Eosinophils, ribonucleases and host defense: Solving the puzzle

Abstract

The eosinophil ribonucleases eosinophil-derived neurotoxin (EDN/ RNase 2) and eosinophil cationic protein (ECP/RNase 3) are among the major secretory effector proteins of human eosinophilic leukocytes, cells whose role in host defense remains controversial and poorly understood. We have recently described the unusual manner in which this ribonuclease lineage has evolved, with extraordinary diversification observed in primate as well as in rodent EDNs and ECPs. The results of our evolutionary studies suggest that the EDN/ ECP ribonucleases are in the process of being tailored for a specific, ribonuclease-related goal. With this in mind, we have begun to look carefully at some of the intriguing associations that link eosinophils and their ribonucleases to disease caused by the single-stranded RNA viral pathogen, respiratory syncytial virus (RSV). Recent work in our laboratory has demonstrated that eosinophils can mediate a direct, ribonuclease-dependent reduction in infectivity of RSV in vitro, and that EDN can function alone as an independent antiviral agent. The results of this work have led us to consider the possibility that the EDN/ECP ribonucleases represent a heretofore unrecognized element of innate and specific antiviral host defense.

Rapid Diversification of RNase A Superfamily Ribonucleases from the Bullfrog, Rana catesbeiana

“…Similar to what was observed among the EAR genes of Mus musculus, the Rana subclusters are characterized by elevated ratios of nonsynonymous to synonymous substitution, with d N /d S > 1.0 for all but two of the 31 pairs of genes within the subclusters. Positive selection (d N /d S > 1.0) was also observed among the primate eosinophil cationic protein genes, (Zhang et al 1998) which, together with provocative functional data, has been interpreted as support for a role for the eosinophil-associated ribonucleases in antiviral host defense (Domachowske et al 1998;Rosenberg and Domachowske 1999). Although it is tempting to consider the possibility of a similar physiologic function for the Rana ribonucleases, this interpretation would be decidedly premature, and it is difficult to envision this sort of role for the proteins that are localized in the oocyte.…”

A Maximum Likelihood Method for Detecting Functional Divergence at Individual Codon Sites, with Application to Gene Family Evolution

“…Both ECP and EDN have host-defense roles, but their specific functions differ. ECP is a nonspecific toxin to bacteria and parasites, probably through cell membrane disruption, whereas EDN acts as a potent antiviral agent through degradation of viral RNA (Rosenberg and Domachowske 1999). ECP also has antiviral activity, but it is substantially less effective than Old World monkey EDN (Domachowske et al 1998).…”

Maximum likelihood methods for detecting adaptive evolution after gene duplication

“…ECP and EDN are ribonucleases present in the large specific granules of eosinophilic leukocytes (Rosenberg and Domachowske, 1999). While both ECP and EDN have hostdefence roles, their specific functions differ.…”

“…ECP is a cationic toxin, apparently functioning as a non-specific toxin to parasites and bacteria (Rosenberg and Domachowske, 1999). EDN is considerably less cationic, but has strong ribonucleic activity making it a potent antiviral agent via ribonucleic degradation of viral RNA (Rosenberg and Domachowske, 1999). Zhang et al (1998) studied the evolution of this gene Figure 2.…”

“…Rosenberg and Domachowske (1999) have speculated that both EDN and ECP might have acquired specialized anti-viral activity, perhaps against respiratory viral pathogens. Perhaps subsequent adaptive evolution in the ECP clade reflects long term selective pressure for effective antiviral activity against respiratory viral pathogens.…”