Species-Specific Host–Virus Interactions: Implications for Viral Host Range and Virulence

Rothenburg, Stefan; Brennan, Greg

doi:10.1016/j.tim.2019.08.007

Cited by 87 publications

(79 citation statements)

References 89 publications

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“…VACV K3 has well-defined species-specific differences in its ability to inhibit PKR across the mammalian phylogeny, defined by both LBR assays and yeast-based studies [8,9,17]. The data presented here support and extend this species-specific sensitivity of PKR to VACV K3L and add to a growing body of evidence that virus-specific differences play an important role in viral host range, as do species-specific differences in host genes [22,23]. Consistent with this concept, in this study we showed that the VACV K3 orthologs from four different orthopoxviruses display dramatic differences in their ability to inhibit PKR from different species, including different sensitivities in closely related species such as mice and rats.…”

Section: Discussionsupporting

confidence: 63%

“…In line with this is a recent report that shows that VACV strains that contain different poxvirus K3 orthologs as their only PKR inhibitors exhibited different replication profiles in cell lines from different species, with some strains showing broader host ranges, whereas others showed narrower host ranges [29]. In a broader context, these chance susceptibilities of host antiviral factors to viral inhibitors that a host has otherwise never been exposed to might play an important role in cross-species transmission of viruses [23].…”

Section: Discussionmentioning

confidence: 54%

“…In some cases, exemplified by SAMD9/SAMD9L inhibition, virus specific differences in distinct and unrelated antagonists that evolved to inhibit some host immune responses adds a further layer of complexity to the task of predicting virus host range a priori. Ultimately, it is likely that a combination of some or all of these interactions is necessary to permit a virus to replicate in a given host [23].…”

Section: Discussionmentioning

confidence: 99%

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Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

Park

Chen

Rahman

et al. 2020

Preprint

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The antiviral protein kinase R (PKR) is an important restriction factor, which poxviruses must overcome to productively infect host cells. Many poxviruses encode a pseudosubstrate mimic of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2), designated K3 in vaccinia virus, to inhibit PKR. Although the interaction between PKR and eIF2a is highly conserved, some K3 orthologs were previously shown to inhibit PKR in a species-specific manner. To better define this host range function, we compared the sensitivity of PKR from 17 mammals to inhibition by K3 orthologs from closely related orthopoxviruses. The K3 orthologs showed species-specific inhibition of PKR and exhibited three distinct inhibition profiles. In some cases, PKR from closely related species showed dramatic differences in their sensitivity to K3 orthologs. Vaccinia virus expressing the camelpox virus K3 ortholog replicated more than three orders of magnitude better in human and sheep cells than a virus expressing vaccinia virus K3, but both viruses replicated comparably well in cow cells. Strikingly, in site-directed mutagenesis experiments between the variola virus and camelpox virus K3 orthologs, we found that the amino acid combinations needed to mediate improved or diminished inhibition of PKR varied between different species. The data presented here show that even closely related species can display drastically different sensitivities to orthopoxvirus PKR inhibitors, and that orthologs from closely related poxviruses can show strong differences in their function. Furthermore, there is likely to be a limited number of possible mutations that disrupt K3-interactions but still maintain PKR/eIF2a interactions. Thus, by chance some potential new hosts may be susceptible to K3-mediated inhibition from a virus it has never previously encountered. We conclude that neither the sensitivity of host proteins to virus inhibition nor the effectiveness of viral host antagonists can be inferred from their phylogenetic relatedness but must be experimentally determined.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

Park

Chen

Rahman

et al. 2020

Preprint

Self Cite

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“…However, the manner in which key immune cell subsets change and their states during COVID-19 have remained largely unclear. Thus, defining these key cellular subsets and their states in COVID-19 is a crucial step in obtaining critical insights into the immune clearance mechanism and developing new therapeutic strategies for COVID- 19.…”

Section: Introductionmentioning

confidence: 99%

Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing

et al. 2020

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COVID-19, caused by SARS-CoV-2, has recently affected over 1,200,000 people and killed more than 60,000. The key immune cell subsets change and their states during the course of COVID-19 remain unclear. We sought to comprehensively characterize the transcriptional changes in peripheral blood mononuclear cells during the recovery stage of COVID-19 by single-cell RNA sequencing technique. It was found that T cells decreased remarkably, whereas monocytes increased in patients in the early recovery stage (ERS) of COVID-19. There was an increased ratio of classical CD14 ++ monocytes with high inflammatory gene expression as well as a greater abundance of CD14 ++ IL1β + monocytes in the ERS. CD4 + T cells and CD8 + T cells decreased significantly and expressed high levels of inflammatory genes in the ERS. Among the B cells, the plasma cells increased remarkably, whereas the naïve B cells decreased. Several novel B cell-receptor (BCR) changes were identified, such as IGHV3-23 and IGHV3-7, and isotypes (IGHV3-15, IGHV3-30, and IGKV3-11) previously used for virus vaccine development were confirmed. The strongest pairing frequencies, IGHV3-23-IGHJ4, indicated a monoclonal state associated with SARS-CoV-2 specificity, which had not been reported yet. Furthermore, integrated analysis predicted that IL-1β and M-CSF may be novel candidate target genes for inflammatory storm and that TNFSF13, IL-18, IL-2, and IL-4 may be beneficial for the recovery of COVID-19 patients.Our study provides the first evidence of an inflammatory immune signature in the ERS, suggesting COVID-19 patients are still vulnerable after hospital discharge. Identification of novel BCR signaling may lead to the development of vaccines and antibodies for the treatment of COVID-19.

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“…A growing number of evidence suggested that hostand virus-specific interactions of viral molecules with the host innate immune system are determinants of virus-host range and virulence (Rothenburg and Brennan 2019). Thus, different species-specific cell types would be necessary in cases of narrow host range such as Nectin4 that is naturally expressed on bovine cells and does not interact with viruses recognizing murine Nectin4, and that variola virus causes solely human smallpox (Haller et al 2014).…”

Section: Technical Obstacles Impose Challenges For Constructing Cellsmentioning

confidence: 99%

Host receptors: the key to establishing cells with broad viral tropism for vaccine production

Dai

Zhang

Ostrikov

et al. 2020

Critical Reviews in Microbiology

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Cell culture-based vaccine technology is a flexible and convenient approach for vaccine production that requires adaptation of the vaccine strains to the new cells. Driven by the motivation to develop a broadly permissive cell line for infection with a wide range of viruses, we identified a set of the most relevant host receptors involved in viral attachment and entry. This identification was done through a review of different viral entry pathways and host cell lines, and in the context of the Baltimore classification of viruses. In addition, we indicated the potential technical problems and proposed some solutions regarding how to modify the host cell genome in order to meet industrial requirements for mass production of antiviral vaccines. Our work contributes to a finer understanding of the importance of breaking the host-virus recognition specificities for the possibility of creating a cell line feasible for the production of vaccines against a broad spectrum of viruses. ARTICLE HISTORY

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Species-Specific Host–Virus Interactions: Implications for Viral Host Range and Virulence

Cited by 87 publications

References 89 publications

Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing

Host receptors: the key to establishing cells with broad viral tropism for vaccine production

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