The liver has strong innate immunity to counteract pathogens from the gastrointestinal tract. During the development of liver cancer, which is typically driven by chronic inflammation, the composition and biological roles of the innate immune cells are extensively altered. Hypoxia is a common finding in all stages of liver cancer development. Hypoxia drives the stabilization of hypoxia-inducible factors (HIFs), which act as central regulators to dampen the innate immunity of liver cancer. HIF signaling in innate immune cells and liver cancer cells together favor the recruitment and maintenance of pro-tumorigenic immune cells and the inhibition of anti-tumorigenic immune cells, promoting immune evasion. HIFs represent attractive therapeutic targets to inhibit the formation of an immunosuppressive microenvironment and growth of liver cancer.
Vincent Wai-Hin Yuen, Carmen Chak-Lui Wong
Intermittent hypoxia (IH) is a hallmark manifestation of obstructive sleep apnea (OSA), a widespread disorder of breathing. This review focuses on the role of hypoxia-inducible factors (HIFs) in hypertension, type 2 diabetes (T2D), and cognitive decline in experimental models of IH patterned after O2 profiles seen in OSA. IH increases HIF-1α and decreases HIF-2α protein levels. Dysregulated HIFs increase reactive oxygen species (ROS) through HIF-1-dependent activation of pro-oxidant enzyme genes in addition to reduced transcription of anti-oxidant genes by HIF-2. ROS in turn activates chemoreflex and suppresses baroreflex, thereby stimulating the sympathetic nervous system and causing hypertension. We will also discuss how increased ROS generation by HIF-1 also contributes to IH-induced insulin resistance and T2D as well as disrupted NMDA receptor signaling in the hippocampus, resulting in cognitive decline.
Nanduri R. Prabhakar, Ying-Jie Peng, Jayasri Nanduri
Although antiretroviral therapies (ARTs) potently inhibit HIV replication, they do not eradicate the virus. HIV persists in cellular and anatomical reservoirs that show minimal decay during ART. A large number of studies conducted during the past 20 years have shown that HIV persists in a small pool of cells harboring integrated and replication-competent viral genomes. The majority of these cells do not produce viral particles and constitute what is referred to as the latent reservoir of HIV infection. Therefore, although HIV is not considered as a typical latent virus, it can establish a state of nonproductive infection under rare circumstances, particularly in memory CD4+ T cells, which represent the main barrier to HIV eradication. While it was originally thought that the pool of latently infected cells was largely composed of cells harboring transcriptionally silent genomes, recent evidence indicates that several blocks contribute to the nonproductive state of these cells. Here, we describe the virological and immunological factors that play a role in the establishment and persistence of the pool of latently infected cells and review the current approaches aimed at eliminating the latent HIV reservoir.
Caroline Dufour, Pierre Gantner, Rémi Fromentin, Nicolas Chomont
Toxoplasma gondii is an incredibly successful parasite owing in part to its ability to persist within cells for the life of the host. Remarkably, at least 350 host species of T. gondii have been described to date, and it is estimated that 30% of the global human population is chronically infected. The importance of T. gondii in human health was made clear with the first reports of congenital toxoplasmosis in the 1940s. However, the AIDS crisis in the 1980s revealed the prevalence of chronic infection, as patients presented with reactivated chronic toxoplasmosis, underscoring the importance of an intact immune system for parasite control. In the last 40 years, there has been tremendous progress toward understanding the biology of T. gondii infection using rodent models, human cell experimental systems, and clinical data. However, there are still major holes in our understanding of T. gondii biology, including the genes controlling parasite development, the mechanisms of cell-intrinsic immunity to T. gondii in the brain and muscle, and the long-term effects of infection on host homeostasis. The need to better understand the biology of chronic infection is underscored by the recent rise in ocular disease associated with emerging haplotypes of T. gondii and our lack of effective treatments to sterilize chronic infection. This Review discusses the cell types and molecular mediators, both host and parasite, that facilitate persistent T. gondii infection. We highlight the consequences of chronic infection for tissue-specific pathology and identify open questions in this area of host-Toxoplasma interactions.
Xiao-Yu Zhao, Sarah E. Ewald
Pediatric cancers, particularly high-risk solid tumors, urgently need effective and specific therapies. Their outlook has not appreciably improved in decades. Immunotherapies such as immune checkpoint inhibitors offer much promise, but most are only approved for use in adults. Though several hundred clinical trials have tested immune-based approaches in childhood cancers, few have been guided by biomarkers or clinical-grade assays developed to predict patient response and, ultimately, to help select those most likely to benefit. There is extensive evidence in adults to show that immune profiling has substantial predictive value, but few studies focus on childhood tumors, because of the relatively small disease population and restricted use of immune-based therapies. For instance, only one published study has retrospectively examined the immune profiles of pediatric brain tumors after immunotherapy. Furthermore, application and integration of advanced multiplex techniques has been extremely limited. Here, we review the current status of immune profiling of pediatric solid tumors, with emphasis on tumor types that represent enormous unmet clinical need, primarily in the context of immune checkpoint inhibitor therapy. Translating optimized and informative immune profiling into standard practice and access to personalized combination therapy will be critical if childhood cancers are to be treated effectively and affordably.
Rachael L. Terry, Deborah Meyran, David S. Ziegler, Michelle Haber, Paul G. Ekert, Joseph A. Trapani, Paul J. Neeson
Cryptococcus neoformans is an opportunistic yeast that is present worldwide and interacts with various organisms. In humans, it is responsible for cryptococcosis, a deadly invasive fungal infection that represents around 220,000 cases per year worldwide. Starting from the natural history of the disease in humans, there is accumulating evidence on the capacity of this organism to enter dormancy. In response to the harsh host environment, the yeast is able to adapt dramatically and escape the vigilance of the host’s immune cells to survive. Indeed, the yeast exposed to the host takes on pleiotropic phenotypes, enabling the generation of populations in heterogeneous states, including dormancy, to eventually survive at low metabolic cost and revive in favorable conditions. The concept of dormancy has been validated in C. neoformans from both epidemiological and genotyping data, and more recently from the biological point of view with the characterization of dormancy through the description of viable but nonculturable cells.
Muscular dystrophies are debilitating disorders that result in progressive weakness and degeneration of skeletal muscle. Although the genetic mutations and clinical abnormalities of a variety of neuromuscular diseases are well known, no curative therapies have been developed to date. The advent of genome editing technology provides new opportunities to correct the underlying mutations responsible for many monogenic neuromuscular diseases. For example, Duchenne muscular dystrophy, which is caused by mutations in the dystrophin gene, has been successfully corrected in mice, dogs, and human cells through CRISPR/Cas9 editing. In this Review, we focus on the potential for, and challenges of, correcting muscular dystrophies by editing disease-causing mutations at the genomic level. Ideally, because muscle tissues are extremely long-lived, CRISPR technology could offer a one-time treatment for muscular dystrophies by correcting the culprit genomic mutations and enabling normal expression of the repaired gene.
Francesco Chemello, Rhonda Bassel-Duby, Eric N. Olson
The critical role of suppressive myeloid cells in immune regulation has come to the forefront in cancer research, with myeloid-derived suppressor cells (MDSCs) as a main oncology immunotherapeutic target. Recent improvement and standardization of criteria classifying tumor-induced MDSCs have led to unified descriptions and also promoted MDSC research in tuberculosis (TB) and AIDS. Despite convincing evidence on the induction of MDSCs by pathogen-derived molecules and inflammatory mediators in TB and AIDS, very little attention has been given to their therapeutic modulation or roles in vaccination in these diseases. Clinical manifestations in TB are consequences of complex host-pathogen interactions and are substantially affected by HIV infection. Here we summarize the current understanding and knowledge gaps regarding the role of MDSCs in HIV and Mycobacterium tuberculosis (co)infections. We discuss key scientific priorities to enable application of this knowledge to the development of novel strategies to improve vaccine efficacy and/or implementation of enhanced treatment approaches. Building on recent findings and potential for cross-fertilization between oncology and infection biology, we highlight current challenges and untapped opportunities for translating new advances in MDSC research into clinical applications for TB and AIDS.
Anca Dorhoi, Leigh A. Kotzé, Jay A. Berzofsky, Yongjun Sui, Dmitry I. Gabrilovich, Ankita Garg, Richard Hafner, Shabaana A. Khader, Ulrich E. Schaible, Stefan H.E. Kaufmann, Gerhard Walzl, Manfred B. Lutz, Robert N. Mahon, Suzanne Ostrand-Rosenberg, William Bishai, Nelita du Plessis
Stroke is the second leading cause of death worldwide and a leading cause of disability. Most strokes are caused by occlusion of a major cerebral artery, and substantial advances have been made in elucidating how ischemia damages the brain. In particular, increasing evidence points to a double-edged role of the immune system in stroke pathophysiology. In the acute phase, innate immune cells invade brain and meninges and contribute to ischemic damage, but may also be protective. At the same time, danger signals released into the circulation by damaged brain cells lead to activation of systemic immunity, followed by profound immunodepression that promotes life-threatening infections. In the chronic phase, antigen presentation initiates an adaptive immune response targeted to the brain, which may underlie neuropsychiatric sequelae, a considerable cause of poststroke morbidity. Here, we briefly review these pathogenic processes and assess the potential therapeutic value of targeting immunity in human stroke.
Costantino Iadecola, Marion S. Buckwalter, Josef Anrather
Herpesviruses infect virtually all humans and establish lifelong latency and reactivate to infect other humans. Latency requires multiple functions: maintaining the herpesvirus genome in the nuclei of cells; partitioning the viral genome to daughter cells in dividing cells; avoiding recognition by the immune system by limiting protein expression; producing noncoding viral RNAs (including microRNAs) to suppress lytic gene expression or regulate cellular protein expression that could otherwise eliminate virus-infected cells; modulating the epigenetic state of the viral genome to regulate viral gene expression; and reactivating to infect other hosts. Licensed antivirals inhibit virus replication, but do not affect latency. Understanding of the mechanisms of latency is leading to novel approaches to destroy latently infected cells or inhibit reactivation from latency.
Jeffrey I. Cohen
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