Type I Interferons Direct Gammaherpesvirus Host Colonization

Tan, Cindy S. E.; Lawler, Clara; May, Janet S.; Belz, Gabrielle T.; Stevenson, Philip G.

doi:10.1371/journal.ppat.1005654

Cited by 13 publications

(23 citation statements)

References 62 publications

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“…Invasive virus inoculations are often more pathogenic than mucosal inoculations because they bypass the outer defenses: i.p. MuHV-4 reaches the spleen directly (12), and in this context, IFNAR blockade greatly increases macrophage infection (36), consistent with IFNAR Ϫ/Ϫ mice succumbing more rapidly to i.p. than to i.n.…”

Section: Discussionsupporting

confidence: 57%

“…IFN-I reduces MuHV-4 reactivation from latency in B cells (34), but heightened reactivation normally attenuates infection (35), and the acute phenotypes of IFNAR deficiency are more suggestive of increased lytic replication before B cell colonization. In the spleen, IFN-I restricts mainly macrophage infection (36). Here we show that IFN-I and NK cells are key components of the SSM barrier to MuHV-4 spread.…”

Section: Human Gammaherpesviruses Cause Cancers By Infecting B Cellsmentioning

confidence: 58%

“…Cre switches its fluorochrome expression irreversibly from mCherry to GFP (MHV-G). Neither MHV-RG nor MHV-G is attenuated in C57BL/6 mice, and neither virus outgrows the other in a mixed infection (36). MHV-M50 has 416 bp of the murine cytomegalovirus (MCMV) IE1 promoter in the 5= untranslated region of ORF50 exon 1.…”

Section: Methodsmentioning

confidence: 99%

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Type I Interferons and NK Cells Restrict Gammaherpesvirus Lymph Node Infection

Lawler

Tan

Simas

et al. 2016

J Virol

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Gammaherpesviruses establish persistent, systemic infections and cause cancers. Murid herpesvirus 4 (MuHV-4) provides a unique window into the early events of host colonization. It spreads via lymph nodes. While dendritic cells (DC) pass MuHV-4 to lymph node B cells, subcapsular sinus macrophages (SSM), which capture virions from the afferent lymph, restrict its spread. Understanding how this restriction works offers potential clues to a more comprehensive defense. Type I interferon (IFN-I) blocked SSM lytic infection and reduced lytic cycle-independent viral reporter gene expression. Plasmacytoid DC were not required, but neither were SSM the only source of IFN-I, as IFN-I blockade increased infection in both intact and SSM-depleted mice. NK cells restricted lytic SSM infection independently of IFN-I, and SSM-derived virions spread to the spleen only when both IFN-I responses and NK cells were lacking. Thus, multiple innate defenses allowed SSM to adsorb virions from the afferent lymph with relative impunity. Enhancing IFN-I and NK cell recruitment could potentially also restrict DC infection and thus improve infection control. IMPORTANCE Human gammaherpesviruses cause cancers by infecting B cells. However, vaccines designed to block virus binding to B cells have not stopped infection. Using a related gammaherpesvirus of mice, we have shown that B cells are infected not via cell-free virus but via infected myeloid cells. This suggests a different strategy to stop B cell infection: stop virus production by myeloid cells. Not all myeloid infection is productive. We show that subcapsular sinus macrophages, which do not pass infection to B cells, restrict gammaherpesvirus production by recruiting type I interferons and natural killer cells. Therefore, a vaccine that speeds the recruitment of these defenses might stop B cell infection.E pstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) persist in B cells and cause cancers (1). Reducing their B cell infections is therefore an important therapeutic goal. Limited viral gene expression (2) makes established infections difficult to clear. The early events of host colonization may provide better targets. However, control mechanisms must be defined in vivo: inferring mechanisms from in vitro studies has proven problematic because immune function and its evasion are context dependent. Thus, EBV gp350-specific antibodies block B cell infection, and CD8 ϩ T cells kill infected B cells in vitro, but vaccinations to induce these effectors have not reduced infection rates (3).The early events of human infections are difficult to analyze because they predate clinical presentation (4). However, gammaherpesviruses long predate human speciation (5), and peak viral diversity in genes that interact with host-diverse functions suggests that viral coevolution has since acted to counter host divergence. Therefore, human and other mammalian gammaherpesviruses should colonize their hosts in similar ways. Murid herpesvirus 4 (MuHV-4) realistically infects la...

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Section: Discussionsupporting

confidence: 57%

Section: Human Gammaherpesviruses Cause Cancers By Infecting B Cellsmentioning

confidence: 58%

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Type I Interferons and NK Cells Restrict Gammaherpesvirus Lymph Node Infection

Lawler

Tan

Simas

et al. 2016

J Virol

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“…, and signaling coreceptors [67,82] Noncoding RNAs (including miRNAs) [41,42,48] Proteins interacting with oriLyts [51] Interferons and other cytokines [30,[32][33][34] Sensors of viral infection [23,83,84] Cell cycle proteins [62,85,86] Proteins regulating apoptosis [87][88][89][90] Transcription factors [91] DNA damage response proteins [5] Proteins involved in epigenetic gene regulation including chromatin assembly, histone modifications[ 3 _ T D $ D I F F ] , and DNA methylation [21][22][23][24][25][26][27][28]63,[92][93][94][95][96][97][98] Autophagy and xenophagy [99][100][101] Ubiquitination and NEDDylation [102][103][104][105] Chaperones [65] Post-translational modification proteins …”

Section: Key Figurementioning

confidence: 99%

“…New data demonstrate cell-type-dependent effects also for type I interferons (IFN-I). Using Mx1-cre mice to tag floxed MHV-68 genomes in IFN-I responding cells, Tan et al [33] demonstrated that the impact of IFN-I on viral replication was strongly cell-type-dependent. In epithelial cells, MHV-68 infection induced only a weak IFN-I response, allowing virus replication.…”

Section: Cytokinesmentioning

confidence: 99%

Herpesviruses and Their Host Cells: A Successful Liaison

Adler

Christine

Adler

2017

Trends in Microbiology

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During a long history of coevolution, herpesviruses have reached a fine-tuned balance with their hosts, allowing them to successfully persist and spread to new hosts without causing too much damage. Only under certain circumstances, as in neonates or immunocompromised individuals, they may cause serious diseases. The delicate balance between herpesviruses and their hosts results from interactions of a great variety of viral and cellular factors which together shape the tropism for a particular host, tissue, or cell. Understanding these interactions will provide insight into the viral life cycle and cell biology in general. Moreover, it will also facilitate comprehension of herpesvirus pathogenesis, enabling the development of new strategies to combat herpesviruses in cases where they cause disease.

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The replication and transcription activator of murine gammaherpesvirus 68 cooperatively enhances cytokine-activated, STAT3-mediated gene expression

Foreman

Armstrong

Santana

et al. 2017

Journal of Biological Chemistry

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Gammaherpesviruses (γHVs) have a dynamic strategy for lifelong persistence, involving productive infection, latency, and intermittent reactivation. In latency reservoirs, such as B lymphocytes, γHVs exist as viral episomes and express 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 γHV replication and transcription activator (RTA) can promote lytic reactivation. In this study, we provide first evidence that RTA of murine γΗV68 (MHV68) selectively binds and enhances the activity of tyrosine-phosphorylated host STAT3. STAT3 is a transcription factor classically activated by specific tyrosine 705 phosphorylation (pTyr-STAT3) in response to cytokine stimulation. pTyr-STAT3 forms a dimer that avidly binds a consensus target site in the promoters of regulated genes, and our results indicate that RTA cooperatively enhances the ability of pTyr-STAT3 to induce expression of a STAT3-responsive reporter gene. As indicated by coimmunoprecipitation, in latently infected B cells that are stimulated to reactivate MHV68, RTA bound specifically to endogenous pTyr-STAT3. An binding assay confirmed that RTA selectively recognizes pTyr-STAT3 and indicated that the C-terminal transactivation domain of RTA was required for enhancing STAT3-directed gene expression. The cooperation of these transcription factors may influence both viral and host genes. During MHV68 infection, pTyr-STAT3 promoted the temporal expression of ORF59, a viral replication protein. Our results demonstrate that MHV68 RTA specifically recognizes and recruits activated pTyr-STAT3 during the lytic phase of infection.

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Type I Interferons Direct Gammaherpesvirus Host Colonization

Cited by 13 publications

References 62 publications

Type I Interferons and NK Cells Restrict Gammaherpesvirus Lymph Node Infection

Type I Interferons and NK Cells Restrict Gammaherpesvirus Lymph Node Infection

Herpesviruses and Their Host Cells: A Successful Liaison

The replication and transcription activator of murine gammaherpesvirus 68 cooperatively enhances cytokine-activated, STAT3-mediated gene expression

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