Immune stimulatory pathways are dysregulated during chronic viral infections, preventing timely T cell and antibody mediated immunity. Human persistent viruses, including human immunodeficiency virus (HIV), hepatitis C and B viruses (HCV and HBV) cause tremendous disease burden worldwide but are restricted to human and nonhuman primates, which in turn poses great limitations for experimental-based research. Importantly, lymphocytic choriomeningitis virus (LCMV) in its natural rodent host has been successfully used as a model system to uncover common principles underlying the regulation of immune responses during persistent viral infections, often highlighting basic mechanisms that were later extended into humans. We have found that interleukin-6 (IL-6) and IL-27 are essential for optimal CD4 T cell differentiation and CD4 T cell survival, respectively, while they redundantly induce IL-21, a critical factor for CD8 T cell and antibody responses, late after infection. Consistently, both IL-6 and IL-27 were absolutely required to control chronic (but not acute) LCMV infection. More recent data indicate that late IL-27 derived from B cells is crucial for viral control and it is regulated by host microbiota during chronic LCMV infection. The overall goal of the current proposal is to fully dissect the mechanisms underlying the antiviral effects of B-cell-derived IL-27 as well as its regulation by host microbiota and related metabolites during persistent infection. To accomplish this goal, we propose three specific aims.
In Aim 1 we will investigate the relationship between B-cell-derived IL-27 and antiviral responses during chronic LCMV infection. We will test the hypothesis that B cell-derived-IL-27 is both a dependent and a driver of CD4 T cell responses during chronic infection, and indirectly enhances antibodies and CD8 T cells, promoting viral control late after infection.
In Aim 2 we will identify the microbiome commensals that enhance IL-27 production by B cells and the impact for antiviral responses and viral control during chronic LCMV infection. We will investigate the possibility that Segmented Filamentous Bacteria (SFB), a commensal that associates with accelerated viral control, enhances IL-27 production by B cells in small intestine as well as T cell responses both locally and at distal sites, overriding the need for IL-6. Finally, in Aim 3 we will identify microbiota-related metabolites that modulate IL-27 production by B cells and the impact for antiviral responses and viral control during chronic LCMV infection. We will investigate the metabolites that associate with the microbiota driving IL-27 production by B cells and evaluate their effects on IL-27 expression (in mouse and human B cells) as well as T cell responses and viral control in LCMV chronically infected mice. The knowledge gained from this study will not only enhance our understanding of the basic biology of key immune regulators (i.e. IL-27, microbiome and related metabolites) but may also be valuable for therapeutically manipulating these factors during infections and perhaps other immune diseases.
One limitation to fight off persistent viruses is the poor knowledge on the factors that could promote immunity in the context of the inhibitory environment that characterizes chronic viral infections. We have identified cytokine and microbiota positive effects on viral control in a murine model of persistent infection. We propose to study the mechanisms involved in order to best harness these factors to prevent or attenuate viral persistence.
|Loureiro, María Eugenia; Zorzetto-Fernandes, Andre Luiz; Radoshitzky, Sheli et al. (2018) DDX3 suppresses type I interferons and favors viral replication during Arenavirus infection. PLoS Pathog 14:e1007125|
|Macal, Monica; Jo, Yeara; Dallari, Simone et al. (2018) Self-Renewal and Toll-like Receptor Signaling Sustain Exhausted Plasmacytoid Dendritic Cells during Chronic Viral Infection. Immunity 48:730-744.e5|
|Harker, James A; Wong, Kurt A; Dallari, Simone et al. (2018) Interleukin-27R Signaling Mediates Early Viral Containment and Impacts Innate and Adaptive Immunity after Chronic Lymphocytic Choriomeningitis Virus Infection. J Virol 92:|
|Wehrens, Ellen J; Wong, Kurt A; Gupta, Ankan et al. (2018) IL-27 regulates the number, function and cytotoxic program of antiviral CD4 T cells and promotes cytomegalovirus persistence. PLoS One 13:e0201249|
|Kakaradov, Boyko; Arsenio, Janilyn; Widjaja, Christella E et al. (2017) Early transcriptional and epigenetic regulation of CD8+ T cell differentiation revealed by single-cell RNA sequencing. Nat Immunol 18:422-432|
|Smelkinson, Margery G; Guichard, Annabel; Teijaro, John R et al. (2017) Influenza NS1 directly modulates Hedgehog signaling during infection. PLoS Pathog 13:e1006588|
|Macal, Monica; Tam, Miguel A; Hesser, Charles et al. (2016) CD28 Deficiency Enhances Type I IFN Production by Murine Plasmacytoid Dendritic Cells. J Immunol 196:1900-9|
|El Ghazal, Roland; Yin, Xin; Johns, Scott C et al. (2016) Glycan Sulfation Modulates Dendritic Cell Biology and Tumor Growth. Neoplasia 18:294-306|
|Movita, Dowty; van de Garde, Martijn D B; Biesta, Paula et al. (2015) Inflammatory monocytes recruited to the liver within 24 hours after virus-induced inflammation resemble Kupffer cells but are functionally distinct. J Virol 89:4809-17|
|Zuniga, Elina I; Macal, Monica; Lewis, Gavin M et al. (2015) Innate and Adaptive Immune Regulation During Chronic Viral Infections. Annu Rev Virol 2:573-97|
Showing the most recent 10 out of 11 publications