Microbiology and Molecular Biology Reviews最新文献

SUMMARYAdvances in modern medical therapies for many previously intractable human diseases have improved patient outcomes. However, successful disease treatment outcomes are often prevented due to invasive fungal infections caused by the environmental mold Aspergillus fumigatus. As contemporary antifungal therapies have not experienced the same robust advances as other medical therapies, defining mechanisms of A. fumigatus disease initiation and progression remains a critical research priority. To this end, the World Health Organization recently identified A. fumigatus as a research priority human fungal pathogen and the Centers for Disease Control has highlighted the emergence of triazole-resistant A. fumigatus isolates. The expansion in the diversity of host populations susceptible to aspergillosis and the complex and dynamic A. fumigatus genotypic and phenotypic diversity call for a reinvigorated assessment of aspergillosis pathobiological and drug-susceptibility mechanisms. Here, we summarize recent advancements in the field and discuss challenges in our understanding of A. fumigatus heterogeneity and its pathogenesis in diverse host populations.

SUMMARYPathogens must acquire essential nutrients to successfully colonize and proliferate in host tissue. Additionally, nutrients provide signals that condition pathogen deployment of factors that promote disease. A series of transcriptomics experiments over the last 20 years, primarily with Cryptococcus neoformans and to a lesser extent with Cryptococcus gattii, provide insights into the nutritional requirements for proliferation in host tissues. Notably, the identified functions include a number of transporters for key nutrients including sugars, amino acids, metals, and phosphate. Here, we first summarize the in vivo gene expression studies and then discuss the follow-up analyses that specifically test the relevance of the identified transporters for the ability of the pathogens to cause disease. The conclusion is that predictions based on transcriptional profiling of cryptococcal cells in infected tissue are well supported by subsequent investigations using targeted mutations. Overall, the combination of transcriptomic and genetic approaches provides substantial insights into the nutritional requirements that underpin proliferation in the host.

SUMMARYHuman papillomaviruses (HPVs) are small DNA viruses that are responsible for significant disease burdens worldwide, including cancers of the cervix, anogenital tract, and oropharynx. HPVs infect stratified epithelia at a variety of body locations and link their productive life cycles to the differentiation of the host cell. These viruses have evolved sophisticated mechanisms to exploit cellular pathways, such as DNA damage repair (DDR), to regulate their life cycles. HPVs activate key DDR pathways such as ATM, ATR, and FA, which are critical for maintaining genomic integrity but are often dysregulated in cancers. Importantly, these DDR pathways are essential for HPV replication in undifferentiated cells and amplification upon differentiation. The ability to modulate these DDR pathways not only enables HPV persistence but also contributes to cellular transformation. In this review, we discuss the recent advances in understanding the mechanisms by which HPV manipulates the host DDR pathways and how these depend upon enhanced topoisomerase activity and R-loop formation. Furthermore, the strategies to manipulate DDR pathways utilized by high-risk HPVs are compared with those used by other DNA viruses that exhibit similarities and distinct differences.

SUMMARYThe development of multicellularity represents a key evolutionary transition that is crucial for the emergence of complex life forms. Although multicellularity has traditionally been studied in eukaryotes, it originates in prokaryotes. Coordinated aggregation of individual cells within the confines of a colony results in emerging, higher-level functions that benefit the population as a whole. During colony differentiation, an almost infinite number of ecological and physiological population-forming forces are at work, creating complex, intricate colony structures with divergent functions. Understanding the assembly and dynamics of such populations requires resolving individual cells or cell groups within such macroscopic structures. Addressing how each cell contributes to the collective action requires pushing the resolution boundaries of key technologies that will be presented in this review. In particular, single-cell techniques provide powerful tools for studying bacterial multicellularity with unprecedented spatial and temporal resolution. These advancements include novel microscopic techniques, mass spectrometry imaging, flow cytometry, spatial transcriptomics, single-bacteria RNA sequencing, and the integration of spatiotemporal transcriptomics with microscopy, alongside advanced microfluidic cultivation systems. This review encourages exploring the synergistic potential of the new technologies in the study of bacterial multicellularity, with a particular focus on individuals in differentiated bacterial biofilms (colonies). It highlights how resolving population structures at the single-cell level and understanding their respective functions can elucidate the overarching functions of bacterial multicellular populations.

SUMMARYVesicular mechanisms of drug resistance are known to exist across prokaryotes and eukaryotes. Vesicles are sacs that form when a lipid bilayer 'bends' to engulf and isolate contents from the cytoplasm or extracellular environment. They have a wide range of functions, including vehicles of communication within and across cells, trafficking of protein intermediates to their rightful organellar destinations, and carriers of substrates destined for autophagy. This review will provide an in-depth understanding of vesicular mechanisms of apicomplexan parasites, Plasmodium and Toxoplasma (that respectively cause malaria and toxoplasmosis). It will integrate mechanistic and evolutionarily insights gained from these and other pathogenic eukaryotes to develop a new model for plasmodial resistance to artemisinins, a class of drugs that have been the backbone of modern campaigns to eliminate malaria worldwide. We also discuss extracellular vesicles that present major vesicular mechanisms of drug resistance in parasite protozoa (that apicomplexans are part of). Finally, we provide a broader context of clinical drug resistance mechanisms of Plasmodium, Toxoplasma, as well as Cryptosporidium and Babesia, that are prominent members of the phyla, causative agents of cryptosporidiosis and babesiosis and significant for human and animal health.

SUMMARYInfection has long been hypothesized as the cause of multiple sclerosis (MS), and recent evidence for Epstein-Barr virus (EBV) as the trigger of MS is clear and compelling. This clarity contrasts with yet uncertain viral mechanisms and their relation to MS neuroinflammation and demyelination. As long as this disparity persists, it will invigorate virologists, molecular biologists, immunologists, and clinicians to ascertain how EBV potentiates MS onset, and possibly the disease's chronic activity and progression. Such efforts should take advantage of the diverse body of basic and clinical research conducted over nearly two centuries since the first clinical descriptions of MS plaques. Defining the contribution of EBV to the complex and multifactorial pathology of MS will also require suitable experimental models and techniques. Such efforts will broaden our understanding of virus-driven neuroinflammation and specifically inform the development of EBV-targeted therapies for MS management and, ultimately, prevention.

SUMMARYThe human malaria parasite Plasmodium falciparum is known for its ability to maintain lengthy infections that can extend for over a year. This property is derived from the parasite's capacity to continuously alter the antigens expressed on the surface of the infected red blood cell, thereby avoiding antibody recognition and immune destruction. The primary target of the immune system is an antigen called PfEMP1 that serves as a cell surface receptor and enables infected cells to adhere to the vascular endothelium and thus avoid filtration by the spleen. The parasite's genome encodes approximately 60 antigenically distinct forms of PfEMP1, each encoded by individual members of the multicopy var gene family. This provides the parasite with a repertoire of antigenic types that it systematically cycles through over the course of an infection, thereby maintaining an infection until the repertoire is exhausted. While this model of antigenic variation based on var gene switching explains the dynamics of acute infections in individuals with limited anti-malarial immunity, it fails to explain reports of chronic, asymptomatic infections that can last over a decade. Recent field studies have led to a re-evaluation of previous conclusions regarding the prevalence of chronic infections, and the application of new technologies has provided insights into the molecular mechanisms that enable chronic infections and how these processes evolved.

SUMMARYEnterococcus faecalis is a significant resident of the gastrointestinal tract of most animals, including humans. Although generally non-pathogenic in healthy hosts, this microbe is adept at the exploitation of compromises in host immune functions, resulting in life-threatening opportunistic infections whose treatments are complicated by a high degree of intrinsic and acquired resistance to antimicrobial chemotherapy. Historically, progress in enterococcal research was limited by a lack of experimental models that replicate natural infection pathways and the relevance of in vitro studies to the natural biology of the organism. In this review, we summarize the history of enterococcal research during the 20th and early 21st centuries and describe more recent genetic and genomic tools and screens developed to address challenges in the field. We also describe how the results of recent studies reveal the importance of previously uncharacterized enterococcal genes, and we provide examples of interesting determinants that have emerged as important contributors to enterococcal biology. These factors may also serve as targets for future vaccines and chemotherapeutic agents to combat life-threatening hospital infections.

SUMMARYHuman coronaviruses cause a range of respiratory diseases, from the common cold (HCoV-229E, HCoV-NL63, HCoV-OC43, and SARS-CoV-2) to lethal pneumonia (SARS-CoV, SARS-CoV-2, and MERS-CoV). Coronavirus interactions with host innate immune antiviral responses are an important determinant of disease outcome. This review compares the host's innate response to different human coronaviruses. Host antiviral defenses discussed in this review include frontline defenses against respiratory viruses in the nasal epithelium, early sensing of viral infection by innate immune effectors, double-stranded RNA and stress-induced antiviral pathways, and viral antagonism of innate immune responses conferred by conserved coronavirus nonstructural proteins and genus-specific accessory proteins. The common cold coronaviruses HCoV-229E and -NL63 induce robust interferon signaling and related innate immune pathways, SARS-CoV and SARS-CoV-2 induce intermediate levels of activation, and MERS-CoV shuts down these pathways almost completely.

SUMMARYLipopolysaccharides (LPS) are an integral part of the outer membrane of Gram-negative bacteria and play essential structural and functional roles in maintaining membrane integrity as well as in stress response and virulence. LPS comprises a membrane-anchored lipid A group, a sugar-based core region, and an O-antigen formed by repeating oligosaccharide units. 3-Deoxy-D-manno-octulosonic acid-lipid A (Kdo₂-lipid A) is the minimum LPS component required for bacterial survival. While LPS modifications are not essential, they play multifaceted roles in stress response and host-pathogen interactions. Gram-negative bacteria encode several distinct LPS-modifying phosphoethanolamine transferases (PET) that add phosphoethanolamine (pEtN) to lipid A or the core region of LPS. The pet genes differ in their genomic locations, regulation mechanisms, and modification targets of the encoded enzyme, consistent with their various roles in different growth niches and under varied stress conditions. The discovery of mobile colistin resistance genes, which represent lipid A-modifying pet genes that are encoded on mobile elements and associated with resistance to the last-resort antibiotic colistin, has led to substantial interest in PETs and pEtN-modified LPS over the last decade. Here, we will review the current knowledge of the functional diversity of pEtN-based LPS modifications, including possible roles in niche-specific fitness advantages and resistance to host-produced antimicrobial peptides, and discuss how the genetic and structural diversities of PETs may impact their function. An improved understanding of the PET group will further enhance our comprehension of the stress response and virulence of Gram-negative bacteria and help contextualize host-pathogen interactions.