Extracellular vesicles are produced by species across all domains of life, suggesting that vesiculation represents a fundamental principle of living matter. In Gram-negative bacteria, membrane vesicles (MVs) can originate either from blebs of the outer membrane or from endolysin-triggered explosive cell lysis, which is often induced by genotoxic stress. Although less is known about the mechanisms of vesiculation in Gram-positive and Gram-neutral bacteria, recent research has shown that both lysis and blebbing mechanisms also exist in these organisms. Evidence has accumulated over the past years that different biogenesis routes lead to distinct types of MV with varied structure and composition. In this Review, we discuss the different types of MV and their potential cargo packaging mechanisms. We summarize current knowledge regarding how MV composition determines their various functions including support of bacterial growth via the disposal of waste material, nutrient scavenging, export of bioactive molecules, DNA transfer, neutralization of phages, antibiotics and bactericidal functions, delivery of virulence factors and toxins to host cells and inflammatory and immunomodulatory effects. We also discuss the advantages of MV-mediated secretion compared with classic bacterial secretion systems and we introduce the concept of quantal secretion.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of deaths and substantial morbidity worldwide. Intense scientific effort to understand the biology of SARS-CoV-2 has resulted in daunting numbers of genomic sequences. We witnessed evolutionary events that could mostly be inferred indirectly before, such as the emergence of variants with distinct phenotypes, for example transmissibility, severity and immune evasion. This Review explores the mechanisms that generate genetic variation in SARS-CoV-2, underlying the within-host and population-level processes that underpin these events. We examine the selective forces that likely drove the evolution of higher transmissibility and, in some cases, higher severity during the first year of the pandemic and the role of antigenic evolution during the second and third years, together with the implications of immune escape and reinfections, and the increasing evidence for and potential relevance of recombination. In order to understand how major lineages, such as variants of concern (VOCs), are generated, we contrast the evidence for the chronic infection model underlying the emergence of VOCs with the possibility of an animal reservoir playing a role in SARS-CoV-2 evolution, and conclude that the former is more likely. We evaluate uncertainties and outline scenarios for the possible future evolutionary trajectories of SARS-CoV-2.

Crimean-Congo haemorrhagic fever (CCHF) is a severe tick-borne illness with a wide geographical distribution and case fatality rates of 30% or higher. Caused by infection with the CCHF virus (CCHFV), cases are reported throughout Africa, the Middle East, Asia and southern and eastern Europe. The expanding range of the Hyalomma tick vector is placing new populations at risk for CCHF, and no licensed vaccines or specific antivirals exist to treat CCHF. Furthermore, despite cases of CCHF being reported annually, the host and viral determinants of CCHFV pathogenesis are poorly understood. CCHFV can productively infect a multitude of animal species, yet only humans develop a severe illness. Within human populations, subclinical infections are underappreciated and may represent a substantial proportion of clinical outcomes. Compared with other members of the Bunyavirales order, CCHFV has a more complex genomic organization, with many viral proteins having unclear functions in viral pathogenesis. In recent years, improved animal models have led to increased insights into CCHFV pathogenesis, and several antivirals and vaccines for CCHFV have shown robust efficacy in preclinical models. Translation of these insights and candidate therapeutics to the clinic will hopefully reduce the morbidity and mortality caused by CCHFV.

Throughout their evolutionary history, bacteria have faced diverse threats from other microorganisms, including competing bacteria, bacteriophages and predators. In response to these threats, they have evolved sophisticated defence mechanisms that today also protect bacteria against antibiotics and other therapies. In this Review, we explore the protective strategies of bacteria, including the mechanisms, evolution and clinical implications of these ancient defences. We also review the countermeasures that attackers have evolved to overcome bacterial defences. We argue that understanding how bacteria defend themselves in nature is important for the development of new therapies and for minimizing resistance evolution.

Overweight, obesity, undernutrition and their respective sequelae have devastating tolls on personal and public health worldwide. Traditional approaches for treating these conditions with diet, exercise, drugs and/or surgery have shown varying degrees of success, creating an urgent need for new solutions with long-term efficacy. Owing to transformative advances in sequencing, bioinformatics and gnotobiotic experimentation, we now understand that the gut microbiome profoundly impacts energy balance through diverse mechanisms affecting both sides of the energy balance equation. Our growing knowledge of microbial contributions to energy metabolism highlights new opportunities for weight management, including the microbiome-aware improvement of existing tools and novel microbiome-targeted therapies. In this Review, we synthesize current knowledge concerning the bidirectional influences between the gut microbiome and existing weight management strategies, including behaviour-based and clinical approaches, and incorporate a subject-level meta-analysis contrasting the effects of weight management strategies on microbiota composition. We consider how emerging understanding of the gut microbiome alters our prospects for weight management and the challenges that must be overcome for microbiome-focused solutions to achieve success.

Comment on Nat Microbiol. 2023 Jan;8(1):121-134.

Haematophagous arthropods, including mosquitoes, ticks, flies, triatomine bugs and lice (here referred to as vectors), are involved in the transmission of various pathogens to mammals on whom they blood feed. The diseases caused by these pathogens, collectively known as vector-borne diseases (VBDs), threaten the health of humans and animals. Although the vector arthropods differ in life histories, feeding behaviour as well as reproductive strategies, they all harbour symbiotic microorganisms, known as microbiota, on which they depend for completing essential aspects of their biology, such as development and reproduction. In this Review, we summarize the shared and unique key features of the symbiotic associations that have been characterized in the major vector taxa. We discuss the crosstalks between microbiota and their arthropod hosts that influence vector metabolism and immune responses relevant for pathogen transmission success, known as vector competence. Finally, we highlight how current knowledge on symbiotic associations is being explored to develop non-chemical-based alternative control methods that aim to reduce vector populations, or reduce vector competence. We conclude by highlighting the remaining knowledge gaps that stand to advance basic and translational aspects of vector-microbiota interactions.

Although new antibiofilm agents have been developed to prevent and eliminate pathogenic biofilms, their widespread clinical use is hindered by poor biocompatibility and bioavailability, unspecific interactions and insufficient local concentrations. The development of innovative drug delivery strategies can facilitate penetration of antimicrobials through biofilms, promote drug dispersal and synergistic bactericidal effects, and provide novel paradigms for clinical application. In this Review, we discuss the potential benefits of such emerging techniques for improving the clinical efficacy of antibiofilm agents, as well as highlighting the existing limitations and future prospects for these therapies in the clinic.

Comment on N Engl J Med. 2023 Feb 9;388(6):518-528.

Comment on Nat Microbiol. 2023 Apr;8(4):679-694.

Forests influence climate and mitigate global change through the storage of carbon in soils. In turn, these complex ecosystems face important challenges, including increases in carbon dioxide, warming, drought and fire, pest outbreaks and nitrogen deposition. The response of forests to these changes is largely mediated by microorganisms, especially fungi and bacteria. The effects of global change differ among boreal, temperate and tropical forests. The future of forests depends mostly on the performance and balance of fungal symbiotic guilds, saprotrophic fungi and bacteria, and fungal plant pathogens. Drought severely weakens forest resilience, as it triggers adverse processes such as pathogen outbreaks and fires that impact the microbial and forest performance for carbon storage and nutrient turnover. Nitrogen deposition also substantially affects forest microbial processes, with a pronounced effect in the temperate zone. Considering plant-microorganism interactions would help predict the future of forests and identify management strategies to increase ecosystem stability and alleviate climate change effects. In this Review, we describe the impact of global change on the forest ecosystem and its microbiome across different climatic zones. We propose potential approaches to control the adverse effects of global change on forest stability, and present future research directions to understand the changes ahead.

A massive number of microorganisms, belonging to different species, continuously divide inside the guts of animals and humans. The large size of these communities and their rapid division times imply that we should be able to watch microbial evolution in the gut in real time, in a similar manner to what has been done in vitro. Here, we review recent findings on how natural selection shapes intrahost evolution (also known as within-host evolution), with a focus on the intestines of mice and humans. The microbiota of a healthy host is not as static as initially thought from the information measured at only one genomic marker. Rather, the genomes of each gut-colonizing species can be highly dynamic, and such dynamism seems to be related to the microbiota species diversity. Genetic and bioinformatic tools, and analysis of time series data, allow quantification of the selection strength on emerging mutations and horizontal transfer events in gut ecosystems. The drivers and functional consequences of gut evolution can now begin to be grasped. The rules of this intrahost microbiota evolution, and how they depend on the biology of each species, need to be understood for more effective development of microbiota therapies to help maintain or restore host health.

The development of antiretroviral therapy for the prevention and treatment of HIV infection has been marked by a series of remarkable successes. However, the efforts to develop a vaccine have largely failed, and efforts to discover a cure are only now beginning to gain traction. In this Review, we describe recent progress on all fronts - pre-exposure prophylaxis, vaccines, treatment and cure - and we discuss the unmet needs, both current and in the coming years. We describe the emerging arsenal of drugs, biologics and strategies that will hopefully address these needs. Although HIV research has largely been siloed in the past, this is changing, as the emerging research agenda is marked by multiple cross-discipline synergies and collaborations. As the limitations of antiretroviral drugs as a means to truly end the epidemic are becoming more apparent, there is a great need for continued efforts to develop an effective preventative vaccine and a scalable cure, both of which remain formidable challenges.

Bacteria and their viruses have coevolved for billions of years. This ancient and still ongoing arms race has led bacteria to develop a vast antiphage arsenal. The development of high-throughput screening methods expanded our knowledge of defence systems from a handful to more than a hundred systems, unveiling many different molecular mechanisms. These findings reveal that bacterial immunity is much more complex than previously thought. In this Review, we explore recently discovered bacterial antiphage defence systems, with a particular focus on their molecular diversity, and discuss the ecological and evolutionary drivers and implications of the existing diversity of antiphage defence mechanisms.

Infectious hepatitis type A and type E are caused by phylogenetically distinct single-stranded, positive-sense RNA viruses that were once considered to be non-enveloped. However, studies show that both are released nonlytically from hepatocytes as 'quasi-enveloped' virions cloaked in host membranes. These virion types predominate in the blood of infected individuals and mediate virus spread within the liver. They lack virally encoded proteins on their surface and are resistant to neutralizing anti-capsid antibodies induced by infection, yet they efficiently enter cells and initiate new rounds of virus replication. In this Review, we discuss the mechanisms by which specific peptide sequences in the capsids of these quasi-enveloped virions mediate their endosomal sorting complexes required for transport (ESCRT)-dependent release from hepatocytes through multivesicular endosomes, what is known about how they enter cells, and the impact of capsid quasi-envelopment on host immunity and pathogenesis.

Antibiotic resistance is currently one of the most important public health problems. The golden age of antibiotic discovery ended decades ago, and new approaches are urgently needed. Therefore, preserving the efficacy of the antibiotics currently in use and developing compounds and strategies that specifically target antibiotic-resistant pathogens is critical. The identification of robust trends of antibiotic resistance evolution and of its associated trade-offs, such as collateral sensitivity or fitness costs, is invaluable for the design of rational evolution-based, ecology-based treatment approaches. In this Review, we discuss these evolutionary trade-offs and how such knowledge can aid in informing combination or alternating antibiotic therapies against bacterial infections. In addition, we discuss how targeting bacterial metabolism can enhance drug activity and impair antibiotic resistance evolution. Finally, we explore how an improved understanding of the original physiological function of antibiotic resistance determinants, which have evolved to reach clinical resistance after a process of historical contingency, may help to tackle antibiotic resistance.

Recent studies applying advanced imaging techniques are changing the way we understand bacterial cell surfaces, bringing new knowledge on everything from single-cell heterogeneity in bacterial populations to their drug sensitivity and mechanisms of antimicrobial resistance. In both Gram-positive and Gram-negative bacteria, the outermost surface of the bacterial cell is being imaged at nanoscale; as a result, topographical maps of bacterial cell surfaces can be constructed, revealing distinct zones and specific features that might uniquely identify each cell in a population. Functionally defined assembly precincts for protein insertion into the membrane have been mapped at nanoscale, and equivalent lipid-assembly precincts are suggested from discrete lipopolysaccharide patches. As we review here, particularly for Gram-negative bacteria, the applications of various modalities of nanoscale imaging are reawakening our curiosity about what is conceptually a 3D cell surface landscape: what it looks like, how it is made and how it provides resilience to respond to environmental impacts.

Plant disease outbreaks pose significant risks to global food security and environmental sustainability worldwide, and result in the loss of primary productivity and biodiversity that negatively impact the environmental and socio-economic conditions of affected regions. Climate change further increases outbreak risks by altering pathogen evolution and host-pathogen interactions and facilitating the emergence of new pathogenic strains. Pathogen range can shift, increasing the spread of plant diseases in new areas. In this Review, we examine how plant disease pressures are likely to change under future climate scenarios and how these changes will relate to plant productivity in natural and agricultural ecosystems. We explore current and future impacts of climate change on pathogen biogeography, disease incidence and severity, and their effects on natural ecosystems, agriculture and food production. We propose that amendment of the current conceptual framework and incorporation of eco-evolutionary theories into research could improve our mechanistic understanding and prediction of pathogen spread in future climates, to mitigate the future risk of disease outbreaks. We highlight the need for a science-policy interface that works closely with relevant intergovernmental organizations to provide effective monitoring and management of plant disease under future climate scenarios, to ensure long-term food and nutrient security and sustainability of natural ecosystems.