Abstract:Maladaptive immune responses are considered to be important factors in the pathogenesis of the two diseases caused by hantaviruses, hemorrhagic fever with renal syndrome and hantavirus cardiopulmonary syndrome (HCPS). While the intensity of adaptive antiviral T-cell responses seems to correlate with the severity of HCPS, there is increasing evidence that innate antiviral responses by endothelial cells, the native targets for hantavirus infection in vivo, are induced within hours of exposure to infectious hanta… Show more
“…Interestingly, lowlevel UV-irradiation of Sin Nombre virus sufficient to abrogate infectivity significantly increased virus-triggered ISG expression (66). These data demonstrate that replication of Sin Nombre virus is not required for induction of innate responses.…”
Section: Discussionsupporting
confidence: 49%
“…Moreover, PHV was shown to induce immediate antiviral responses via IRF3 (36). In contrast to these results, early induction of innate responses triggered by UV-treated Sin Nombre virus was reported to be independent from IRF3, TLRs, or other currently known PRRs (66,67). These findings indicate that different hantaviruses may use different modes of PRR activation and, in addition to currently known PRRs, other cellular receptors and signaling pathways may play important roles in induction of innate responses, which await identification in the future.…”
Immediately after viral infection, innate responses including expression of IFN-α/β and IFN-stimulated genes (ISGs) are elicited ubiquitously by recruitment of specific pathogen recognition receptors. The velocity to induce IFN-α/β and ISGs in response to an infection is often decisive for virulence. Interestingly, in primary endothelial cells ISGs are induced later by hantaviruses pathogenic to humans than those considered to be nonpathogenic or of low virulence. Here we demonstrate that pathogenic Hantaan (HTNV) and putatively nonpathogenic Prospect Hill hantavirus (PHV) differentially activate innate responses in the established cell lines A549 and HuH7. STAT1α phosphorylation was detectable 3 h after PHV inoculation but not within the first 2 days after HTNV inoculation. The velocity to induce the ISGs MxA and ISG15 correlated inversely with amounts of virus produced. Moreover, expression of the inflammatory chemokine CCL5 was also induced differentially. Both hantaviruses induced innate responses via TRAF3 (TNF receptor-associated factor 3), and TLR3 was required for HTNV-induced expression of MxA, but not for the MxA induction triggered by PHV. Infection of RIG-I-deficient HuH7.5 cells revealed that RIG-I (retinoic acid receptor I) was not necessary for induction of innate responses by PHV. Taken together, these data suggest that HTNV and PHV elicit different signaling cascades that converge via TRAF3. Early induction of antiviral responses might contribute to efficient elimination of PHV. Subsequent to clearance of the infection, innate responses most likely cease; vice versa, retarded induction of antiviral responses could lead to increased HTNV replication and dissemination, which might cause a prolonged inflammatory response and might contribute to the in vivo virulence.
“…Interestingly, lowlevel UV-irradiation of Sin Nombre virus sufficient to abrogate infectivity significantly increased virus-triggered ISG expression (66). These data demonstrate that replication of Sin Nombre virus is not required for induction of innate responses.…”
Section: Discussionsupporting
confidence: 49%
“…Moreover, PHV was shown to induce immediate antiviral responses via IRF3 (36). In contrast to these results, early induction of innate responses triggered by UV-treated Sin Nombre virus was reported to be independent from IRF3, TLRs, or other currently known PRRs (66,67). These findings indicate that different hantaviruses may use different modes of PRR activation and, in addition to currently known PRRs, other cellular receptors and signaling pathways may play important roles in induction of innate responses, which await identification in the future.…”
Immediately after viral infection, innate responses including expression of IFN-α/β and IFN-stimulated genes (ISGs) are elicited ubiquitously by recruitment of specific pathogen recognition receptors. The velocity to induce IFN-α/β and ISGs in response to an infection is often decisive for virulence. Interestingly, in primary endothelial cells ISGs are induced later by hantaviruses pathogenic to humans than those considered to be nonpathogenic or of low virulence. Here we demonstrate that pathogenic Hantaan (HTNV) and putatively nonpathogenic Prospect Hill hantavirus (PHV) differentially activate innate responses in the established cell lines A549 and HuH7. STAT1α phosphorylation was detectable 3 h after PHV inoculation but not within the first 2 days after HTNV inoculation. The velocity to induce the ISGs MxA and ISG15 correlated inversely with amounts of virus produced. Moreover, expression of the inflammatory chemokine CCL5 was also induced differentially. Both hantaviruses induced innate responses via TRAF3 (TNF receptor-associated factor 3), and TLR3 was required for HTNV-induced expression of MxA, but not for the MxA induction triggered by PHV. Infection of RIG-I-deficient HuH7.5 cells revealed that RIG-I (retinoic acid receptor I) was not necessary for induction of innate responses by PHV. Taken together, these data suggest that HTNV and PHV elicit different signaling cascades that converge via TRAF3. Early induction of antiviral responses might contribute to efficient elimination of PHV. Subsequent to clearance of the infection, innate responses most likely cease; vice versa, retarded induction of antiviral responses could lead to increased HTNV replication and dissemination, which might cause a prolonged inflammatory response and might contribute to the in vivo virulence.
“…Spleens and bone marrow cells were recovered from infected deer mice and made into single-cell suspensions, and aliquots were frozen in 5% FBS-RPMI medium 1640 containing 5% DMSO at Ϫ70°C for subsequent cell culture. RNA was extracted from lungs by using an RNeasy Mini kit (Qiagen, Valencia, CA) and a BeadBeater (BioSpec Products, Inc., Bartlesville, OK), and the presence of viral S segment was verified by RT-PCR; the detection of viral S segment has been shown previously to reflect similarly virus isolation methods in deer mice (32).…”
Section: Methodsmentioning
confidence: 99%
“…Viral S segment was detected by RT-PCR in the lungs of all infected deer mice but not in uninfected controls (data not shown) (32). T cell lines established from three persistently infected deer mice were sampled at days 10 and 25 of culture for the abundance of viral S segment genomic RNA by using a TaqMan real-time PCR assay.…”
Section: Deer Mouse T Cell Cultures Do Not Support the Propagation Ofmentioning
Hantavirus cardiopulmonary syndrome is a zoonotic illness associated with a systemic inflammatory immune response, capillary leak, noncardiogenic pulmonary edema, and shock in humans. Cytokines, including TNF, IFN-␥, and lymphotoxin, are thought to contribute to its pathogenesis. In contrast, infected rodent reservoirs of hantaviruses experience few or no pathologic changes and the host rodent can remain persistently infected for life. Generally, it is unknown why such dichotomous immune responses occur between humans and reservoir hosts. Thus, we examined CD4 ؉ T cell responses from one such reservoir, the deer mouse (Peromy-
“…ANDV Gc can inhibit the phosphorylation of transcription factors STAT1 and STAT2 and this was also shown in HTNV infected cells (22). Furthermore, another HPS-causing hantavirus, Sin Nombre virus, was also unable to induce production of IFN-α/β during infection (18). Considering the clinical relevance of TNF-α during infection, we sought to determine if HTNV might also interfere with this inflammatory pathway.…”
Section: Hantaan Virus (Htnv) Nucleocapsid (N) Protein Interferes Witmentioning
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Abstract:We examined the ability of viruses in the Hantavirus and Nairovirus genera of the family Bunyaviridae to interfere with host signaling pathways involved in innate immunity. For the nairovirus, Crimean Congo hemorrhagic fever virus (CCHFV), we found that the viral polymerase gene contains a predicted ovarian tumor (OTU) protease domain that functions to deconjugate ubiquitin and interferon stimulated gene product 15 (ISG15) from host proteins. Both ubiquitin and ISG15 reversibly conjugate to proteins via a conserved LRLRGG C-terminal motif, mediating important innate antiviral responses. We showed that the OTU domain-containing protease of CCHFV hydrolyzes ubiquitin and ISG15 from many cellular target proteins. This broad activity contrasts with the target specificity of known mammalian OTU domaincontaining proteins. The biological significance of this activity of viral OTU domain-containing proteases was evidenced by their capacity to inhibit nuclear factor kappa B (NF-κB) dependent signaling and to antagonize the antiviral effects of ISG15. The deconjugating activity of viral OTU proteases represents a novel viral immune evasion mechanism that inhibits ubiquitin-and ISG15-dependent antiviral pathways. For the hantavirus, Hantaan virus (HTNV), we found that the nucleocapsid protein was able to inhibit tumor necrosis factor alpha (TNF-α)-induced activation of NF-κB as measured by a reporter assay and activation of endogenous p65, a NF-κB subunit. We showed an interaction between HTNV N protein and importin-α, a nuclear import molecule responsible for shuttling NF-κB to the nucleus. These data suggest that HTNV N protein can sequester NF-κB in the cytoplasm, thus inhibiting its activity.
INTRODUCTION:The overarching goal of this project is to identify common mechanisms that hemorrhagic fever viruses use to evade host innate immune responses and to develop means to overcome those evasion strategies. Among the viruses in our study are representatives of three different genera of the family Bunyaviridae: Hantaan (HTNV), Rift Valley fever (RVFV), and Crimean Congo hemorrhagic fever (CCHFV). In addition, we are studying members of the Filoviridae and Arenaviridae families: Ebola virus (EBOV) and Lassa virus (LASV), respectively. Our approach and goals are to (1) determine if the viruses evade host innate immunity; (2) to identify viral genes and proteins involved in immune evasion; (3) elucidate the mechanism(s) by which evasion occurs; and, (4) search for therapeutics that are not susceptible ...
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