Pathogen Manipulation of cIL-10 Signaling Pathways: Opportunities for Vaccine Development?

Eberhardt, Meghan K.; Barry, Peter A.

doi:10.1007/978-3-662-43492-5_5

Cited by 11 publications

(17 citation statements)

References 166 publications

(162 reference statements)

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“…Exploitation of cellular interleukin-10 (cIL-10) or IL-10 receptor (IL-10R) signaling is a common theme in the natural histories of diverse pathogenic and nonpathogenic microbes that establish lifelong persistence, including viruses, pathogenic and commensal bacteria, protozoa, helminths, and fungi (4)(5)(6)(7). This unifying linkage via cIL-10 suggests the potential for development of novel interventions to prevent and/or disrupt persistent infections.…”

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confidence: 99%

Vaccination against a Virus-Encoded Cytokine Significantly Restricts Viral Challenge

Eberhardt

Deshpande

Chang

et al. 2013

J Virol

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T here is ample precedent from studies of licensed viral and microbial vaccines that vaccine-mediated stimulation of pathogen-specific B cell immunity is critical for protection from infection and/or disease (1). Many new vaccine designs are predicated on the induction of antibodies that neutralize viral attachment to susceptible cells. As phase 2 clinical trials on human cytomegalovirus (HCMV) vaccination have shown, however, this approach only partially protects against challenge virus infection. In one study, seronegative women who had given birth within the previous year were vaccinated against HCMV glycoprotein B (gB) (2), the predominant virion target for antibodies that neutralize infection of fibroblasts. While significant protection against primary HCMV infection was observed in the vaccine group, the effect was limited in magnitude (50%) and duration. In the second placebocontrolled, randomized study, liver and kidney transplant candidates were similarly immunized with gB and prospectively evaluated for parameters of HCMV infection posttransplantation (3). Vaccine-mediated increases in gB-specific antibody titers were inversely correlated with the duration of HCMV viremia posttransplantation. Similar to the trial involving seronegative women, however, vaccination against gB alone in transplant recipients did not completely protect those at risk for HCMV infection.

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confidence: 99%

Vaccination against a Virus-Encoded Cytokine Significantly Restricts Viral Challenge

Eberhardt

Deshpande

Chang

et al. 2013

J Virol

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“…Studies of MCMV-infected mice revealed that there is a marked increase in the number of CD4 ϩ cells expressing cIL-10 in tissue sites of persistence (salivary glands) but not in tissues where MCMV establishes a latent infection (e.g., spleen) (7). While MCMV does not encode an ortholog of cIL-10, the results of this study imply that MCMV, like many viral and nonviral pathogens (3), has co-opted the cIL-10/IL-10R1 signaling cascade to enable persistence in an immune host.…”

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confidence: 58%

“…Human cytomegalovirus (HCMV) is a ubiquitous persistent pathogen with worldwide seroprevalence rates in adults that range from ϳ50 to 100%, and there is accumulating evidence that persistence is mediated through viral modulation of host immunity, including manipulation of the IL-10R pathway (3,(8)(9)(10). HCMV is generally considered a virus with low pathogenic potential in immunocompetent hosts, consistent with the interpretation that host immune responses to HCMV infection are protective against HCMV sequelae.…”

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confidence: 89%

“…Cellular interleukin-10 (cIL-10) is an anti-inflammatory cytokine that is considered a master regulator of the immune system due to its positive and negative effects on cells bearing the IL-10 receptor (IL-10R) (2). Manipulation of the cIL-10/IL-10R signaling pathway has been increasingly associated with long-term persistent infections in immunocompetent hosts (3). Multiple evolutionarily diverse microbes (viral, pathogenic and commensal bacterial, fungal, protozoal, and helminthic) activate the IL-10R-mediated signaling pathway as part of their natural histories.…”

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confidence: 99%

“…Taken together, host immunity mostly protects against HCMV disease during primary infection, but host immune responses are insufficient to clear persistent reservoirs in infected hosts, despite extraordinarily large HCMV-specific T cell responses (11) and the induction of neutralizing antibodies against multiple HCMV glycoproteins (4,(12)(13)(14). The viral mechanisms of persistence are incompletely resolved, but there is increasing evidence that cIL-10 signaling through binding to its high-affinity receptor (IL-10R1) is critical for maintaining persistence (2,3). Studies of MCMV-infected mice revealed that there is a marked increase in the number of CD4 ϩ cells expressing cIL-10 in tissue sites of persistence (salivary glands) but not in tissues where MCMV establishes a latent infection (e.g., spleen) (7).…”

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confidence: 99%

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Exploitation of Interleukin-10 (IL-10) Signaling Pathways: Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection

Eberhardt

Deshpande

Fike

et al. 2016

J Virol

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There is accumulating evidence that the viral interleukin-10 (vIL-10) ortholog of both human and rhesus cytomegalovirus (HCMV and RhCMV, respectively) suppresses the functionality of cell types that are critical to contain virus dissemination and help shape long-term immunity during the earliest virus-host interactions. In particular, exposure of macrophages, peripheral blood mononuclear cells, monocyte-derived dendritic cells, and plasmacytoid dendritic cells to vIL-10 suppresses multiple effector functions including, notably, those that link innate and adaptive immune responses. Further, vaccination of RhCMV-uninfected rhesus macaques with nonfunctional forms of RhCMV vIL-10 greatly restricted parameters of RhCMV infection following RhCMV challenge of the vaccinees. Vaccinees exhibited significantly reduced shedding of RhCMV in saliva and urine following RhCMV challenge compared to shedding in unvaccinated controls. Based on the evidence that vIL-10 is critical during acute infection, the role of vIL-10 during persistent infection was analyzed in rhesus macaques infected long term with RhCMV to determine whether postinfection vaccination against vIL-10 could change the virus-host balance. RhCMV-seropositive macaques, which shed RhCMV in saliva, were vaccinated with nonfunctional RhCMV vIL-10, and shedding levels of RhCMV in saliva were evaluated. Following robust increases in vIL-10-binding and vIL-10-neutralizing antibodies, shedding levels of RhCMV modestly declined, consistent with the interpretation that vIL-10 may play a functional role during persistent infection. However, a more significant association was observed between the levels of cellular IL-10 secreted in peripheral blood mononuclear cells exposed to RhCMV antigens and shedding of RhCMV in saliva. This result implies that RhCMV persistence is associated with the induction of cellular IL-10 receptor-mediated signaling pathways. IMPORTANCEHuman health is adversely impacted by viruses that establish lifelong infections that are often accompanied with increased morbidity and mortality (e.g., infections with HIV, hepatitis C virus, or human cytomegalovirus). A longstanding but unfulfilled goal has been to develop postinfection vaccine strategies that could "reboot" the immune system of an infected individual in ways that would enable the infected host to develop immune responses that clear reservoirs of persistent virus infection, effectively curing the host of infection. This concept was evaluated in rhesus macaques infected long term with rhesus cytomegalovirus by repeatedly immunizing infected animals with nonfunctional versions of the rhesus cytomegalovirus-encoded viral interleukin-10 immune-modulating protein. Following vaccine-mediated boosting of antibody titers to viral interleukin-10, there was modest evidence for increased immunological control of the virus following vaccination. More significantly, data were also obtained that indicated that rhesus cytomegalovirus is able to persist due to upregulation of the cellular interleukin-...

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Exploiting viral natural history for vaccine development

Barry

2015

Med Microbiol Immunol

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The partial successes of the Phase 2 gB-based vaccine trials for HCMV highlight the very real likelihood that vaccine-mediated induction of antibodies that neutralize the fusion pathway of fibroblast infection is not sufficient as a singular strategy to confer protective efficacy against primary HCMV infection. Alternative strategies that serve as adjuncts to gB-based vaccines are likely required to target different aspects of the complex lifecycle of HCMV infection. There has been considerable recent interest in targeting the gH/gL/UL128/UL130/UL131 pentamer complex (gH/gL-PC) to neutralize the endocytic pathway of HCMV infection of epithelial and endothelial cells. Since both cell types are critical during primary mucosal infection, intrahost spread, and shedding of HCMV in an infected host, the gH/gL-PC represents a high-value target for vaccination to interrupt the HCMV lifecycle. The natural history of HCMV is exceedingly complex and incompletely resolved, and the protective efficacy generated by gH/gL-PC remains to be validated in clinical trials. Yet, there are salient aspects of its lifecycle that offer clues about how other novel vaccine strategies can be targeted to especially susceptible parts of the viral proteome to significantly disrupt HCMV’s ability to infect susceptible hosts. In particular, the protracted evolution of Herpesvirales has endowed HCMV with two remarkable properties of its natural history: (1) lifelong persistence within immune hosts that develop extraordinarily large antiviral immune responses and (2) the ability to reinfect those with prior immunity. The latter phenotype strongly implies that, if HCMV can overcome prior immunity to initiate a new infection, it is likely irrelevant whether prior immunity derives from prior infection or prior vaccination. Both phenotypes are unified by the extensive devotion of the HCMV coding repertoire (~50 %) to viral proteins that modulate host cell signaling, trafficking, activation, antigen presentation, and resistance to apoptosis. Collectively, these viral proteins are the likely reason for the high barrier to success for the 4-decade effort to design an HCMV vaccine, and they represent the viral proteins that make HCMV be the virus that it is. James Hanshaw wrote in 1971 that, based on a 15-year retrospective of congenital HCMV cases, “… any thoughtful program designed at prevention or treatment deserves consideration”. Drawing upon natural history data from the nonhuman primate model of HCMV persistence and pathogenesis, a “thoughtful program” is put forth that HCMV immune-modulating proteins should be considered as vaccine candidates.

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Pathogen Manipulation of cIL-10 Signaling Pathways: Opportunities for Vaccine Development?

Cited by 11 publications

References 166 publications

Vaccination against a Virus-Encoded Cytokine Significantly Restricts Viral Challenge

Vaccination against a Virus-Encoded Cytokine Significantly Restricts Viral Challenge

Exploitation of Interleukin-10 (IL-10) Signaling Pathways: Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection

Exploiting viral natural history for vaccine development

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