Pathogen-derived resistance to viral infection using a negative regulatory molecule

The principle of pathogen-derived resistance (the use of pathogen-derived genes to interfere with the pathogenic process and thereby confer disease resistance to the host) has been put forward as a broadly applicable conceptual tool for use in the genetic engineering of resistance to pathogens and parasites. It was previously predicted that four mechanisms of pathogen-derived resistance could be established using the bacteriophage QB and its host, Escherichia coli, as a model system. This paper demonstrates and helps illucidate the first of these mechanisms by using a viral regulatory protein, the QB coat protein, to block viral replication. The QB coat protein gene was transferred to susceptible E. coli. Expression of this gene had no obvious detrimental effect on the host. Low-level, constituitive expression of the coat protein conditions very high levels of resistance to QB infection. The resulting resistance is not associated with RNA interference or loss of pili as attachment sites, and does not appear to be associated premature encapsidation. This low-level expression of the QB coat protein also produces an intermediate level of resistance to the closely related phage SP, but fails to protect against the unrelated phage f2. Thus the resistance does not result from a generalized antiviral host response induced by the presence of the coat protein. We conclude that the QB coat protein blocks viral infection, as was predicted, due to its action as a negative regulatory molecule. The use of negative regulatory molecules may provide an effective mechanism for use in the genetic engineering of pathogen-derived resistance.