IL-33 Augments Virus-Specific Memory T Cell Inflation and Potentiates the Efficacy of an Attenuated Cytomegalovirus-Based Vaccine.

Candidate vaccines designed to generate T cell-based immunity are typically vectored by nonpersistent viruses, which largely fail to elicit durable effector memory T cell responses. This limitation can be overcome using recombinant strains of CMV. Proof-of-principle studies have demonstrated the potential benefits of this approach, most notably in the SIV model, but safety concerns require the development of nonreplicating alternatives with comparable immunogenicity. In this study, we show that IL-33 promotes the accumulation and recall kinetics of circulating and tissue-resident memory T cells in mice infected with murine CMV. Using a replication-deficient murine CMV vector, we further show that exogenous IL-33 boosts vaccine-induced memory T cell responses, which protect against subsequent heterologous viral challenge. These data suggest that IL-33 could serve as a useful adjuvant to improve the efficacy of vaccines based on attenuated derivatives of CMV.

Cytomegalovirus-Specific IL-10-Producing CD4+ T Cells Are Governed by Type-I IFN-Induced IL-27 and Promote Virus Persistence.

CD4+ T cells support host defence against herpesviruses and other viral pathogens. We identified that CD4+ T cells from systemic and mucosal tissues of hosts infected with the ß-herpesviridae human cytomegalovirus (HCMV) or murine cytomegalovirus (MCMV) express the regulatory cytokine interleukin (IL)-10. IL-10+CD4+ T cells co-expressed TH1-associated transcription factors and chemokine receptors. Mice lacking T cell-derived IL-10 elicited enhanced antiviral T cell responses and restricted MCMV persistence in salivary glands and secretion in saliva. Thus, IL-10+CD4+ T cells suppress antiviral immune responses against CMV. Expansion of this T-cell population in the periphery was promoted by IL-27 whereas mucosal IL-10+ T cell responses were ICOS-dependent. Infected Il27rα-deficient mice with reduced peripheral IL-10+CD4+ T cell accumulation displayed robust T cell responses and restricted MCMV persistence and shedding. Temporal inhibition experiments revealed that IL-27R signaling during initial infection was required for the suppression of T cell immunity and control of virus shedding during MCMV persistence. IL-27 production was promoted by type-I IFN, suggesting that ß-herpesviridae exploit the immune-regulatory properties of this antiviral pathway to establish chronicity. Further, our data reveal that cytokine signaling events during initial infection profoundly influence virus chronicity.

CD200 receptor restriction of myeloid cell responses antagonizes antiviral immunity and facilitates cytomegalovirus persistence within mucosal tissue.

CD200 receptor (CD200R) negatively regulates peripheral and mucosal innate immune responses. Viruses, including herpesviruses, have acquired functional CD200 orthologs, implying that viral exploitation of this pathway is evolutionary advantageous. However, the role that CD200R signaling plays during herpesvirus infection in vivo requires clarification. Utilizing the murine cytomegalovirus (MCMV) model, we demonstrate that CD200R facilitates virus persistence within mucosal tissue. Specifically, MCMV infection of CD200R-deficient mice (CD200R(-/-)) elicited heightened mucosal virus-specific CD4 T cell responses that restricted virus persistence in the salivary glands. CD200R did not directly inhibit lymphocyte effector function. Instead, CD200R(-/-) mice exhibited enhanced APC accumulation that in the mucosa was a consequence of elevated cellular proliferation. Although MCMV does not encode an obvious CD200 homolog, productive replication in macrophages induced expression of cellular CD200. CD200 from hematopoietic and non-hematopoietic cells contributed independently to suppression of antiviral control in vivo. These results highlight the CD200-CD200R pathway as an important regulator of antiviral immunity during cytomegalovirus infection that is exploited by MCMV to establish chronicity within mucosal tissue.

Estimating the number of sex workers in South Africa: rapid population size estimation.

Although recognized as a vulnerable population, there is no national population size estimate for sex workers in South Africa. A rapid sex worker enumeration exercise was undertaken in twelve locations across the country based on principles of participatory mapping and Wisdom of the Crowd. Sites with a range of characteristics were selected, focusing on level of urbanisation, trucking, mining and borders. At each site, sex worker focus groups mapped local hotspots. Interviews with sex workers at identified hotspots were used to estimate the numbers and genders of sex workers working in each. Estimates provided in the literature were combined with enumeration exercise results to define assumptions that could be applied to a national extrapolation. A working estimate was reached of between 131,000 and 182,000 sex worker in South Africa, or between 0.76 and 1 % of the adult female population. The success of the exercise depended on integral involvement of sex worker peer educators and strong ethical considerations.

Human X-linked variable immunodeficiency caused by a hypomorphic mutation in XIAP in association with a rare polymorphism in CD40LG.

The present study focuses on a large family with an X-linked immunodeficiency in which there are variable clinical and laboratory phenotypes, including recurrent viral and bacterial infections, hypogammaglobulinemia, Epstein-Barr virus-driven lymphoproliferation, splenomegaly, colitis, and liver disease. Molecular and genetic analyses revealed that affected males were carriers of a hypomorphic hemizygous mutation in XIAP (XIAP(G466X)) that cosegregated with a rare polymorphism in CD40LG (CD40 ligand(G219R)). These genes are involved in the X-linked lymphoproliferative syndrome 2 and the X-linked hyper-IgM syndrome, respectively. Single expression of XIAP(G466X) or CD40L(G219R) had no or minimal effect in vivo, although in vitro, they lead to altered functional activities of their gene products, which suggests that the combination of XIAP and CD40LG mutations contributed to the expression of clinical manifestations observed in affected individuals. Our report of a primary X-linked immunodeficiency of oligogenic origin emphasizes that primary immunodeficiencies are not caused by a single defective gene, which leads to restricted manifestations, but are likely to be the result of an interplay between several genetic determinants, which leads to more variable clinical phenotypes.

IL-10 restricts activation-induced death of NK cells during acute murine cytomegalovirus infection.

IL-10 is an immunomodulatory cytokine that acts to antagonize T cell responses elicited during acute and chronic infections. Thus, the IL-10R signaling pathway provides a potential therapeutic target in strategies aimed at combating infectious diseases. In this study, we set out to investigate whether IL-10 expression had an effect on NK cells. Murine CMV infection provides the best characterized in vivo system to evaluate the NK cell response, with NK cells being critical in the early control of acute infection. Blockade of IL-10R during acute murine CMV infection markedly reduced the accumulation of cytotoxic NK cells in the spleen and lung, a phenotype associated with a transient elevation of virus DNA load. Impaired NK cell responsiveness after IL-10R blockade was attributed to elevated levels of apoptosis observed in NK cells exhibiting an activated phenotype. Therefore, we conclude that IL-10 contributes to antiviral innate immunity during acute infection by restricting activation-induced death in NK cells.

Heightened risk of unintended pregnancy among sex workers and sex worker organizations' response during the stringent COVID-19 containment measures in East and Southern Africa.

The UNFPA 2022 State of the World Population (SWOP) report recognises that certain populations of young women and girls are at a higher risk of unintended pregnancy, but did not adequately address the grave situation of female sex workers (FSWs), who experience the worst sexual and reproductive health outcomes, especially during humanitarian crises. This study assesses the risks of unintended pregnancy among FSWs and sex worker organizations? response during the stringent COVID-19 containment measures in East and Southern Africa (ESA). A mixed-methods approach consisting of a desk review, key informant interviews and an online survey was used for data collection. Key informants and survey respondents included representatives of sex worker-led organisations and networks, organisations providing services to sex workers, development partners, advocacy organisations and donors, with priority given to key informants who had direct experience of providing services to sex workers during the COVID-19 pandemic. In total, 21 key informants were interviewed and 69 respondents participated in the online survey, with representation from 14 out of 23 countries in the ESA region. The study findings show that the disruption to livelihoods and threats to human rights occasioned by the stringent COVID-19 containment measures intersected with sex workers' access to contraception and risk of unintended pregnancy. Looking to the uncertain future of humanitarian crises, the study concludes by outlining critical issues that need to be addressed to ensure resilience of SRHR services for populations in vulnerable positions, such as sex workers.

IL-10 restricts memory T cell inflation during cytomegalovirus infection.

The beta-herpesvirus CMV induces a substantial and progressive expansion of virus-specific memory CD8 T cells, which protect the host against viral reactivation from latency. In this paper, we report that this expansion, or "inflation," of memory T cells is amplified dramatically during mouse CMV infection of IL-10 knockout (IL-10(-/-)) mice. T cells from IL-10(-/-) mice were oligoclonal, exhibited a highly activated phenotype, expressed antiviral cytokines, and degranulated in response to cognate Ag encounter ex vivo. Moreover, latent viral load was reduced in IL-10(-/-) mice. Importantly, these results were recapitulated by IL-10R blockade during chronic/latent infection of wild-type mice. These data demonstrate that regulatory immune mechanisms can influence CMV-specific T cell memory and suggest a possible rationale for the acquisition of functional IL-10 orthologs by herpesviruses.

The antiviral restriction factor IFN-induced transmembrane protein 3 prevents cytokine-driven CMV pathogenesis.

The antiviral restriction factor IFN-induced transmembrane protein 3 (IFITM3) inhibits cell entry of a number of viruses, and genetic diversity within IFITM3 determines susceptibility to viral disease in humans. Here, we used the murine CMV (MCMV) model of infection to determine that IFITM3 limits herpesvirus-associated pathogenesis without directly preventing virus replication. Instead, IFITM3 promoted antiviral cellular immunity through the restriction of virus-induced lymphopenia, apoptosis-independent NK cell death, and loss of T cells. Viral disease in Ifitm3-/- mice was accompanied by elevated production of cytokines, most notably IL-6. IFITM3 inhibited IL-6 production by myeloid cells in response to replicating and nonreplicating virus as well as following stimulation with the TLR ligands Poly(I:C) and CpG. Although IL-6 promoted virus-specific T cell responses, uncontrolled IL-6 expression in Ifitm3-/- mice triggered the loss of NK cells and subsequently impaired control of MCMV replication. Thus, IFITM3 represents a checkpoint regulator of antiviral immunity that controls cytokine production to restrict viral pathogenesis. These data suggest the utility of cytokine-targeting strategies in the treatment of virus-infected individuals with impaired IFITM3 activity.

The Role of IL-22 in Viral Infections: Paradigms and Paradoxes.

Interleukin-22 (IL-22) is a member of the IL-10 family of cytokines. Hematopoietic cells express IL-22, and this cytokine signals through the heterodimeric IL-22 receptor expressed by non-hematopoietic cells. A growing body of evidence points toward a role for IL-22 in a diverse array of biological functions ranging from cellular proliferation, tissue protection and regeneration, and inflammation. In recent years, the role that IL-22 plays in antiviral immune responses has been examined in a number of infection models. Herein, we assess our current understanding of how IL-22 determines the outcome of viral infections and define common mechanisms that are evident from, sometimes paradoxical, findings derived from these studies. Finally, we discuss the potential therapeutic utility of IL-22 manipulation in the treatment and prevention of viral infections and associated pathologies.

Neutrophils recruited by IL-22 in peripheral tissues function as TRAIL-dependent antiviral effectors against MCMV.

During primary infection, murine cytomegalovirus (MCMV) spreads systemically, resulting in virus replication and pathology in multiple organs. This disseminated infection is ultimately controlled, but the underlying immune defense mechanisms are unclear. Investigating the role of the cytokine IL-22 in MCMV infection, we discovered an unanticipated function for neutrophils as potent antiviral effector cells that restrict viral replication and associated pathogenesis in peripheral organs. NK-, NKT-, and T cell-secreted IL-22 orchestrated antiviral neutrophil-mediated responses via induction in stromal nonhematopoietic tissue of the neutrophil-recruiting chemokine CXCL1. The antiviral effector properties of infiltrating neutrophils were directly linked to the expression of TNF-related apoptosis-inducing ligand (TRAIL). Our data identify a role for neutrophils in antiviral defense, and establish a functional link between IL-22 and the control of antiviral neutrophil responses that prevents pathogenic herpesvirus infection in peripheral organs.

Herpesvirus exploitation of host immune inhibitory pathways.

Herpesviruses employ a plethora of mechanisms to circumvent clearance by host immune responses. A key feature of mammalian immune systems is the employment of regulatory pathways that limit immune responsiveness. The primary functions of these mechanisms are to control autoimmunity and limit exuberant responses to harmless antigen in mucosal surfaces. However, such pathways can be exploited by viral pathogens to enable acute infection, persistence and dissemination. Herein, we outline the current understanding of inhibitory pathways in modulating antiviral immunity during herpesvirus infections in vivo and discuss strategies employed by herpesviruses to exploit these pathways to limit host antiviral immunity.