Systems-level analysis of innate immunity.

Systems-level analysis of biological processes strives to comprehensively and quantitatively evaluate the interactions between the relevant molecular components over time, thereby enabling development of models that can be employed to ultimately predict behavior. Rapid development in measurement technologies (omics), when combined with the accessible nature of the cellular constituents themselves, is allowing the field of innate immunity to take significant strides toward this lofty goal. In this review, we survey exciting results derived from systems biology analyses of the immune system, ranging from gene regulatory networks to influenza pathogenesis and systems vaccinology.

One world, one health.

The past year has underscored the threat that emerging viruses pose to global health. The 2021 John Dirks Canada Gairdner Global Health award recognizes the contributions of Joseph Sriyal Malik Peiris and Yi Guan toward understanding the origins and options for control of newly emerging infectious disease outbreaks in Asia, notably zoonotic influenza and severe acute respiratory syndrome (SARS). Nicole Neuman of Cell corresponded with Malik Peiris about his path to studying emerging infectious diseases and the challenges of this work. Excerpts of their exchange are included here.

Baseline innate and T cell populations are correlates of protection against symptomatic influenza virus infection independent of serology.

Evidence suggests that innate and adaptive cellular responses mediate resistance to the influenza virus and confer protection after vaccination. However, few studies have resolved the contribution of cellular responses within the context of preexisting antibody titers. Here, we measured the peripheral immune profiles of 206 vaccinated or unvaccinated adults to determine how baseline variations in the cellular and humoral immune compartments contribute independently or synergistically to the risk of developing symptomatic influenza. Protection correlated with diverse and polyfunctional CD4+ and CD8+ T, circulating T follicular helper, T helper type 17, myeloid dendritic and CD16+ natural killer (NK) cell subsets. Conversely, increased susceptibility was predominantly attributed to nonspecific inflammatory populations, including γδ T cells and activated CD16- NK cells, as well as TNFα+ single-cytokine-producing CD8+ T cells. Multivariate and predictive modeling indicated that cellular subsets (1) work synergistically with humoral immunity to confer protection, (2) improve model performance over demographic and serologic factors alone and (3) comprise the most important predictive covariates. Together, these results demonstrate that preinfection peripheral cell composition improves the prediction of symptomatic influenza susceptibility over vaccination, demographics or serology alone.

Africa Needs a New Public Health Order to Tackle Infectious Disease Threats.

The SARS-CoV-2 pandemic has revealed that Africa needs a new public health order to be resilient, to adapt, and to cope with 21st-century disease threats. The new order will need strengthened continental and national public health institutions; local manufacturing of vaccines, therapeutics, and diagnostics; attraction, training, and retention of a public health workforce; and fostering of respectful local and international partnerships.

Why and How Vaccines Work.

Vaccines save millions of lives from infectious diseases caused by viruses and bacteria. As the world awaits safe and effective COVID-19 vaccines, we celebrate the progresses made and highlight challenges ahead in vaccines and the science behind them.

microRNA regulation of inflammatory responses.

The mammalian inflammatory response is a rapid and complex physiological reaction to noxious stimuli including microbial pathogens. Although inflammation plays a valuable role in combating infection, its dysregulation often occurs in people and can cause a variety of pathologies, ranging from chronic inflammation, to autoimmunity, to cancer. In recent years, our understanding of both the cellular and molecular networks that regulate inflammation has improved dramatically. Although much of the focus has been on the study of protein regulators of inflammation, recent evidence also points to a critical role for a specific class of noncoding RNAs, called microRNAs (miRNAs), in managing certain features of the inflammatory process. In this review, we discuss recent advances in our understanding of miRNAs and their connection to inflammatory responses. Additionally, we consider the link between perturbations in miRNA levels and the onset of human inflammatory diseases.

The microbiome in infectious disease and inflammation.

The mammalian alimentary tract harbors hundreds of species of commensal microorganisms (microbiota) that intimately interact with the host and provide it with genetic, metabolic, and immunological attributes. Recent reports have indicated that the microbiota composition and its collective genomes (microbiome) are major factors in predetermining the type and robustness of mucosal immune responses. In this review, we discuss the recent advances in our understanding of host-microbiota interactions and their effect on the health and disease susceptibility of the host.

Inflammasomes and adaptive immune responses.

A fundamental concept in immunology is that the innate immune system initiates or instructs downstream adaptive immune responses. Inflammasomes are central players in innate immunity to pathogens, but how inflammasomes shape adaptive immunity is complex and relatively poorly understood. Here we highlight recent work on the interplay between inflammasomes and adaptive immunity. We address how inflammasome-dependent release of cytokines and antigen activates, shapes or even inhibits adaptive immune responses. We consider how distinct tissue or cellular contexts may alter the effects of inflammasome activation on adaptive immunity and how this contributes to beneficial or detrimental outcomes in infectious diseases, cancer and autoimmunity. We aspire to provide a framework for thinking about inflammasomes and their connection to the adaptive immune response.

Not-so-opposite ends of the spectrum: CD8+ T cell dysfunction across chronic infection, cancer and autoimmunity.

CD8+ T cells are critical mediators of cytotoxic effector function in infection, cancer and autoimmunity. In cancer and chronic viral infection, CD8+ T cells undergo a progressive loss of cytokine production and cytotoxicity, a state termed T cell exhaustion. In autoimmunity, autoreactive CD8+ T cells retain the capacity to effectively mediate the destruction of host tissues. Although the clinical outcome differs in each context, CD8+ T cells are chronically exposed to antigen in all three. These chronically stimulated CD8+ T cells share some common phenotypic features, as well as transcriptional and epigenetic programming, across disease contexts. A better understanding of these CD8+ T cell states may reveal novel strategies to augment clearance of chronic viral infection and cancer and to mitigate self-reactivity leading to tissue damage in autoimmunity.

Human determinants of age-dependent patterns of death from infection.

Regardless of microbial virulence (i.e., the global infection-fatality ratio), age generally drives the prevalence of death from infection in unvaccinated humans. Four mortality patterns are recognized: the common U- and L-shaped curves of endemic infections and the unique W- and J-shaped curves of pandemic infections. We suggest that these patterns result from different sets of human genetic and immunological determinants. In this model, it is the interplay between (1) monogenic genotypes affecting immunity to primary infection that preferentially manifest early in life and related genotypes or their phenocopies, including auto-antibodies, which manifest later in life and (2) the occurrence and persistence of adaptive, acquired immunity to primary or cross-reactive infections, which shapes the age-dependent pattern of human deaths from infection.

Human organoids: model systems for human biology and medicine.

The historical reliance of biological research on the use of animal models has sometimes made it challenging to address questions that are specific to the understanding of human biology and disease. But with the advent of human organoids - which are stem cell-derived 3D culture systems - it is now possible to re-create the architecture and physiology of human organs in remarkable detail. Human organoids provide unique opportunities for the study of human disease and complement animal models. Human organoids have been used to study infectious diseases, genetic disorders and cancers through the genetic engineering of human stem cells, as well as directly when organoids are generated from patient biopsy samples. This Review discusses the applications, advantages and disadvantages of human organoids as models of development and disease and outlines the challenges that have to be overcome for organoids to be able to substantially reduce the need for animal experiments.

Small intestinal resident eosinophils maintain gut homeostasis following microbial colonization.

The intestine harbors a large population of resident eosinophils, yet the function of intestinal eosinophils has not been explored. Flow cytometry and whole-mount imaging identified eosinophils residing in the lamina propria along the length of the intestine prior to postnatal microbial colonization. Microscopy, transcriptomic analysis, and mass spectrometry of intestinal tissue revealed villus blunting, altered extracellular matrix, decreased epithelial cell turnover, increased gastrointestinal motility, and decreased lipid absorption in eosinophil-deficient mice. Mechanistically, intestinal epithelial cells released IL-33 in a microbiota-dependent manner, which led to eosinophil activation. The colonization of germ-free mice demonstrated that eosinophil activation in response to microbes regulated villous size alterations, macrophage maturation, epithelial barrier integrity, and intestinal transit. Collectively, our findings demonstrate a critical role for eosinophils in facilitating the mutualistic interactions between the host and microbiota and provide a rationale for the functional significance of their early life recruitment in the small intestine.

Cancer in the Wilderness.

How a chance discovery in the Tasmanian rainforest changed the course of my scientific career.

The Awesome Power of Human Genetics of Infectious Disease.

Since the identification of sickle cell trait as a heritable form of resistance to malaria, candidate gene studies, linkage analysis paired with sequencing, and genome-wide association (GWA) studies have revealed many examples of genetic resistance and susceptibility to infectious diseases. GWA studies enabled the identification of many common variants associated with small shifts in susceptibility to infectious diseases. This is exemplified by multiple loci associated with leprosy, malaria, HIV, tuberculosis, and coronavirus disease 2019 (COVID-19), which illuminate genetic architecture and implicate pathways underlying pathophysiology. Despite these successes, most of the heritability of infectious diseases remains to be explained. As the field advances, current limitations may be overcome by applying methodological innovations such as cellular GWA studies and phenome-wide association (PheWA) studies as well as by improving methodological rigor with more precise case definitions, deeper phenotyping, increased cohort diversity, and functional validation of candidate loci in the laboratory or human challenge studies.

Old foes and new enemies.

Better understanding of the biology of infectious agents and of the mechanisms of efficient immune responses advances strategies to achieve protection against infectious diseases.

From Hype to Hope: The Gut Microbiota in Enteric Infectious Disease.

One of the clearest functions of the gut microbiota in humans is resistance to colonization by enteric bacterial pathogens. Reconstitution of the microbiota offers an exciting therapeutic approach, but great challenges must be overcome.

A meta-analysis on global change drivers and the risk of infectious disease.

Anthropogenic change is contributing to the rise in emerging infectious diseases, which are significantly correlated with socioeconomic, environmental and ecological factors1. Studies have shown that infectious disease risk is modified by changes to biodiversity2-6, climate change7-11, chemical pollution12-14, landscape transformations15-20 and species introductions21. However, it remains unclear which global change drivers most increase disease and under what contexts. Here we amassed a dataset from the literature that contains 2,938 observations of infectious disease responses to global change drivers across 1,497 host-parasite combinations, including plant, animal and human hosts. We found that biodiversity loss, chemical pollution, climate change and introduced species are associated with increases in disease-related end points or harm, whereas urbanization is associated with decreases in disease end points. Natural biodiversity gradients, deforestation and forest fragmentation are comparatively unimportant or idiosyncratic as drivers of disease. Overall, these results are consistent across human and non-human diseases. Nevertheless, context-dependent effects of the global change drivers on disease were found to be common. The findings uncovered by this meta-analysis should help target disease management and surveillance efforts towards global change drivers that increase disease. Specifically, reducing greenhouse gas emissions, managing ecosystem health, and preventing biological invasions and biodiversity loss could help to reduce the burden of plant, animal and human diseases, especially when coupled with improvements to social and economic determinants of health.

A guiding map for inflammation.

Biologists, physicians and immunologists have contributed to the understanding of the cellular participants and biological pathways involved in inflammation. Here, we provide a general guide to the cellular and humoral contributors to inflammation as well as to the pathways that characterize inflammation in specific organs and tissues.

T Follicular Helper Cell Biology: A Decade of Discovery and Diseases.

Helping B cells and antibody responses is a major function of CD4+ T cells. It has been 10 years since the publication of Bcl6 as the lineage-defining transcription factor for T follicular helper (Tfh) differentiation and the requirement of Tfh cells as the specialized subset of CD4+ T cells needed for germinal centers (the microanatomical sites of B cell mutation and antibody affinity maturation) and related B cell responses. A great deal has been learned about Tfh cells in the past 10 years, particularly regarding their roles in a surprising range of diseases. Advances in the understanding of Tfh cell differentiation and function are discussed, as are the understanding of Tfh cells in infectious diseases, vaccines, autoimmune diseases, allergies, atherosclerosis, organ transplants, and cancer. This includes discussion of Tfh cells in the human immune system. Based on the discoveries to date, the next decade of Tfh research surely holds many more surprises. VIDEO ABSTRACT.

Infectious diseases and discrimination: Sicily's Lampedusa migrants.

Lampedusa, a picturesque Italian island in the Mediterranean, serves as a gateway for migrants from Africa and Asia to Europe. Despite populist rhetoric portraying migrants as carriers of disease, epidemiological data reveal very low levels of communicable diseases among migrants, challenging false narratives and xenophobic sentiments propagated by populist governments.