Current Topics in Microbiology and Immunology

Bordetella pertussis, a slow-growing Gram-negative coccobacillus and the causative agent of whooping cough, is one of the leading causes of vaccine-preventable death and morbidity globally. A state of asymptomatic human carriage has not yet been demonstrated by population studies but is likely to be an important reservoir for community transmission of infection. Such a carriage state may be a target for future vaccine strategies. This chapter presents a short summary of the characteristics of B. pertussis, which should be taken into account when developing a human challenge model and any future experimental medicine interventions...

Coronaviruses have a broad host range and exhibit high zoonotic potential. In this chapter, we describe their genomic organization in terms of encoded proteins and provide an introduction to the peculiar discontinuous transcription mechanism. Further, we present evolutionary conserved genomic RNA secondary structure features, which are involved in the complex replication mechanism. With a focus on computational methods, we review the emergence of SARS-CoV-2 starting with the 2019 strains. In that context, we also discuss the debated hypothesis of whether SARS-CoV-2 was created in a laboratory...

Members of the family Arenaviridae are classified into four genera: Antennavirus, Hartmanivirus, Mammarenavirus, and Reptarenavirus. Reptarenaviruses and hartmaniviruses infect (captive) snakes and have been shown to cause boid inclusion body disease (BIBD). Antennaviruses have genomes consisting of 3, rather than 2, segments, and were discovered in actinopterygian fish by next-generation sequencing but no biological isolate has been reported yet. The hosts of mammarenaviruses are mainly rodents and infections are generally asymptomatic...

Chronic infection with hepatitis C virus (HCV) is an important contributor to the global incidence of liver diseases, including liver cirrhosis and hepatocellular carcinoma. Although common for single-stranded RNA viruses, HCV displays a remarkable high level of genetic diversity, produced primarily by the error-prone viral polymerase and host immune pressure. The high genetic heterogeneity of HCV has led to the evolution of several distinct genotypes and subtypes, with important consequences for pathogenesis, and clinical outcomes...

Fitness of viruses has become a standard parameter to quantify their adaptation to a biological environment. Fitness determinations for RNA viruses (and some highly variable DNA viruses) meet with several uncertainties. Of particular interest are those that arise from mutant spectrum complexity, absence of population equilibrium, and internal interactions among components of a mutant spectrum. Here, concepts, fitness measurements, limitations, and current views on experimental viral fitness landscapes are discussed...

Viruses are studied at each level of biological complexity: from within-cells to ecosystems. The same basic evolutionary forces and principles operate at each level: mutation and recombination, selection, genetic drift, migration, and adaptive trade-offs. Great efforts have been put into understanding each level in great detail, hoping to predict the dynamics of viral population, prevent virus emergence, and manage their spread and virulence. Unfortunately, we are still far from this. To achieve these ambitious goals, we advocate for an integrative perspective of virus evolution...

Mutation, recombination and pseudo-recombination are the major forces driving the evolution of viruses by the generation of variants upon which natural selection, genetic drift and gene flow can act to shape the genetic structure of viral populations. Recombination between related virus genomes co-infecting the same cell usually occurs via template swapping during the replication process and produces a chimeric genome. The family Geminiviridae shows the highest evolutionary success among plant virus families, and the common presence of recombination signatures in their genomes reveals a key role in their evolution...

The wealth of variability amongst genes controlling immunity against potyviruses in pepper (Capsicum spp.) has been instrumental in understanding plant-virus co-evolution and major determinants of plant resistance durability. Characterization of the eukaryotic initiation factor 4E1 (eIF4E1), involved in mRNA translation, as the basis of potyvirus resistance in pepper initiated a large body of work that showed that recessive resistance to potyviruses and other single-stranded positive-sense RNA viruses resulted from mutations in eukaryotic initiation factors in many plant crop species...

The creation of fitness maps from viral populations especially in the case of RNA viruses, with high mutation rates producing quasispecies, is complex since the mutant spectrum is in a very high-dimensional space. In this work, a new approach is presented using a class of neural networks, Self-Organized Maps (SOM), to represent realistic fitness landscapes in two RNA viruses: Human Immunodeficiency Virus type 1 (HIV-1) and Hepatitis C Virus (HCV). This methodology has proven to be very effective in the classification of viral quasispecies, using as criterium the mutant sequences in the population...

The landscape paradigm is revisited in the light of evolution in simple systems. A brief overview of different classes of fitness landscapes is followed by a more detailed discussion of the RNA model, which is currently the only evolutionary model that allows for a comprehensive molecular analysis of a fitness landscape. Neutral networks of genotypes are indispensable for the success of evolution. Important insights into the evolutionary mechanism are gained by considering the topology of sequence and shape spaces...

Varicella zoster virus (VZV) is a medically important human herpesvirus that has co-evolved with the human host to become a highly successful and ubiquitous pathogen. Whilst it is clear the innate and adaptive arms of the immune response play key roles in controlling this virus during both primary and reactivated infections, it is also apparent that VZV "fights back" by encoding multiple functions that impair a wide range of immune molecules. This capacity to manipulate the immune response is likely to be important in underpinning the success of VZV as a human pathogen...

Lassa Fever (LF) is a viral hemorrhagic fever endemic in West Africa. LF begins with flu-like symptoms that are difficult to distinguish from other common endemic diseases such as malaria, dengue, and yellow fever making it hard to diagnose clinically. Availability of a rapid diagnostic test and other serological and molecular assays facilitates accurate diagnosis of LF. Lassa virus therapeutics are currently in different stages of preclinical development. Arevirumab, a cocktail of monoclonal antibodies, demonstrates a great safety and efficacy profile in non-human primates...

Despite considerable momentum in the development of RSV vaccines and therapeutics, there remain substantial barriers to the development and licensing of effective agents, particularly in high-risk populations. The unique immunobiology of RSV and lack of clear protective immunological correlates has held back RSV vaccine development, which, therefore, depends on large and costly clinical trials to demonstrate efficacy. Studies involving the deliberate infection of human volunteers offer an intermediate step between pre-clinical and large-scale studies of natural infection...

Venetian quarantine 400 years ago was an important public health measure. Since 1900 this has been refined to include "challenge" or deliberate infection with pathogens be they viruses, bacteria, or parasites. Our focus is virology and ranges from the early experiments in Cuba with Yellow Fever Virus to the most widespread pathogen of our current times, COVID-19. The latter has so far caused over four million deaths worldwide and 190 million cases of the disease. Quarantine and challenge were also used to investigate the Spanish Influenza of 1918 which caused over 100 million deaths...

Controlled human infection studies have contributed significantly to the understanding of pathogeneses and treatment of infectious diseases. In malaria, deliberately infecting humans with malaria parasites was used as a treatment for neurosyphilis in the early 1920s. More recently, controlled human malaria infection (CHMI) has become a valuable, cost-effective tool to fast-track the development and evaluation of new anti-malarial drugs and/or vaccines. CHMI studies have also been used to define host/parasite interactions and immunological correlates of protection...

Like other herpesviruses, varicella-zoster virus (VZV) evolved a wide range of functions to modulate a broad array of host defences, presumably as a means to provide a survival advantage to the virus during infection. In addition to control of components of the adaptive immune response, VZV also modulates a range of innate responses. In this context, it has become increasingly apparent that VZV encodes specific functions that interfere with programmed cell death (PCD) pathways. This review will overview the current understanding of VZV-mediated control of PCD pathways, focussing on the three most well-defined PCD pathways: apoptosis, necroptosis and pyroptosis...

Host-pathogen interactions involve complex inside-out and outside-in signal transmission through critical cellular networks that dictate disease outcomes. The phosphoinositide 3-kinase (PI3K)/Akt pathway is a pivotal junction that regulates several cell functions, and phospho-Akt (pAkt) is often found to be constitutively active in cancer cells, similar to phospho-STAT3. In this chapter, we discuss the regulation of PI3K/Akt pathway in VZV infected cells and of other pathways including p53 which, unlike pAkt and pSTAT3, directs cells towards apoptosis...

Shigella-controlled human infection models (CHIMs) are an invaluable tool utilized by the vaccine community to combat one of the leading global causes of infectious diarrhea, which affects infants, children and adults regardless of socioeconomic status. The impact of shigellosis disproportionately affects children in low- and middle-income countries (LMICs) resulting in cognitive and physical stunting, perpetuating a cycle that must be halted. Shigella-CHIMs not only facilitate the early evaluation of enteric countermeasures and up-selection of the most promising products but also provide insight into mechanisms of infection and immunity that are not possible utilizing animal models or in vitro systems...

The human challenge model permits an estimate of the vaccine protection against moderate and severe cholera. It eliminates the difficulty in setting up a vaccine study in endemic area including uncertainties about the incidence of cholera and the logistic arrangements for capturing those who do/do not become ill. Valuable information from small groups of subjects can be obtained in a short period. Under proper precautions and study design, the challenge model is safe and efficient. Although the model has evolved since it was introduced over 50 years ago, it has been used extensively to test vaccine efficacy...

Controlled human infection models (CHIMs) have provided pivotal scientific advancements, contributing to the licensure of new vaccines for many pathogens. Despite being one of the world's oldest known pathogens, there are still significant gaps in our knowledge surrounding the immunobiology of Mycobacterium tuberculosis (M. tb). Furthermore, the only licensed vaccine, BCG, is a century old and demonstrates limited efficacy in adults from endemic areas. Despite good global uptake of BCG, tuberculosis (TB) remains a silent epidemic killing 1...