In 1996, Dean et al. (Science), demonstrated that a loss-of-function allele (CCR5Δ32) encoding a version of the chemokine receptor, CCR5, confers very substantial resistance to infection with HIV-1 in the homozygous state and slows progression in the heterozygous state. Given the relatively recent origin of HIV-1, this finding raised the question of what source of selection could account for the frequency, approximately 0.08 among Caucasians according to Dean et al., of this allele. A recent paper (Alonzo et al., 2013) offers new information on a relationship between CCR5 and a different pathogen that might offer insight into the evolutionary trajectory of CCR5Δ32.
The new study presents compelling evidence that leukotoxin ED (LukED), one of a family of bi-component exotoxins produced by Staphylococcus aureus, can bind to CCR5 and thereby cause cell death. LukED consistently produces substantially more cytotoxicity for CCR5+ than CCR5– cell lines of several types. Ligands for CCR5, including the drug, maraviroc, which is approved for clinical treatment of HIV-1 infection, significantly inhibit both the binding of LukED to cells and the magnitude of associated cytotoxicity. LukED also binds to and kills CCR5+ primarycells, such as human memory T cells, macrophages, and dendritic cells.
Additional studies, employing respectively both immunoprecipitation and surface plasmon resonance, demonstrated direct and specific binding of LukE (but not LukD) to purified CCR5. Consistent with studies described above, these interactions were inhibited by physiological and pharmacologic ligands for CCR5 as well as by a monoclonal antibody specific for the extracellular loop 2 of CCR5. A monoclonal antibody specific for the N-terminus of CCR5 did not inhibit the LukE-CCR5 interaction.
In the present study, the authors further show that LukED kills host cells in vivo and is a significant contributor to S. aureus pathogenicity in mouse models of infection. The latter inference is based on the fact that deletion of either the genes encoding LukE and LukD from S. aureus or CCR5 from the host decreased bacterial replication following infection and also reduced mortality among infected mice.
Earlier studies (Moore and Lindsay, 2002; Vandenesch et al., 2003; vonEiff et al., 2004) suggest that up to 70% of clinical isolates produce LukED. Thus, the authors reasonably suggest that LukED may have contributed to selection for CCR5Δ32 as a means for host cells to evade cytotoxicity in the context of S. aureus infection. Of course, we do not yet know how far back into human history LukED-producing strains of S. aureus extend or what magnitude of selection they would have mediated. We can hope that future studies can illuminate these aspects of our evolutionary past.
Even if additional studies provide new insights into the plausibility of LukED-synthesizing S. aureus accounting for the relatively high allele frequency of CCR5Δ32 in Caucasians, we do not then necessarily have the whole story. Murphy and colleagues (Glass et al., 2006) have reported substantially increased risk for serious morbidity and mortality in the context of infection with West Nile Virus when CCR5Δ32 was present in homozygous form. So, it could prove quite challenging to provide a definitive account of the selection pressures pertaining to CCR5Δ32, as it is not obvious how we can be certain that all relevant pathogen-CCR5 interactions have been identified. Furthermore, there may be other selective pressures that pertain to CCR5 that are not directly related to infectious agents. Nevertheless, the new results of Alonzo et al. are of substantial interest and perhaps even medical value.
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Alonzo F 3rd, Kozhaya L, Rawlings SA, Reyes-Robles T, DuMont AL, Myszka DG, Landau NR, Unutmaz D, Torres VJ. CCR5 is a receptor for Staphylococcus aureus leukotoxin ED. Nature. 2013 Jan 3;493(7430):51-5. doi: 10.1038/nature11724. Epub 2012 Dec 12. PubMed PMID: 23235831; PubMed Central PMCID: PMC3536884.
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Glass WG, McDermott DH, Lim JK, Lekhong S, Yu SF, Frank WA, Pape J, Cheshier RC, Murphy PM. CCR5 deficiency increases risk of symptomatic West Nile virus infection. J Exp Med. 2006 Jan 23;203(1):35-40. Epub 2006 Jan 17. PubMed PMID: 16418398; PubMed Central PMCID: PMC2118086.