles fail to accumulate near the nucleus as they normally do. Both of these blockages point to the role of vimentin in vesicular transport. And it’s not just parvovruses that need vimentin – herpesviruses do too (Hertel, L. (2011) Herpesviruses and intermediate filaments: close encounters with the third type. Viruses, 3(7), 1015-1040), and possibly dengue virus and HIV also.

Unfortunately, you’re not likely to be swallowing any drugs which disrupt your cytoskeleton because you are infected with a virus – that would be a really bad idea. But in terms of understanding how all the various components invoked in virus replication are moved to the correct location at the right time, the vimentin story is turning out to be very interesting.


The intermediate filament network protein, vimentin, is required for parvoviral infection. Virology. 06 Jul 2013 pii: S0042-6822(13)00358-9. doi: 10.1016/j.virol.2013.06.009
Intermediate filaments (IFs) have recently been shown to serve novel roles during infection by many viruses. Here we have begun to study the role of IFs during the early steps of infection by the parvovirus minute virus of mice (MVM). We found that during early infection with MVM, after endosomal escape, the vimentin IF network was considerably altered, yielding collapsed immunofluorescence staining near the nuclear periphery. Furthermore, we found that vimentin plays an important role in the life cycle of MVM. The number of cells, which successfully replicated MVM, was reduced in infected cells in which the vimentin network was genetically or pharmacologically modified; viral endocytosis, however, remained unaltered. Perinuclear accumulation of MVM-containing vesicles was reduced in cells lacking vimentin. Our data suggests that vimentin is required for the MVM life cycle, presenting possibly a dual role: (1) following MVM escape from endosomes and (2) during endosomal trafficking of MVM.

How Parvoviruses Escape Interferon Control

Tuesday, May 28th, 2013

MVM Most cell types in mammalian hosts detect virus infection via pattern recognition receptors (PRRs), which sense the nucleic acid products of virus replication. The RIG-I-like receptors (RLRs), RIG-I (retinoic acid inducible gene-I) and MDA5 (melanoma differentiation-associated gene 5), are involved in sensing cytosolic RNA species, and activation via the adapter molecule MAVS leads to the production of type I IFNs, via IRF3, and of pro-inflammatory cytokines, via NF-κB.

This paper examines the role of MAVS, which is involved in the detection of RNA Pol III-synthesized RNA intermediates in response to dsDNA viruses. The results suggest that the Minute virus of mice parvovirus (MVM) efficiently evades antiviral immune mechanisms imposed by type I IFNs. Clever virus – small, but perfectly formed.


Parvovirus evades interferon-dependent viral control in primary mouse embryonic fibroblasts. Virology. 2013 May 12. pii: S0042-6822(13)00173-6. doi: 10.1016/j.virol.2013.03.020
Engagement of innate viral sensors elicits a robust antiviral program via the induction of type I interferons (IFNs). Innate defense mechanisms against ssDNA viruses are not well defined. Here, we examine type I IFN induction and effectiveness in controlling a ssDNA virus. Using mouse embryonic fibroblasts (MEFs), we found that a murine parvovirus, minute virus of mice (MVMp), induced a delayed but significant IFN response. MEFs deficient in mitochondrial antiviral signaling protein (MAVS) mounted a wild-type IFN response to MVMp infection, indicating that RIG-I-dependent RNA intermediate recognition is not required for innate sensing of this virus. However, MVMp-induced IFNs, as well recombinant type I IFNs, were unable to inhibit viral replication. Finally, MVMp infected cells became unresponsive to Poly (I:C) stimulation. Together, these data suggest that the MVMp efficiently evades antiviral immune mechanisms imposed by type I IFNs, which may in part explain their efficient transmission between mice.


First detailed characterization of a novel human virus

Friday, November 11th, 2011

PARV4 Parvoviruses are small non-enveloped, icosahedral DNA viruses with a diameter of 18–26 nm that encapsidate a single-stranded genome of approximately (~)5–6 kb. To date, there are a number of parvoviruses known to infect humans, including adeno-associated viruses (AAVs), parvovirus B19 (B19V), and two newly identified human parvoviruses, which are the human bocavirus (HBoV) and human parvovirus 4 (PARV4).

HBoV was firstly identified in respiratory samples from children with lower respiratory tract infections and subsequently proven epidemiologically to be associated with the diseases. PARV4 was initially found in a blood sample from an intravenous drug user with acute viral infection syndrome. Subsequently, the PARV4 genome was detected in human plasma pools at a low titer. PARV4 had also been found in the livers of hepatitis C virus-positive individuals and the bone marrow of HIV-positive individuals. Recently, PARV4 DNA was detected in cerebrospinal fluid of two children with encephalitis of unknown etiology – however, the disease association of PARV4 remains unclear.

HBoV has been classified as a member in the genus Bocavirus based on the similarity of its genome sequence with those of the two animal bocaviruses. However, the known PARV4 incomplete genome, which lacks information of the terminal repeats, does not show a close relationship to any of the known parvoviruses in the genera of the family Parvoviridae that have been classified to date. This has led to the proposed classification of the PARV4 and PARV4-like viruses as members in a new genus called Partetravirus in the family Parvoviridae by the International Committee on Taxonomy of Viruses (ICTV).

Little is known about the gene expression of PARV4 and the function of PARV4 proteins. Since the PARV4 has not been cultured in vitro, and the full-length genome with terminal repeats has not been sequenced, researchers profiled the gene expression of PARV4 by transfecting a replication-competent PARV4 genome. This study has revelealed for the first time the detailed transcription map of PARV4, which can be beneficial for subsequent study of PARV4 infection.


Molecular characterization of the newly identified human parvovirus 4 in the family Parvoviridae. Virology. Oct 30 2011
Human parvovirus 4 (PARV4) is an emerging human virus, and little is known about the molecular aspects of PARV4 apart from its incomplete genome sequence, which lacks information of the termini. We analyzed the gene expression profile of PARV4 using a nearly full-length HPV4 genome in a replication competent system in 293 cells. We found that PARV4 utilizes two promoters to transcribe non-structural protein- and structural protein-encoding mRNAs, respectively, which were polyadenylated at the right end of the genome. Three major proteins, including the large non-structural protein NS1a, whose mRNA is spliced, and capsid proteins VP1 and VP2, were detected. Additional functional analysis of the NS1a revealed its capability to induce cell cycle arrest at G2/M phase in ex vivo-generated human hematopoietic stem cells. Taken together, our characterization of the molecular features of PARV4 suggests that PARV4 represents a new genus in the family Parvoviridae.

Does human bocavirus infection depend on helper viruses?

Friday, September 16th, 2011

Human bocavirus Human bocavirus (HBoV) was discovered in 2005. HBoV has been detected in patients suffering from respiratory infections and gastrointestinal diseases, but a proof that HBoV is the causative agent in such cases is missing as it remains impossible so far to fulfil Koch’s modified postulates. The latter problem is caused by the fact that HBoV is difficult to propagate in cell culture and that no animal model is available.

Since HBoV infections are accompanied by co-pathogens in a very high frequency, it has been suggested that HBoV is a passenger rather than a pathogen in airway infections, despite the fact that HBoV causes a productive infection with viral shedding, viremia, and putative persistence in different organs. Although HBoV meanwhile was classified as an autonomous parvovirus rather than a Dependovirus like the Adeno-associated virus (AAV), there remains the possibility that HBoV infections depend on helper viruses or at least contributes synergistically to the clinical course of disease.


Does human bocavirus infection depend on helper viruses? A challenging case report. Virology Journal 2011, 8: 417 doi:10.1186/1743-422X-8-417
A case of severe diarrhoea associated with synergistic human bocavirus type 1 (HBoV) and human herpes virus type 6 (HHV6) is reported. The case supports the hypotheses that HBoV infection under clinical conditions may depend on helper viruses, or that HBoV replicates by a mechanism that is atypical for parvoviruses, or that HBoV infection can be specifically treated with cidofovir.

Productive Parvovirus B19 Infection of Primary Human Cells

Tuesday, June 21st, 2011

Parvovirus Human parvovirus B19 (B19V) is the etiological agent of fifth disease seen in children, aplastic crisis in sickle cell disease patients, chronic anemia in immunocompromised patients, and hydrops fetalis in pregnant women. 35 years after its discovery, it was still not possible to propagate B19V in vitro in a productive and sustainable manner, which delayed progress in the study of B19V pathogenesis, and consequently finding ways to treat patients infected with B19V.

Researchers cultured human erythroid progenitor cells under hypoxic conditions by mimicking the natural niches of human bone marrow. This work demonstrates, for the first time, a long-term B19V infection of ex vivo expanded erythroid progenitor cells. This finding will largely facilitate the study of the mechanisms underlying B19V infection and more importantly, identification of approaches to treat B19V infection. Identification of the cellular signaling pathways in regulating B19V replication sheds light on the virus-host interaction and will nominate potential candidates for anti-virus drug targeting.


Productive Parvovirus B19 Infection of Primary Human Erythroid Progenitor Cells at Hypoxia Is Regulated by STAT5A and MEK Signaling but not HIFα. (2011) PLoS Pathog 7(6): e1002088. doi:10.1371/journal.ppat.1002088
Human parvovirus B19 (B19V) causes a variety of human diseases. Disease outcomes of bone marrow failure in patients with high turnover of red blood cells and immunocompromised conditions, and fetal hydrops in pregnant women are resulted from the targeting and destruction of specifically erythroid progenitors of the human bone marrow by B19V. Although the ex vivo expanded erythroid progenitor cells recently used for studies of B19V infection are highly permissive, they produce progeny viruses inefficiently. In the current study, we aimed to identify the mechanism that underlies productive B19V infection of erythroid progenitor cells cultured in a physiologically relevant environment. Here, we demonstrate an effective reverse genetic system of B19V, and that B19V infection of ex vivo expanded erythroid progenitor cells at 1% O2 (hypoxia) produces progeny viruses continuously and efficiently at a level of approximately 10 times higher than that seen in the context of normoxia. With regard to mechanism, we show that hypoxia promotes replication of the B19V genome within the nucleus, and that this is independent of the canonical PHD/HIFα pathway, but dependent on STAT5A and MEK/ERK signaling. We further show that simultaneous upregulation of STAT5A signaling and down-regulation of MEK/ERK signaling boosts the level of B19V infection in erythroid progenitor cells under normoxia to that in cells under hypoxia. We conclude that B19V infection of ex vivo expanded erythroid progenitor cells at hypoxia closely mimics native infection of erythroid progenitors in human bone marrow, maintains erythroid progenitors at a stage conducive to efficient production of progeny viruses, and is regulated by the STAT5A and MEK/ERK pathways.