African Swine Fever Virus Multigene Family 360 and 530 Genes Affect Host Interferon Response

Abstract

African swine fever is a significant disease of domestic swine, with mortality rates approaching 100%. No vaccine is currently available, making quarantine and slaughter the only effective control strategy (44).African swine fever virus (ASFV), the causative agent of African swine fever, is a unique and complex DNA virus that infects cells of the mononuclear-phagocytic system, including fixed-tissue macrophages and specific lineages of reticular cells. Affected tissues show extensive necrosis following infection with highly virulent viral strains (13,36,38). Moderately virulent ASFV strains also appear to infect these cell types, but the degree of tissue involvement and the resulting tissue damage are much less severe (13,36,38). The abilities of ASFV to replicate and efficiently induce marked cytopathology in monocytes-macrophages in vivo appear to be critical factors for ASFV virulence.ASFV is the sole member of the family Asfarviridae and the only known DNA arbovirus (14,38). ASFV is a large, icosahedral virus that contains a linear double-stranded DNA genome (170 to 190 kbp) encoding approximately 165 genes (50; C. A. Balinsky et al., unpublished data). The availability of complete ASFV genome sequences has revealed that, similar to poxviruses, ASFVs encode proteins with functions essential for viral replication, including those involving structure and assembly of the virion and those responsible for biogenesis of mRNA and DNA. A large number of ASFV genes are of unknown function and may be involved in aspects of viral virulence and host range (46,50; Balinsky et al., unpublished).Pathogenic ASFV genomes contain 11 to 15 multigene family 360 (MGF360) genes and either 9 or 10 multigene family 530 (MGF530) genes (Balinsky et al., unpublished). Recently, we have identified MGF360 and MGF530 genes as novel macrophage host range determinants necessary for efficient growth in macrophages (54). Infection of macrophage cell cultures with MGF360-MGF530 (MGF360/530) gene deletion mutant Pr4⌬35 (six MGF360 and two MGF530 genes deleted) resulted in a 2-to 3-log reduction in virus titers and early cell death, suggesting a direct or indirect role for these genes in some aspect of infected-cell survival (54) (L. Zsak, unpublished data). In addition, a swine virulence determinant (VAD) containing MGF360/530 genes was mapped by using in vivo marker rescue to the left variable region of the ASFV genome (37).The mode of action of the ASFV MGF360/530 genes is unknown. Homology searches reveal no homology to other known genes. MGF360/530 genes have a conserved motif of 100 amino acids (28% amino acid identity) at the amino ter-

Related strains of African swine fever virus with different virulence: genome comparison and analysis

“…This was confirmed in macrophages infected with L60 and NHV, where higher levels of IFNa were produced in the early stages of infection with NHV than with L60, in addition to other cytokines involved in inflammatory responses and cellular immunity (Gil et al, 2008). Pr4D35 is also attenuated in swine (Afonso et al, 2004). NHV and OURT88/3 have the same MGF 505 and 360 genes deleted or truncated, supporting their effect in immunosuppression and virulence.…”

“…The MGF 360 and 505 genes also have a role in suppressing type I IFN responses, since the Pr4D35 strain induced a strong type I IFN-related transcriptional response in pig macrophages, contrarily to the parental Pretorisuskop/96/ 4, and supernatants of infected macrophages with Pr4D35 contained IFNa (Afonso et al, 2004). This was confirmed in macrophages infected with L60 and NHV, where higher levels of IFNa were produced in the early stages of infection with NHV than with L60, in addition to other cytokines involved in inflammatory responses and cellular immunity (Gil et al, 2008).…”

Comparison of the genome sequences of non-pathogenic and pathogenic African swine fever virus isolates

“…The N-terminal regions of members of MGFs 300, 360 and 505/530 share significant similarity with each other (Yozawa et al, 1994). Several genes in MGF 360 and 505/530 determine host range and virulence (Afonso et al, 2004;Neilan et al, 2002;Tulman & Rock, 2001). It has also been observed that repeated passage of field isolates of ASFV through tissue culture results in the loss of members of the MGF 110 family (Almendral et al, 1990;de la Vega et al, 1990;Pires et al, 1997).…”

Examination of animal and zoonotic pathogens using microarrays

“…While cell culture and organ culture models that have been used extensively to study the interaction of pathogen with the host cells provide information about limited events, microarray scans whole gene expression during a single event [1,107]. Over the past five years, many research groups have employed DNA arrays to analyze host gene expressions in the presence of pathogens in both human and livestock species, however, work examining simultaneous response of both host and the pathogen during an infectious process was not found.…”

“…It is known that the multigene family 360 and 530 (MGF 360/530) of ASFV affects viral growth and virulence in pigs. The transcriptional response within macrophages infected by ASFV and MGF 360/530 deletion mutant was studied using swine cDNA array at various time intervals post infection [1]. The study revealed the suppression of the IFN response by ASFV MGF 360/530.…”