Bacteriophages direct several aspects of bacterial behavior and, considering the diversity and prevalence of the means described to date, we predict that the discovery of novel ways in which phages shape biological interaction networks will continue. As phages have been found that can impact carbon acquisition and metabolism, phages likely have roles in other key metabolic bacterial processes, such as nitrogen fixing. The ability of phages to alter bacterial survival in adverse conditions leads us to surmise that they may have roles in other specific behaviors such as chemotaxis and other adaptations in challenging environments, e.g. to heavy metal poisoning and exposure to irradiation.
Phages can modify bacterial behaviors either by directly introducing additional functions or by indirectly by regulating bacterial genes, e.g. by phage-encoded sigma factors. This paper presents several examples of how phages could increase cells defense, virulence, or survival in particular environments. The agr quorum sensing (QS) system is known to promote many of the behaviors and phenotypes discussed in this article, including toxin production, biofilm formation, motility, and sporulation. Alternatively, the phage QS genes may be a form of informing an expanded population of the same lysogen, (and therefore the phage), of its density within the environment with implications for induction and phage dynamics.
Bacteriophage behavioral ecology: How phages alter their bacterial host’s habits. Bacteriophage (2014) 4: e29866. doi: 10.4161/bact.29866
Bacteriophages have an essential gene kit that enables their invasion, replication, and production. In addition to this “core” genome, they can carry “accessory” genes that dramatically impact bacterial biology, and presumably boost their own success. The content of phage genomes continue to surprise us by revealing new ways that viruses impact bacterial biology. The genome of a Clostridium difficile myovirus, phiCDHM1, contains homologs of three bacterial accessory gene regulator (agr) genes. The agr system is a type of quorum sensing (QS), via which the phage may modify C. difficile interactions with its environment. Although their mechanism of action is unknown, mutants in bacterial versions of these genes impact sporulation and virulence. To explore how phage QS genes may influence C. difficile biology, we examine the main categories of bacterial behavior that phages have been shown to influence and discuss how interactions via QS could influence behavior at a wider level.
The major structural proteins of most viruses, including both naked icosahedral and enveloped types, are present in a dense array on the virion surface. This pattern has likely evolved to promote structural integrity, maximize cell binding and entry, and minimize genome size. HIV and related simian lentiviruses are unusual in having a low density of envelope protein spikes on their surfaces. Why has HIV evolved this unusual virion structure?
This discussion paper suggests that having low numbers of envelope spikes retards the induction of a broad spectrum antibody response. Neutralizing antibodies are exceptionally slow to develop during HIV infection, and nearly all broadly neutralizing antibodies invariably have undergone a large number of hypersomatic mutations. Artificial virus-like particles (VPLs) with a high density of envelope spikes might make a safe and efecting prophylactic vaccine against HIV by allowing the development of a neutralizing antibody response.
Why HIV Virions Have Low Numbers of Envelope Spikes: Implications for Vaccine Development. (2014) PLoS Pathog 10(8): e1004254. doi:10.1371/journal.ppat.1004254
Salmonella enterica serovar Typhi (S. Typhi) is a strictly human-adapted pathogen associated with a disseminated febrile illness, termed typhoid fever. In contrast, S. enterica serovar Typhimurium causes an infection that manifests as a localized gastroenteritis in immunocompetent individuals. To control a bacterial infection, neutrophils have to first migrate toward the microbe and then ingest and kill the intruder. Since Salmonella Typhi has a greater ability than S. Typhimurium to spread from its port of entry, researchers investigated whether both pathogens differ in their ability to evade neutrophil chemotaxis.
Surprisingly, S. Typhi, but not S. Typhimurium, inhibited neutrophil chemotaxis. Investigation of the underlying mechanism revealed that microbe-guided chemotaxis proceeded through a C5a- dependent mechanism, which could be blocked by the Vi capsular polysaccharide of S. Typhi. These data suggest that the chemotactic chase of neutrophils is a host defense mechanism operational during gastroenteritis, but not during the initial stages of typhoid fever.
The Vi Capsular Polysaccharide Enables Salmonella enterica Serovar Typhi to Evade Microbe-Guided Neutrophil Chemotaxis. (2014) PLoS Pathog 10(8): e1004306. doi:10.1371/journal.ppat.1004306
Salmonella enterica serovar Typhi (S. Typhi) causes typhoid fever, a disseminated infection, while the closely related pathogen S. enterica serovar Typhimurium (S. Typhimurium) is associated with a localized gastroenteritis in humans. Here we investigated whether both pathogens differ in the chemotactic response they induce in neutrophils using a single-cell experimental approach. Surprisingly, neutrophils extended chemotactic pseudopodia toward Escherichia coli and S. Typhimurium, but not toward S. Typhi. Bacterial-guided chemotaxis was dependent on the presence of complement component 5a (C5a) and C5a receptor (C5aR). Deletion of S. Typhi capsule biosynthesis genes markedly enhanced the chemotactic response of neutrophils in vitro. Furthermore, deletion of capsule biosynthesis genes heightened the association of S. Typhi with neutrophils in vivo through a C5aR-dependent mechanism. Collectively, these data suggest that expression of the virulence-associated (Vi) capsular polysaccharide of S. Typhi obstructs bacterial-guided neutrophil chemotaxis.
Ebola virus is back – but why?
Ebola virus is back, this time in West Africa, with over 350 cases and a 69% case fatality ratio. The culprit is the Zaire ebolavirus species, the most lethal Ebola virus known, with case fatality ratios up to 90%. The epicenter and site of first introduction is the region of Guéckédou in Guinea’s remote southeastern forest region, spilling over into various other regions of Guinea as well as to neighboring Liberia and Sierra Leone. News of this outbreak engenders three basic questions: (1) What in the world is Zaire ebolavirus doing in West Africa, far from its usual haunts in Central Africa? (2) Why Guinea, where no Ebola virus has ever been seen before? (3) Why now? We’ll have to wait for the outbreak to conclude and more data analysis to occur to answer these questions in detail, and even then we may never know, but some educated speculation may be illustrative – which a new paper (below) provides.
The precise factors that result in an Ebola virus outbreak remain unknown, but a broad examination of the complex and interwoven ecology and socioeconomics may help us better understand what has already happened and be on the lookout for what might happen next, including determining regions and populations at risk. Although the focus is often on the rapidity and efficacy of the short-term international response, attention to these admittedly challenging underlying factors will be required for long-term prevention and control.
Outbreak of Ebola Virus Disease in Guinea: Where Ecology Meets Economy. (2014) PLoS Negl Trop Dis 8(7): e3056. doi:10.1371/journal.pntd.0003056
During their replication in the nucleus of infected cells, influenza viruses hijack the host splicing machinery to process some of their RNA segments, the M and NS segments. This review provides an overview of the current knowledge gathered on this interplay between influenza viruses and the cellular spliceosome, with a particular focus on influenza A viruses. These viruses have developed accurate regulation mechanisms to reassign the host spliceosome to alter host cellular expression and enable an optimal expression of specific spliced viral products throughout infection.
Influenza virus segments undergoing splicing display high levels of similarity with human consensus splice sites and their viral transcripts show noteworthy secondary structures. Sequence alignments and consensus analyses, along with recently published studies, suggest both conservation and evolution of viral splice site sequences and structure for improved adaptation to the host. This emphasizes the ability of influenza virus to be well adapted to the host’s splicing machinery, and further investigations may contribute to a better understanding of splicing regulation with regard to viral replication, host range, and pathogenesis.
Influenza Viruses and mRNA Splicing: Doing More with Less. (2014) mBio, 5(3), e00070-14
In contrast to their negative reputation as disease causing agents, some viruses can perform crucial biological and evolutionary functions that help to shape the world we live in today, according to a new free report by the American Academy of Microbiology: Viruses Throughout Life and Time: Friends, Foes, Change Agents.
Viruses participate in essential Earth processes and influence all life forms on the planet, from contributing to biogeochemical cycles, shaping the atmospheric composition, and driving major speciation events. Recent metagenomic studies of viruses have indicated we know very little about the real world of viruses. Almost all published research is about the viruses that cause disease in humans and their domesticated plants and animals. This certainly represents only a very small fraction of the viruses that really exist. It is very important to understand the real world of viruses, as this can inform our basic understanding of life and its origins, as well as major earth phenomena like carbon cycling.
Beyond their pathogenic impact, the report examines in depth the size of the virosphere, the origin of viruses, the overlooked biological and microbial ecological role of viruses, and how these live forms have contributed to evolution. Additional highlights from the report explain how some viruses are commensal organisms or symbionts, their functioning in microbial communities, and their role in maintaining the biosphere. The array of responsibilities taken on by viruses is due to their incredible sequence diversity and genomic plasticity, referred to as “viral dark matter”.
The report concludes by stimulating the readers to think about key questions: “What if viruses had never existed on Earth? Would life have evolved quite differently?” Continued virus research will help to answer these enticing questions.
More than three decades after the discovery of HIV, AIDS remains a major public health problem affecting greater than 35.3 million people worldwide. Current antiretroviral therapy fails to eradicate HIV infection, partly due to the persistence of virus reservoirs. A new paper just published shows that RNA-guided HIV-1 genome cleavage by Cas9 CRISPR technology has shown promising efficacy in disrupting the HIV-1 genome in latently infected cells, suppressing virus gene expression and replication, and immunizing uninfected cells against HIV-1 infection. These properties may provide a viable path toward a permanent cure for AIDS, and provide a means to vaccinate against other pathogenic viruses. Given the ease and rapidity of Cas9/guide RNA development, personalized therapies for individual patients with HIV-1 variants might be developed quickly.
Comment: In spite of the breezy optimism of this paper (and this is progress), the work described has only been carried out on cultured cells in vitro. It is not clear whether or how easily it will be to replicate this finding in animals, and we’re still along way away from clinical trials which will be needed to show if this approach works in HIV-infected people.
RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection. PNAS USA July 21, 2014, doi: 10.1073/pnas.1405186111
AIDS remains incurable due to the permanent integration of HIV-1 into the host genome, imparting risk of viral reactivation even after antiretroviral therapy. New strategies are needed to ablate the viral genome from latently infected cells, because current methods are too inefficient and prone to adverse off-target effects. To eliminate the integrated HIV-1 genome, we used the Cas9/guide RNA (gRNA) system, in single and multiplex configurations. We identified highly specific targets within the HIV-1 LTR U3 region that were efficiently edited by Cas9/gRNA, inactivating viral gene expression and replication in latently infected microglial, promonocytic, and T cells. Cas9/gRNAs caused neither genotoxicity nor off-target editing to the host cells, and completely excised a 9,709-bp fragment of integrated proviral DNA that spanned from its 5′ to 3′ LTRs. Furthermore, the presence of multiplex gRNAs within Cas9-expressing cells prevented HIV-1 infection. Our results suggest that Cas9/gRNA can be engineered to provide a specific, efficacious prophylactic and therapeutic approach against AIDS.