Publications

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induction of necroptotic cell death by viral activation of the rig-i or sting pathway.necroptosis is a form of necrotic cell death that requires the activity of the death domain-containing kinase rip1 and its family member rip3. necroptosis occurs when rip1 is deubiquitinated to form a complex with rip3 in cells deficient in the death receptor adapter molecule fadd or caspase-8. necroptosis may play a role in host defense during viral infection as viruses like vaccinia can induce necroptosis while murine cytomegalovirus encodes a viral inhibitor of necroptosis. to see how general ...201728060376
the viral bcl-2 homologs of kaposi's sarcoma-associated herpesvirus and rhesus rhadinovirus share an essential role for viral replication.ks-bcl-2 is a kaposi's sarcoma-associated herpesvirus (kshv)-encoded viral bcl-2 (vbcl-2) homolog which has apoptosis- and autophagy-inhibiting activity when expressed in transfected cells. however, little is known about its function during viral infection. as ks-bcl-2 is expressed during the lytic replication cycle, we used constitutively lytic and inducibly lytic kshv mutants to investigate the role of ks-bcl-2 during the lytic cycle. we show that kshv cannot complete the lytic replication cyc ...201728053098
comparative study of two models of combined pulmonary fibrosis and emphysema in mice.combined pulmonary fibrosis and emphysema (cpfe) is an "umbrella term" encompassing emphysema and pulmonary fibrosis, but its pathogenesis is not known. we established two models of cpfe in mice using tracheal instillation with bleomycin (blm) or murine gammaherpesvirus 68 (mhv-68). experimental mice were divided randomly into four groups: a (normal control, n=6), b (emphysema, n=6), c (emphysema+mhv-68, n=24), d (emphysema+blm, n=6). group c was subdivided into four groups: c1 (sacrificed on da ...201728233574
rta occupancy of the origin of lytic replication during murine gammaherpesvirus 68 reactivation from b cell latency.rta, the viral replication and transcription activator, is essential for rhadinovirus lytic gene expression upon de novo infection and reactivation from latency. lipopolysaccharide (lps)/toll-like receptor (tlr)4 engagement enhances rhadinovirus reactivation. we developed two new systems to examine the interaction of rta with host nf-kappab (nf-κb) signaling during murine gammaherpesvirus 68 (mhv68) infection: a latent b cell line (he-rit) inducible for rta-flag expression and virus reactivation ...201728212352
the effect of isoprinosine treatment on persistent infection of balb/c mice infected with murine gammaherpesvirus 68.we demonstrated the positive effect of isoprinosine treatment on persistent infection of balb/c mice with murine gammaherpesvirus 68 (mhv-68). increased number of leukocytes, increased percentage of neutrophils, elevated levels of virus-neutralizing (vn) antibodies, reduced number of atypical lymphocytes and reduced virus titers were detected in the examined organs after a 14-day treatment. the positive effect of isoprinosine therapy vanished after 120-150 days. after this interval, we demonstra ...201728105852
tick-borne transmission of murine gammaherpesvirus 68.herpesviruses are a large group of dna viruses infecting mainly vertebrates. murine gammaherpesvirus 68 (mhv68) is often used as a model in studies of the pathogenesis of clinically important human gammaherpesviruses such as epstein-barr virus and kaposi's sarcoma-associated herpesvirus. this rodent virus appears to be geographically widespread; however, its natural transmission cycle is unknown. following detection of mhv68 in field-collected ticks, including isolation of the virus from tick sa ...201729164067
murine gammaherpesvirus 68: a small animal model for gammaherpesvirus-associated diseases.murine gammaherpesvirus 68 (mhv68) is a naturally occurring pathogen of murid rodents that is genetically related to the human gammaherpesviruses epstein-barr virus (ebv) and kaposi sarcoma-associated herpesvirus (kshv). viral, immunologic, and disease parameters following experimental infection of laboratory mice with mhv68 closely resemble what occurs during primary ebv infection of humans, which suggests that mhv68 infection of mice offers a small animal model to study in general the pathogen ...201729052141
epstein-barr virus bkrf4 gene product is required for efficient progeny production.epstein-barr virus (ebv), a member of human gammaherpesvirus, infects mainly b cells. ebv has two alternative life cycles, latent and lytic, and is reactivated occasionally from the latent stage to the lytic cycle. to combat ebv-associated disorders, understanding the molecular mechanisms of the ebv lytic replication cycle is also important. here, we focused on an ebv lytic gene, bkrf4. using our anti-bkrf4 antibody, we revealed that the bkrf4 gene product is expressed during the lytic cycle wit ...201728904200
antiviral activity of 20(r)-ginsenoside rh2 against murine gammaherpesvirus.ginsenosides are the major components of panax ginseng meyer, an herbal medicine used for the treatment of various diseases. different ginsenosides contribute to the biological properties of ginseng, such as antimicrobial, anticancer, and immunomodulatory properties. in this study, we investigated the antiviral effects of 15 ginsenosides and compound k on gammaherpesvirus.201729021696
unsupervised learning techniques reveal heterogeneity in memory cd8(+) t cell differentiation following acute, chronic and latent viral infections.cd8(+) t lymphocytes are critical for the control of gammaherpesvirus latency. to determine how memory cd8(+) t cells generated during latency differ from those primed during acute or chronic viral infection, we adoptively transferred naive p14 cd8(+) t cells into uninfected recipients, and examined surface proteins, cytokines and transcription factors following infection with the armstrong (acute) or clone 13 (chronic) strains of lymphocytic choriomeningitis virus (lcmv), or murine gammaherpesv ...201728689040
transformation of cells by photoinactivated murine gamma-herpesvirus 68 during nonproductive and quiescent infection.infection of human mrc-5 cells and mouse nih-3t3 cells with a murine gamma-herpesvirus (muhv-4 strain 68; mhv-68) photoinactivated by visible light in the presence of methylene blue (mb) resulted in nonproductive infection and the appearance of morphologically transformed cells. two stably transformed cell lines were derived from both of these cell types and were confirmed to contain both viral dna and antigen. next, a quiescent mhv-68 infection in mrc-5 and nih-3t3 cells was established after c ...201728848176
the replication and transcription activator of murine gammaherpesvirus 68 cooperatively enhances cytokine-activated, stat3-mediated gene expression.gammaherpesviruses (γηvs) have a dynamic strategy for life-time persistence, involving productive infection, latency, and intermittent reactivation. in latency reservoirs, such as b lymphocytes, γηv exists as a viral episome and expresses few viral genes. although the ability of γhv to reactivate from latency and re-enter the lytic phase is challenging to investigate and control, it is known that the γηv replication and transcription activator, rta, can promote lytic reactivation. in this study, ...201728821622
murine gammaherpesvirus m2 antigen modulates splenic b cell activation and terminal differentiation in vivo.murine gammaherpesvirus 68 (mhv68) infection of laboratory strains of mice has provided a tractable small animal model for dissecting gammaherpesvirus pathogenesis. the mhv68 latency associated antigen m2 promotes viral latency establishment in germinal center (gc) b cells and plays an important role in virus infection of plasma cells (pcs), which is linked to virus reactivation. more recently, m2 has been highlighted as a potent immunomodulatory molecule capable of hindering both cell-mediated ...201728767707
mhv68 expressing kshv lana reveals both functional conservation and divergence in lana homologs.latency-associated nuclear antigen (lana) is a multifunctional protein encoded by members of the rhadinovirus genus of gammaherpesviruses. studies using murine gammaherpesvirus 68 (mhv68) demonstrated that lana is important for acute replication, latency establishment, and reactivation in vivo despite structural similarities in their dna-binding domains (dbds), lana homologs from kaposi sarcoma-associated herpesvirus (kshv) and mhv68 exhibit considerable sequence divergence. we sought to determi ...201728747501
the major envelope glycoprotein of murid herpesvirus 4 promotes sexual transmission.gammaherpesviruses are important human and animal pathogens. infection control has proven difficult because the key process of transmission is ill understood. murid herpesvirus 4 (muhv-4), a gammaherpesvirus of mice, is transmitted sexually. we show that this depends on the major virion envelope glycoprotein gp150. gp150 is redundant for host entry, and in vitro, it regulates rather than promotes cell binding. we show that gp150-deficient muhv-4 reaches and replicates normally in the female geni ...201728424280
cd8+ t cell evasion mandates cd4+ t cell control of chronic gamma-herpesvirus infection.gamma-herpesvirus infections are regulated by both cd4+ and cd8+ t cells. however clinical disease occurs mainly in cd4+ t cell-deficient hosts. in cd4+ t cell-deficient mice, cd8+ t cells control acute but not chronic lung infection by murid herpesvirus-4 (muhv-4). we show that acute and chronic lung infections differ in distribution: most acute infection was epithelial, whereas most chronic infection was in myeloid cells. cd8+ t cells controlled epithelial infection, but cd4+ t cells and ifnγ ...201728394921
the influence of dual infection with herpes and influenza viruses on the differential blood cell count of mice.based on our previous results, which confirmed the role of latent gammaherpesvirus infection in alteration of immune homeostasis, we studied the influence of simultaneous infection with gammaherpes and influenza viruses on selected parameters of innate immunity, particularly on the subpopulations of peripheral blood cell leukocytes. the aim was to analyze changes of differential blood cell count of balb/c mice persistently infected with murine gammaherpesvirus 68 (mhv-68) and subsequently co-inf ...201727928917
nanoparticle exposure reactivates latent herpesvirus and restores a signature of acute infection.inhalation of environmental (nano) particles (np) as well as persistent herpesvirus-infection are potentially associated with chronic lung disease and as both are omnipresent in human society a coincidence of these two factors is highly likely. we hypothesized that np-exposure of persistently herpesvirus-infected cells as a second hit might disrupt immune control of viral latency, provoke reactivation of latent virus and eventually lead to an inflammatory response and tissue damage.201728069010
regulation of the viral life cycle by murine gammaherpesvirus 68 micrornas.γ-herpesviruses (γhv) such as epstein-barr virus and kaposi's sarcoma-associated herpesvirus are important human pathogens involved in lymphoproliferation and tumorigenesis. murine gammaherpesvirus 68 (mhv-68, γhv-68) is an effective model for the study of γhv pathogenesis and host-virus interaction because it is closely related to human γhv. similarly to human γhv, mhv-68 encodes 15 micrornas (mirnas). although their functions remain unknown, they are thought to regulate the viral life cycle or ...201727837274
recognizing the sines of infection: regulation of retrotransposon expression and modulation of host cell processes.short interspersed elements (sines) are a family of retrotransposons evolutionarily derived from cellular rna polymerase iii transcripts. over evolutionary time, sines have expanded throughout the human genome and today comprise ~11% of total chromosomal dna. while generally transcriptionally silent in healthy somatic cells, sine expression increases during a variety of types of stresses, including dna virus infection. the relevance of sine expression to viral infection was largely unexplored, h ...201729258254
a gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes.the hygiene hypothesis postulates that the recent increase in allergic diseases such as asthma and hay fever observed in western countries is linked to reduced exposure to childhood infections. here we investigated how infection with a gammaherpesvirus affected the subsequent development of allergic asthma. we found that murid herpesvirus 4 (muhv-4) inhibited the development of house dust mite (hdm)-induced experimental asthma by modulating lung innate immune cells. specifically, infection with ...201729035391
cross-species conservation of episome maintenance provides a basis for in vivo investigation of kaposi's sarcoma herpesvirus lana.many pathogens, including kaposi's sarcoma herpesvirus (kshv), lack tractable small animal models. kshv persists as a multi-copy, nuclear episome in latently infected cells. kshv latency-associated nuclear antigen (klana) binds viral terminal repeat (ktr) dna to mediate episome persistence. model pathogen murine gammaherpesvirus 68 (mhv68) mlana acts analogously on mtr dna. klana and mlana differ substantially in size and ktr and mtr show little sequence conservation. here, we find klana and mla ...201728910389
type i interferon signaling to dendritic cells limits murid herpesvirus 4 spread from the olfactory epithelium.murid herpesvirus 4 (muhv-4) is a b cell-tropic gammaherpesvirus that can be studied in vivo despite viral evasion, type i interferons (ifn-i) limit its spread. after muhv-4 inoculation into footpads, ifn-i protect lymph node subcapsular sinus macrophages (ssm) against productive infection; after peritoneal inoculation, they protect splenic marginal zone macrophages, and they limit muhv-4 replication in the lungs. while invasive infections can be used to test specific aspects of host colonizatio ...201728904198
gamma-herpesvirus colonization of the spleen requires lytic replication in b cells.gamma-herpesviruses infect lymphocytes and cause lymphocytic cancers. murid herpesvirus-4 (muhv-4), epstein-barr virus and the kaposi's sarcoma-associated herpesvirus all infect b cells. latent infection can spread by b cell recirculation and proliferation, but whether this alone achieves systemic infection is unclear. to test the need of muhv-4 for lytic infection in b cells we flanked its essential orf50 lytic transactivator with loxp sites, then infected mice with b cell-specific cre expressi ...201829343572
conditional mutagenesis in vivo reveals cell type- and infection stage-specific requirements for lana in chronic mhv68 infection.gammaherpesvirus (ghv) pathogenesis is a complex process that involves productive viral replication, dissemination to tissues that harbor lifelong latent infection, and reactivation from latency back into a productive replication cycle. traditional loss-of-function mutagenesis approaches in mice using murine gammaherpesvirus 68 (mhv68), a model that allows for examination of ghv pathogenesis in vivo, have been invaluable for defining requirements for specific viral gene products in ghv infection ...201829364981
first detection of murine herpesvirus 68 in adult ixodes ricinus ticks.murine herpesvirus 68 (mhv-68) is a natural pathogen that infects murid rodents, which serves as hosts for ixodes ricinus ticks. for the first time, mhv-68 was detected in immature i. ricinus ticks feeding on lacerta viridis lizards trapped in slovakia, which supports the idea that ticks can acquire the virus from feeding on infected hosts. the recent discovery of mhv-68 infection and mhv-68 m3 gene transcripts in dermacentor reticulatus ticks collected in slovakia also supports this suggestion. ...201829352410
regulation of gammaherpesvirus lytic replication by endoplasmic reticulum stress-induced transcription factors atf4 and chop.the stress-induced unfolded protein response (upr) in the endoplasmic reticulum (er) involves various signaling crosstalks and controls cell fate. b-cell receptor (bcr) signaling, which can trigger upr, induces gammaherpesvirus lytic replication and serves as a physiological mechanism for gammaherpesvirus reactivation in vivo. however, how the upr regulates bcr-mediated gammaherpesvirus infection is unknown. here, we demonstrate that the er stressors tunicamycin and thapsigargin inhibit bcr-medi ...201829305424
host tumor suppressor p18ink4c functions as a potent cell-intrinsic inhibitor of γhv68 reactivation and pathogenesis.gammaherpesviruses are common viruses associated with lifelong infection and increased disease risk. reactivation from latency aids the virus in maintaining infection throughout the life of the host and is responsible for a wide array of disease outcomes. previously, we demonstrated that the virus encoded cyclin (v-cyclin) of murine gammaherpesvirus 68 (γhv68) is essential for optimal reactivation from latency in normal mice but not in mice lacking the host tumor suppressor, p18ink4c (p18). whet ...201829298882
common vole (microtus arvalis) and bank vole (myodes glareolus) derived permanent cell lines differ in their susceptibility and replication kinetics of animal and zoonotic viruses.pathogenesis and reservoir host adaptation of animal and zoonotic viruses are poorly understood due to missing adequate cell culture and animal models. the bank vole (myodes glareolus) and common vole (microtus arvalis) serve as hosts for a variety of zoonotic pathogens. for a better understanding of virus association to a putative animal host, we generated two novel cell lines from bank voles of different evolutionary lineages and two common vole cell lines and assayed their susceptibility, rep ...201931513859
birds belonging to the family paridae as another potential reservoir of murine gammaherpesvirus 68.ecology and epidemiology of murine gammaherpesvirus 68 (mhv-68) have been intensively studied since the isolation of the virus from murid rodents in 1976. this virus was detected in various mammalian species that share the biotope with rodent reservoirs of mhv-68. however, a survey of mhv-68 in birds has not so far been performed. therefore, the aim of this study was to investigate the presence of mhv-68 in blood samples from two bird species captured at four localities in slovakia. using the ne ...202134339313
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