Identification of innate and adaptive immune responses that restrict ASFV replication

Lead Research Organisation: The Pirbright Institute
Department Name: UNLISTED

Abstract

Dendritic cells (DC) are central to the induction and control of immune responses and are an important link between innate and adaptive immunity. We will characterise the interaction of African swine fever virus (ASFV) with conventional DC and plasmacytoid DC and determine how these interactions modulate the function of lymphocytes. Evidence suggests that the innate host interferon (IFN) response is important in determining the outcome of infection with ASFV. IFNa treatment of virus susceptible cells leads to a significant reduction in virus titres and ASFV isolates of differing virulence may vary in their ability to replicate in the presence of porcine IFNa. Although IFN-inducible porcine genes limiting ASFV replication have not been defined, a human IFN-regulated gene, MxA, can effectively inhibit ASFV replication in vitro. Preliminary studies suggest that porcine Mx1, the porcine homolog of MxA, may act in a similar way to MxA. We hypothesise that IFN-regulated genes are required to limit ASFV replication and that virus virulence is linked to the ability of the virus to overcome the anti-viral state. We will identify the porcine IFN-regulated genes that are required to inhibit ASFV replication; determine any differences in IFN-regulated genes in cells from genetically distinct swine; and determine what effect ASFV infection has on the anti-viral state. The presence of ASFV-specific CD4hiCD8+perforin+ memory cells that produce IFNg in pigs vaccinated with avirulent ASFV correlate with protection against certain virulent strains of ASFV but by unknown mechanisms. We will investigate the ability of porcine IFNg to restrict ASFV replication and other molecules produced by immune ASFV-specific T cells that may mediate protection. In addition, we will investigate the ASFV proteins recognised by IFN gamma producing CD8+ T cells in pigs infected with ASFV and determine the influence of porcine MHC class I genotype on the antigenic specificity of the CD8+ T cells.

Publications

10 25 50
 
Description African swine fever virus (ASFV) replicates primarily in blood monocytes and macrophages in the lymphoid tissues and organs. Type I interferon (IFN) participates in the host innate immune response to viral infection and regulates the expression of many different genes, known as IFN-stimulated genes that restrict viral replication. Infection of pigs with an avirulent ASFV strain did not induce biologically active IFN in serum, whereas high levels of IFN were induced following infection with virulent strains of ASFV. In vitro studies suggested that plasmacytoid dendritic cells were primarily responsible for IFN induction by ASFV.
Studies on the effect of recombinant porcine IFNa1 on ASFV replication in porcine macrophages demonstrated that replication of avirulent, but not virulent strains of ASFV are inhibited by IFN. Resistance to the antiviral effects of IFNa was mediated, at least in part, by members of multigene families (MGF), MGF 360 and MGF 505/530.Preliminary results suggest that Mx1 is not essential for inhibiting replication of avirulent ASFV. A human embryonic kidney cell line expressing the human IFN-stimulated gene viperin reduced ASFV DNA replication while not affecting infectivity of the virus. ASFV capsid protein pE120R was reduced in viperin expressing cells. This suggests that IFN-stimulated gene viperin can target ASFV replication, although the mechanism has not been determined.

There is no effective ASFV vaccine. However, previous studies have demonstarted that pigs infected with an avirulent virus are protected against challenge with a closely related virulent virus. Analysis of ASFV-specific lymphocytes from pigs that had been immunised with an avirulent strain of ASFV demonstrated a correlation between CD4hiCD8+ perforin+IFN-gamma producing lymphocytes and protection against infection with virulent ASFV. Further studies were undertaken to try and identify the antigens recognised by IFN-gamma producing ASFV-immune T cells, using pig cells transfected with 17 different ASFV genes. None of these ASFV proteins were recognised by ASFV-immune cells.
Further studies to develop an ASFV vaccine used a library of 47 ASFV genes to vaccinate pigs, which were boosted with a library of recombinant vaccinia viruses expressing the same 47 ASFV genes. Following chalenge with virulent ASFV, vaccinated pigs showed partial protection against ASFV replication. These findings indicate that some of the ASFV genes contained in the library can induce some protective immunity.
Exploitation Route The identification of correlates of protective immunity to ASFV in pigs will aid vaccine design.
Sectors Agriculture, Food and Drink

 
Description Oxford Human & Veterinary Vaccinology course 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Industry/Business
Results and Impact 30 people (post-graduate students, scientsits from academia and industry) attended. Presentations and workshops sparked questions and discussion.

Not known
Year(s) Of Engagement Activity 2012,2013,2014,2015
URL https://www.conted.ox.ac.uk/courses/C900-1