Cytomegalovirus (CMV) and all members of Herpesvirales derived from a progenitor herpesvirus (HV) ~200M years ago. As obligate intracellular pathogens, the fact that HV's remain extant to infect their hosts suggests sophisticated viral mechanisms to counter host immune responses. The sophistication of viral immunomodulation is emphasized by the ability of HV's to maintain a lifelong persistence within immune competent hosts. Emerging evidence indicates that a common mechanistic link by which different CMV members attenuate the functionality of host immunity is by targeting the cellular interleukin-10 (cIL-10) signaling pathway. Only primate CMV's (HCMV and RhCMV) encode a viral version of cIL-10 (cmvIL-10 and rhcmvIL-10) that, despite extreme genetic drift from the originally transduced cIL-10 gene, has the identical immunosuppressive properties of cIL10. In parallel approaches conducted in rhesus macaques (RM), we have shown that rhcmvIL-10 is essential for (i) acute and long-term modulation of host immune responses and (ii) enabling long-term shedding of virus in bodily fluids following parenteral RhCMV challenge. Our results indicate that rhcmvIL-10 is a critical viral determinant that skews virus-host interactions towards those that favor the establishment of a persistence in an immune competent host. We hypothesize that immunization of na?ve monkeys against rhcmvIL-10 will significantly increase resistance to mucosally transmitted RhCMV challenge. Our study will demonstrate that vaccine-mediated neutralization of rhcmvIL- 10 can protect against repeated mucosal exposure to RhCMV through the following Aims. (1) Immunization of naive RM with non-functional forms of rhcmvIL-10, RhCMV gB, and rhcmvIL-10 + gB.;(2) Mucosal challenge of immunized RM by introducing them into a cohort of RhCMV- excreting RM under housing conditions that enable horizontal transmission of RhCMV;(3) Development and in vitro characterization of non-functional forms of HCMV cmvIL-10;(4) Vaccination of RM with non-functional HCMV cmvIL-10 and in vitro demonstration of (i) broadly cross-reactive neutralizing antibodies (N-Ab) against HCMV cmvIL-10 sequence variants, and (ii) an absence of antibodies that are cross-reactive with human cIL-10.
Our data in the rhesus model supports the concept that, in the absence of rhcmvIL-10, de novo host immune responses to other viral antigens after RhCMV challenge confer greater protection. Our approach expands historical HCMV vaccine strategies, which have focused on viral proteins encoding neutralizing and cellular epitopes, by targeting cmvIL-10 to neutralize its immunosuppressive properties on host immune responses.
|Eberhardt, Meghan K; Deshpande, Ashlesha; Fike, Joseph et al. (2016) Exploitation of Interleukin-10 (IL-10) Signaling Pathways: Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection. J Virol 90:9920-9930|
|Yue, Yujuan; Kaur, Amitinder; Lilja, Anders et al. (2016) The susceptibility of primary cultured rhesus macaque kidney epithelial cells to rhesus cytomegalovirus strains. J Gen Virol 97:1426-1438|
|Kuruganti, Srilalitha; Miersch, Shane; Deshpande, Ashlesha et al. (2016) Cytokine Activation by Antibody Fragments Targeted to Cytokine-Receptor Signaling Complexes. J Biol Chem 291:447-61|
|Zhang, Mingce; Bracaglia, Claudia; Prencipe, Giusi et al. (2016) A Heterozygous RAB27A Mutation Associated with Delayed Cytolytic Granule Polarization and Hemophagocytic Lymphohistiocytosis. J Immunol 196:2492-503|
|Khass, Mohamed; Blackburn, Tessa; Burrows, Peter D et al. (2016) VpreB serves as an invariant surrogate antigen for selecting immunoglobulin antigen-binding sites. Sci Immunol 1:|
|Barry, Peter A (2015) Exploiting viral natural history for vaccine development. Med Microbiol Immunol 204:255-62|
|Eberhardt, Meghan K; Barry, Peter A (2014) Pathogen manipulation of cIL-10 signaling pathways: opportunities for vaccine development? Curr Top Microbiol Immunol 380:93-128|
|Deere, Jesse D; Barry, Peter A (2014) Using the nonhuman primate model of HCMV to guide vaccine development. Viruses 6:1483-501|
|Kuruganti, Srilalitha; Accavitti-Loper, Mary Ann; Walter, Mark R (2014) Production and characterization of thirteen human type-I interferon-? subtypes. Protein Expr Purif 103:75-83|
|Walter, Mark R (2014) The molecular basis of IL-10 function: from receptor structure to the onset of signaling. Curr Top Microbiol Immunol 380:191-212|
Showing the most recent 10 out of 29 publications