Lung type II alveolar epithelial cells collaborate with CCR2+ inflammatory monocytes in host defense against poxvirus infection

Yang, Ning; Luna, Joseph M.; Dai, Peihong; Wang, Yi; Rice, Charles M.; Deng, Liang

doi:10.21203/rs.3.rs-109678/v1

Cited by 3 publications

(3 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Phylogenetic analyses revealed M062's divergency to highly conserved orthopoxvirus C7L homologs, designated Clade I members. 9 Although VACV C7 protein appeared binding to SAMD9, it may have evolved to target other pathways connecting to SAMD9 pathway (unpublished data and 43 ). This is not surprising, as mammalian poxviruses employ different strategies to evade host surveillance and defense mechanisms, such as lessons learned from poxvirus inhibition of NF-κB signaling.…”

Section: Discussionmentioning

confidence: 99%

Antagonizing the SAMD9 pathway is key to myxoma virus host shut-off and immune evasion

Raza,

Perterson,

Liem

et al. 2024

Preprint

View full text Add to dashboard Cite

Poxviruses have life cycles exclusively in the cytoplasm. With many immunoregulatory proteins manipulating host cellular signaling transduction to evade host immunity during a productive infection, these viruses can have profound impact to host transcription. Being able to successfully perform viral protein synthesis in host cells is critical to its ability for immune evasion. Many mammalian poxviruses encode more than one viral protein to interact with the host SAMD9 protein. In myxoma virus (MYXV), a rabbit specific poxvirus and non-pathogenic for other species, e.g., humans, viral M062 protein is the lone inhibitor to SAMD9 with broad species specificity, as the loss of M062R gene caused abortive infection in almost all cells tested from different mammalian species. However, infection by DeltaM062R is not yet examined on what defects during infection may be associated with the phenotypes observed. Through the investigation of a mutant MYXV with targeted deletion of an essential host range determinant, M062R, we previously revealed a unique transcriptomic landscape in monocytes/macrophages that is associated with the crosstalk between the SAMD9 pathway and cGAS/STING/IRF3 DNA sensing pathway. In this study we completed the characterization of deltaM062R infection. We found that surprisingly, although this replication-defective virus does not appear to present early protein synthesis defect, the infection failed to perform host shutoff. Despite a defect in viral DNA replication, deltaM062R infection retained intact intermediate protein synthesis comparable to that of the wildtype virus. Using time course RNAseq analyses we found that the overall viral gene transcription profile was not affected, largely indistinguishable from that of the wildtype MYXV. However, the slightly attenuated late RNA synthesis along with the block at viral protein synthesis led to its infection defect. Infection by deltaM062R in differentiated macrophages potentiated the antiviral responses to new danger signals. We provided an initial characterization of such a state in which host antiviral protein synthesis may be promoted leading to the immunological consequence.

show abstract

Section: Discussionmentioning

confidence: 99%

Antagonizing the SAMD9 pathway is key to myxoma virus host shut-off and immune evasion

Raza,

Perterson,

Liem

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Mda5 -/- mice were generated in Marco Colonna’s laboratory (Washington University) 59 . Mda5 -/- Sting Gt/Gt were bred in our lab 60 .…”

Section: Methodsmentioning

confidence: 99%

IL-12-expressing highly immunogenic recombinant modified vaccinia virus Ankara reprograms tumor-infiltrating myeloid cells to overcome immune resistance

Liu

Mazo

Yang

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Novel strategies to reprogram tumor-infiltrating myeloid cells for cancer immunotherapy are urgently needed, given that the primary and acquired resistance to immune checkpoint blockade (ICB) therapy has hindered the overall success of immunotherapy. Modified vaccinia virus Ankara (MVA) is a highly attenuated, non-replicative vaccinia virus and an approved vaccine against smallpox and monkeypox. Here we report rational engineering of recombinant MVA, MQ833, by removing three immune suppressive genes, E5R, E3L, and WR199, from the MVA genome and inserting three transgenes encoding Flt3L, OX40L, and IL-12. Intratumoral (IT) delivery of MQ833 generates potent antitumor responses dependent on CD8+ T cells, neutrophils, and M1-like macrophages, the nucleic acid-sensing pathways mediated by MDA5/STING, and interferon feedback loop. IT MQ833 promotes the recruitment and activation of neutrophils and inflammatory monocytes into the injected tumors, depletion of M2-like macrophages, and expansion of M1-like macrophages, generating potent antitumor immunity against tumors resistant to ICB.

show abstract

“…VACV encodes many immunomodulatory genes to evade the host immune system [27][28][29] . Inactivation of VACV or MVA, by heating VACV or MVA at 55 °C for 1 h, reduces infectivity by more than 1000-fold and much more potently induces type I IFN production than live viruses in conventional DCs (cDCs) or plasmacytoid DCs (pDCs) [30][31][32] .…”

Section: Introductionmentioning

confidence: 99%

Heat-inactivated modified vaccinia virus Ankara boosts Th1 cellular and humoral immunity as a vaccine adjuvant

et al. 2022

View full text Add to dashboard Cite

Protein or peptide-based subunit vaccines have generated excitement and renewed interest in combating human cancer or COVID-19 outbreak. One major concern for subunit vaccine application is the weak immune responses induced by protein or peptides. Developing novel and effective vaccine adjuvants are critical for the success of subunit vaccines. Here we explored the potential of heat-inactivated MVA (heat-iMVA) as a vaccine adjuvant. Heat-iMVA dramatically enhances T cell responses and antibodies responses, mainly toward Th1 immune responses when combined with protein or peptide-based immunogen. The adjuvant effect of Heat-iMVA is stronger than live MVA and is dependent on the cGAS/STING-mediated cytosolic DNA-sensing pathway. In a therapeutic vaccination model based on tumor neoantigen peptide vaccine, Heat-iMVA significantly extended the survival and delayed tumor growth. When combined with SARS-CoV-2 spike protein, Heat-iMVA induced more robust spike-specific antibody production and more potent neutralization antibodies. Our results support that Heat-iMVA can be developed as a safe and potent vaccine adjuvant for subunit vaccines against cancer or SARS-CoV-2.

show abstract

Lung type II alveolar epithelial cells collaborate with CCR2+ inflammatory monocytes in host defense against poxvirus infection

Cited by 3 publications

References 42 publications

Antagonizing the SAMD9 pathway is key to myxoma virus host shut-off and immune evasion

Antagonizing the SAMD9 pathway is key to myxoma virus host shut-off and immune evasion

IL-12-expressing highly immunogenic recombinant modified vaccinia virus Ankara reprograms tumor-infiltrating myeloid cells to overcome immune resistance

Heat-inactivated modified vaccinia virus Ankara boosts Th1 cellular and humoral immunity as a vaccine adjuvant

Contact Info

Product

Resources

About