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

Abstract

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-...

Intrahost cytomegalovirus population genetics following antibody pretreatment in a monkey model of congenital transmission

“…Both UCD52 and UCD59 are derived from serial propagation on primary monkey kidney epithelial cells, which express epithelial cell morphology and cell-specific markers [31] and contain a full-length UL128-UL131 coding capacity [32]. Previous studies have shown that inoculation of RhCMV-naïve rhesus macaques with UCD52 and UCD59 results in similar patterns of viremia and shedding in bodily fluids, comparable to those observed in colony-reared macaques naturally infected with circulating strains of endemic RhCMV [32][33][34]. On the other hand, CMV strain 180.92 was derived from serial propagation on rhesus fibroblasts, and is known to be a mixed virus with the dominant strain containing deletions in the UL/b' region while retaining an intact UL128-UL131 locus.…”

“…Because of this, it is likely that UCD52 has higher viral fitness in vivo, relative to both UCD59 and 180.92. The reason for UCD52 dominance over UCD59 is unknown: RhCMVnaïve macaques inoculated with UCD52 and UCD59 have similar patterns of viremia and shedding in bodily fluids [32][33][34]. That strain 180.92 did not become dominant is not surprising given previous findings of only low-level viral shedding and limited tissue dissemination of this strain in inoculated RhCMV-naïve macaques [35].…”

Porcine Circovirus Type 2 Rep Enhances IL-10 Production in Macrophages via Activation of p38-MAPK Pathway

“…Interleukin-10 (IL-10), originally identified as an inhibitor of interferon-gamma (IFN-γ) and Interleukin-2 synthesis in Th2 cells [7], efficiently inhibits proliferative and cytokine responses in T cells and has shown to mediate both immunological unresponsiveness and the suppression of immune reactions [8,9]. As a key regulatory anti-inflammatory cytokine of multiple immune cells, IL-10 plays a pivotal role in limiting excessive inflammatory responses [10]. In the context of infectious disease, studies have reported an increase in pathogen clearance in the absence of IL-10 [11,12].…”

Interleukin-10 Production by T and B Cells Is a Key Factor to Promote Systemic Salmonella enterica Serovar Typhimurium Infection in Mice

“…Typhimurium to cause systemic infection was described in mice treated with a neutralizing antibody that blocks the function of IL-10 ( 24 ). Interestingly, studies assessing persistent pathogens, such as Leishmania major ( 25 ), human cytomegalovirus ( 26 ), or Mycobacterium tuberculosis ( 27 ), have demonstrated that the absence of IL-10 leads to a better clearance of these pathogens, with variable degrees of immunopathology.…”