Cell-Intrinsic CD38 Expression Sustains Exhausted CD8 T Cells by Regulating Their Survival and Metabolism during Chronic Viral Infection.

Acute and chronic viral infections result in the differentiation of effector and exhausted T cells with functional and phenotypic differences that dictate whether the infection is cleared or progresses to chronicity. High CD38 expression has been observed on CD8 T cells across various viral infections and tumors in patients, suggesting an important regulatory function for CD38 on responding T cells. Here, we show that CD38 expression was increased and sustained on exhausted CD8 T cells following chronic lymphocytic choriomeningitis virus (LCMV) infection, with lower levels observed on T cells from acute LCMV infection.

SREBP2-dependent lipid gene transcription enhances the infection of human dendritic cells by Zika virus.

The emergence of Zika virus (ZIKV) as a global health threat has highlighted the unmet need for ZIKV-specific vaccines and antiviral treatments. ZIKV infects dendritic cells (DC), which have pivotal functions in activating innate and adaptive antiviral responses; however, the mechanisms by which DC function is subverted to establish ZIKV infection are unclear. Here we develop a genomics profiling method that enables discrete analysis of ZIKV-infected versus neighboring, uninfected primary human DCs to increase the sensitivity and specificity with which ZIKV-modulated pathways can be identified.

PD-1 Immune Checkpoint Blockade and PSGL-1 Inhibition Synergize to Reinvigorate Exhausted T Cells.

Chronic viral infections where the antigen persists long-term, induces an exhaustion phenotype in responding T cells. It is now evident that immune checkpoints on T cells including PD-1, CTLA-4, and PSGL-1 () are linked with the differentiation of exhausted cells. Chronic T cell receptor signaling induces transcriptional signatures that result in the development of various exhausted T cell subsets, including the stem-like T cell precursor exhausted (Tpex) cells, which can be reinvigorated by immune checkpoint inhibitors (ICIs).

A Zika virus mutation enhances transmission potential and confers escape from protective dengue virus immunity.

Zika virus (ZIKV) and dengue virus (DENV) are arthropod-borne pathogenic flaviviruses that co-circulate in many countries. To understand some of the pressures that influence ZIKV evolution, we mimic the natural transmission cycle by repeating serial passaging of ZIKV through cultured mosquito cells and either DENV-naive or DENV-immune mice. Compared with wild-type ZIKV, the strains passaged under both conditions exhibit increased pathogenesis in DENV-immune mice.

Targeting the PSGL-1 Immune Checkpoint Promotes Immunity to PD-1-Resistant Melanoma.

Immune-checkpoint inhibitors have had impressive efficacy in some patients with cancer, reinvigorating long-term durable immune responses against tumors. Despite the clinical success of these therapies, most patients with cancer continue to be unresponsive to these treatments, highlighting the need for novel therapeutic options. Although P-selectin glycoprotein ligand-1 (PSGL-1) has been shown to inhibit immune responses in a variety of disease models, previous work has yet to address whether PSGL-1 can be targeted therapeutically to promote antitumor immunity.

The Ability of Zika virus Intravenous Immunoglobulin to Protect From or Enhance Zika Virus Disease.

The closely related flaviviruses, dengue and Zika, cause significant human disease throughout the world. While cross-reactive antibodies have been demonstrated to have the capacity to potentiate disease or mediate protection during flavivirus infection, the mechanisms responsible for this dichotomy are still poorly understood. To understand how the human polyclonal antibody response can protect against, and potentiate the disease in the context of dengue and Zika virus infection we used intravenous hyperimmunoglobulin (IVIG) preparations in a mouse model of the disease.

PSGL-1 Immune Checkpoint Inhibition for CD4 T Cell Cancer Immunotherapy.

Immune checkpoint inhibition targeting T cells has shown tremendous promise in the treatment of many cancer types and are now standard therapies for patients. While standard therapies have focused on PD-1 and CTLA-4 blockade, additional immune checkpoints have shown promise in promoting anti-tumor immunity. PSGL-1, primarily known for its role in cellular migration, has also been shown to function as a negative regulator of CD4 T cells in numerous disease settings including cancer.

Detection of Zika virus in mouse mammary gland and breast milk.

Clinical reports of Zika Virus (ZIKV) RNA detection in breast milk have been described, but evidence conflicts as to whether this RNA represents infectious virus. We infected post-parturient AG129 murine dams deficient in type I and II interferon receptors with ZIKV. ZIKV RNA was detected in pup stomach milk clots (SMC) as early as 1 day post maternal infection (dpi) and persisted as late as 7 dpi.

Maternally Acquired Zika Antibodies Enhance Dengue Disease Severity in Mice.

Antibody (Ab)-dependent enhancement can exacerbate dengue virus (DENV) infection due to cross-reactive Abs from an initial DENV infection, facilitating replication of a second DENV. Zika virus (ZIKV) emerged in DENV-endemic areas, raising questions about whether existing immunity could affect these related flaviviruses. We show that mice born with circulating maternal Abs against ZIKV develop severe disease upon DENV infection.

Deconvolution of pro- and antiviral genomic responses in Zika virus-infected and bystander macrophages.

Genome-wide investigations of host-pathogen interactions are often limited by analyses of mixed populations of infected and uninfected cells, which lower sensitivity and accuracy. To overcome these obstacles and identify key mechanisms by which Zika virus (ZIKV) manipulates host responses, we developed a system that enables simultaneous characterization of genome-wide transcriptional and epigenetic changes in ZIKV-infected and neighboring uninfected primary human macrophages. We demonstrate that transcriptional responses in ZIKV-infected macrophages differed radically from those in uninfected neighbors and that studying the cell population as a whole produces misleading results.

Synergism between the tyrosine kinase inhibitor sunitinib and Anti-TNF antibody protects against lethal dengue infection.

Dengue virus (DENV) currently circulates in more than 100 countries and causes an estimated 390 million infections per year. While most cases manifest as a self-resolving fever, ∼1.5% of infections develop into a more severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), which causes ∼20,000 deaths annually.