Roadmap for the development of a candidate vaccine for ASF

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Identity of immunomodulators

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Dependencies

Next steps

Identity of immunomodulators

Research Question

ASFV attempts to modulate the host’s immune responses so that it can survive and replicate
Identifying and removal of the factors contributing to the virus stealth mechanisms could contribute to the generation of improved attenuated vaccine candidates

Research Gaps and Challenges

Identify the mechanisms of immunomodulation and the virus
proteins responsible
Apply the interactomic approach for ASFV infection

Solution Routes

Generation of a range of knock-out viruses where the genes for various immunomodulatory factors or other stealth mechanisms have been removed and their use in experimental infections
Studies of the modulation of innate immune responses

Dependencies

Improve understanding of virus-macrophage interaction – viral and macrophage gene expression in different in vivo environments (macrophages from naïve and immune hosts)

State Of the Art

ASFV-infected macrophages mediate changes in cellular immune function and are likely play a role in the severe apoptosis observed in lymphoid tissue. ASFV inhibits phorbol myristic acid-induced expression of pro-inflammatory cytokines such as TNF-α, IFN-α, and IL-8 while inducing production of TGF-β from infected macrophages but TNF-α expression has also been reported after ASFV infection in vitro and in vivo ASFV strains with different virulence phenotypes differ in their ability to induce expression of pro-inflammatory cytokine or IFN-related genes in macrophages early in infection. The ASFV ankyrin repeatcontaining protein pA238L (5EL), a homolog of cellular IκB proteins and the cytoplasmic inhibitors of the NFκB/Rel family of cellular transcription factors, is thought to be important in evading host immune responses. NFκB transcriptional pathways play an important role in inducing expression of a wide range of proinflammatory and antiviral mediators and cytokines. Consistent with this role, pA238L is able to regulate expression of cyclooxygenase-2 (COX-2), TNF-α, and inducible nitric-oxide synthase (iNOS). COX-2 downregulation occurs in an NFκB-independent, but NFAT-dependent, manner. Similarly, pA238L inhibits
expression of iNOS, and ultimately production of nitric oxide, by a mechanism likely involving p300 transactivation. However, deletion of A238L from pathogenic
ASFV does not affect viral growth in macrophages in vitro or viral pathogenesis and virulence in domestic swine. Other proteins involved in modulation of host
responses include ASFV 8DR protein (pEP402R), the only known viral homolog of cellular CD2, a T cell protein involved in co-regulation of cell activation. 8DR is
necessary and sufficient for mediating haemadsorption by ASFV-infected cells. Deletion of the 8DR gene from the ASFV genome led to decreased early virus
replication and generalization of infection in swine, and 8DR suppressed cellular immune responses in vitro. The ASFV pEP153R (8CR) protein is similar to cellular
and poxviral proteins resembling C-type lectin-like proteins, including membrane-bound immunoactivation and immunoregulatory proteins CD69 and NKG2. A
potential role for pEP153R in immunomodulation may be subtle, however, since pEP153R does not affect viral pathogenesis or virulence in domestic. Evidence
also suggests that ASFV dramatically affects Th2/B cell responses, including upregulation of Th2 cytokines by a soluble virulence factor (p36) released from ASFVinfected monocytes and the nonspecific activation and apoptosis seen in B cell populations from ASFV-infected animals. ASFV multigene family 360 and 530
genes play a role in modulating host innate responses. Unlike wild type virus, infection of macrophages with Pr4Δ35, a mutant virus lacking MGF360/530 genes,
resulted in increased mRNA levels for several type I interferon early-response genes. Analysis of IFN-α mRNA and secreted IFN-α levels at 3, 8, and 24 hours post
infection (p.i.) revealed undetectable IFN-α in mock and wild type-infected macrophages but significantly increased IFN-α levels at 24 hours p.i. in Pr4Δ35-
infected macrophages, indicating that MGF360/530 genes either directly or indirectly suppress a type I IFN response. This effect may account for the growth
defect of Pr4Δ35 in macrophages and its attenuation in swine