In previous commentaries (http://evmedreview.com/?p=1863; http://evmedreview.com/?p=837; http://evmedreview.com/?p=385), I have discussed the critical role of extensive B-cell and immunoglobulin gene evolution in generating broadly neutralizing antibodies for HIV-1. Of course, the unprecedented magnitude of antibody evolution necessary to achieve potent neutralization of a high percentage of HIV strains reflects the unprecedented evolutionary plasticity of HIV that originates in both high mutation and recombination rates for the HIV genome (Korber et al., 2001). A new study by Caskey et al. (Nature, 2015) from the Nussenzweig Laboratory reports results for a first-in-human dose escalation phase I clinical trial of a human monoclonal antibody (mAb) specific for the HIV envelope (env) protein. READ MORE »
Posts in category Infection
Last month, Murphy and colleagues (Cell, 2015) published a fascinating report about a patient with an immunodeficiency syndrome that underwent spontaneous resolution. The mechanism for this remarkable outcome points to the importance of somatic cell selection and evolution in the origins, pathogenesis, and most dramatically in this case, elimination of disease. READ MORE »
Cellular ‘Gold’: Competition for Iron as the Cause of Reciprocal Positive Selection of Host and Pathogen Iron-Binding Proteins
Iron is a critical metal for essential cellular processes, such as respiration, in both human and microbial cells. Thus, in the context of infection, iron is a high-value cellular commodity and an evolutionist might reasonably expect a metallic tug-of-war between host and pathogen iron-binding proteins or other iron-binding molecules (siderophores). This speculation is impressively supported in a paper published this month (Barber and Elde, 2014). These authors provide strong evidence for positive selection affecting several sites in host (transferrin, Tf) and pathogen (transferrin binding protein A) iron-binding proteins based on a combination of genetic, structural, and functional experimental methods. READ MORE »
Eukaryotic Exploitation of Bacterial Anti-Microbial Genes via Trans-Kingdom Horizontal Gene Transfer
An article published online at the Nature web site on November 24 (Chou et al., 2014) presents a fascinating study of examples in which bacterial genes have found their way to a number of distinct eukaryotic lineages including ticks and mites, gastropod (e.g., snails and slugs) and bivalve mollusks (e.g. clams and oysters), and choanoflagellates (a subset of ptotozoans). Type VI secretion amidase effector (Tae) molecules (encoded by tae genes) can kill rival bacteria by degrading their cells walls when delivered into those competing cells. The eukaryotes cited above all have “domesticated amidase effectors” (dae) genes, all of which are extremely similar to one of the four extant bacterial tae genes. Of the four tae genes found in bacterial species, three have been transferred to one or another eukaryotic genome. READ MORE »
After posting my last commentary on the ongoing Ebola outbreak in West Africa, I listened to the netcast, This Week in Virology (www.twiv.tv), for September 14, 2014. TWiV sessions, hosted by Vincent Racaniello, a well-known virologist at Columbia University, are generally highly informative, typically offering thoughtful discussions about recently published studies pertaining to viruses or addressing broad areas of virus-related research. READ MORE »
Over the past several weeks the health news has been dominated by the outbreak of infections by Ebola virus (EBOV) in several West African nations: Guinea, Sierra Leone, Liberia, and Nigeria. A study (Gire et al., 2014) published online at the end of August and now in print by a large collaborative group based in the U.S., the U.K., or West Africa applied massively parallel sequencing of the genomes of clinical isolates of the Ebola virus primarily from Sierra Leone. The results bear on the origins of the outbreak and the transmission patterns of the responsible virus lineages and may inform future investigations pertaining to diagnostic tests, the development of vaccines, and the design of therapies based on small-molecule drugs or biologics. READ MORE »
Epistasis refers to the influence of one genomic mutation or variant on the phenotypic effects of another mutation or variant. Based on available evidence and theory, this phenomenon has a major influence on evolutionary trajectories for organisms of all sorts. The role of epistasis has been studied primarily in the context of adaptive evolutionary change. In a recent paper (2014), Gong and Bloom attempt to determine the relative frequencies of epistatic interactions in adaptive versus stochastic evolution, i.e. evolution driven by selection as opposed to evolution resulting from random processes without a significant selective ‘pressure.’ Gong and Bloom perform this comparison by analyzing homologous nucleoprotein (NP) genes in human and swine influenza A viruses. The authors argue that the human viruses are subject to substantially more intense selection than the swine viruses since domestic swine are much shorter lived and their viruses are not as likely to be subjected to immune memory responses. READ MORE »
A careful reading of the review of fever in “Fever: Friend or Foe?”, reveals the embarrassing deficiency in medical science’s understanding of how fever, much less anorexia, functions in infection. Since fever (as well as anorexia and other components of the acute-phase response) is induced by our own cytokines, it is virtually axiomatic that fever has been more beneficial than harmful on an evolutionary scale (since otherwise the response would have been deleted). As a “fan” of fever, I’ve compiled a list of six potential benefits of fever, each of which is found in the literature and has a reasonable experimental or theoretical basis (and each likely has some degree of correctness). Note that the first four are based on fever being a heat stressor. Have a look and then see my take on it.
Fever may work by:
1) directly harming pathogens,*
2) inducing apoptosis of infected cells (and neoplastic cells),
3) inducing host’s heat shock proteins to protect host cells during infection,
4) inducing heat shock proteins in pathogens—extracellular heat shock proteins activate immune responses as “danger signals”,
5) increasing efficacy of immune responses since they work better at slightly elevated temperatures,*
6) turning down the immune response by causing apoptosis of neutrophils and lymphocytes. READ MORE »
A central focus of recent research aimed at developing a vaccine for HIV-1 is the identification of potent broadly-neutralizing antibodies (bNAbs). Due to work from several laboratories, many such antibodies have now been identified, produced in quantity as monoclonal antibodies, and characterized with respect to key properties such as epitope specificity, affinity for the corresponding HIV-1 epitope, and neutralizing activity against many strains of varying susceptibility to antibody-mediated inactivation (important examples of these publications are: Scheid et al., 2009; Walker et al., 2009; Wu et al., 2010; Walker et al., 2011; Huang et al., 2012). These successes notwithstanding, the scale of the challenge facing the vaccine developers is clarified by the following facts: 1) potent bNAbs only develop in 10-30% of infected individuals, 2) it typically takes between two and three or four years after initial infection for these antibodies to appear in the blood of these individuals, and 3) antibodies with the desired attributes often have extraordinary numbers of somatic mutations in the variable domains that mediate binding to the HIV-1 antigen (Klein et al., 2013a). A study (Klein et al., 2013b) published earlier this year from the laboratory of Michel Nussenzweig both illuminates one possible factor accounting for the impressive length of time and number of mutations associated with the generation of potent bNAbs and provides an extraordinary example of the power of intense selection to confound expectations arising from previously observed associations. In this instance, the undermined expectations related to the well-established functional correlates of hypervariable and framework regions within antibody variable domains. READ MORE »
The Case for Applying Negative Selection to Thoughts on Clonal Selection by Prospect Magazine’s Number One 2013 “World Thinker”
Currently, I am on vacation near the beach in South Carolina. Consequently, I have opted for a topic that is bit different than the majority of my monthly commentaries in that it focuses not on a recent original report but instead on a conceptual point made in a book over thirty years ago. Nevertheless, after a somewhat less strictly scientific diversion I will come to the central idea at issue, which is arguably the premier exemplar of the relevance of evolutionary principles to the operation of the immune system on short time scales, by which I refer to the concept of clonal selection. But first, we make a foray into the world of magazine publishing and the niche within that domain focusing on the arguably more intellectual readers. READ MORE »
Phenotypic and Genotypic Variation of a Fungal Pathogen Powered by Codon Ambiguity and Degenerate Translation
The term “genetic code” is associated with a measure of ambiguity. For molecular biologists, “genetic code” has historically referred to a table that provides for each messenger RNA ribonucleotide triplet the corresponding amino acid that is incorporated into the growing end of a nascent polypeptide chain, i.e. the translation from RNA sequence to protein sequence. In colloquial parlance, “genetic code” is frequently used to refer to all or part of the deoxribonucleotide sequence of a genome. A recent paper, published online ahead of print in Proceedings of the National Academy of Sciences (Bezerra et al., PNAS, 2013) demonstrates that this semantic ambiguity can have a counterpart in the ribosomal interpretation of the genetic code, using the technical molecular biological meaning of the latter term. READ MORE »
In 1996, Dean et al. (Science), demonstrated that a loss-of-function allele (CCR5Δ32) encoding a version of the chemokine receptor, CCR5, confers very substantial resistance to infection with HIV-1 in the homozygous state and slows progression in the heterozygous state. Given the relatively recent origin of HIV-1, this finding raised the question of what source of selection could account for the frequency, approximately 0.08 among Caucasians according to Dean et al., of this allele. A recent paper (Alonzo et al., 2013) offers new information on a relationship between CCR5 and a different pathogen that might offer insight into the evolutionary trajectory of CCR5Δ32.
The new study presents compelling evidence that leukotoxin ED (LukED), one of a family of bi-component exotoxins produced by Staphylococcus aureus, can bind to CCR5 and thereby cause cell death. LukED consistently produces substantially more cytotoxicity for CCR5+ than CCR5– cell lines of several types. Ligands for CCR5, including the drug, maraviroc, which is approved for clinical treatment of HIV-1 infection, significantly inhibit both the binding of LukED to cells and the magnitude of associated cytotoxicity. LukED also binds to and kills CCR5+ primarycells, such as human memory T cells, macrophages, and dendritic cells. READ MORE »
A major problem confronting physicians, nurses, and other hospital personnel is transmission of pathogens among inpatients or between medical personnel and inpatients (in either direction). A crucial component in efforts to control such infectious outbreaks in hospital wards is determining whether particular cases are linked by instances of person-to-person transmission. Standard methods of analysis involve epidemiological data, determinations of antibiotic sensitivities, and evaluation (multilocus sequence typing or MLST) of alleles at a limited number (<1%) of bacterial loci. A recent paper by Harris et al. in Lancet Infect Dis. (2012) offers results that support the use of whole-genome sequencing (WGS), which covers >95% of loci, of infectious isolates from individuals that might reasonably be thought to be part of an outbreak. In this particular study, focused on infection by methicillin-resistant Staphylococcus aureus (MRSA), both inpatients and outpatients were likely involved.
A paper recently appearing in Science (Näsvall et al. 2012) offers a new insights into the mechanisms by which gene duplication can lead to new genes, gene products, and functions. The new scheme is termed the innovation-amplification-divergence (IAD) model. READ MORE »
Influenza A viruses continue to be of enormous interest to biomedical researchers and clinicians alike. In addition to the annual influenza epidemics, which have been inferred to cause substantial excess mortality, there is the ever-present threat of a global pandemic due to several features of influenza virus biology. A high mutation rate associated with a segmented negative-sense RNA genome that facilitates recombination confers on these orthomyxoviruses a prodigious ability to evolve in ways that confound and evade the human immune system. The ability of influenza viruses to infect domesticated mammals, such as pigs, as well as birds, both wild and domesticated, provides additional opportunities for the virus to try out new genetic combinations and to disseminate around the globe by means both dependent and independent of human travel.
A recent paper by Jagger et al. (Science 2012) reveals that influenza A viruses are also, not surprisingly, capable of exploiting rather subtle and ingenious genetic “tricks” to maximize the value of every base pair in a total of a mere 13.5 kilobases of genome. These authors have discovered a new influenza gene product, PA-X, that represents a fusion protein incorporating 191 amino-terminal amino acids of the well-known RNA-dependent RNA polymerase (PA) protein and another carboxy-terminal 61 amino acids of a protein from a reading frame shifted by one nucleotide downstream. They present evidence from multiple experiments suggesting that the frameshift is related to a highly conserved codon that is rarely employed in mammalian and avian genomes and therefore interacts with a cognate tRNA of relatively low concentration in the cytosol. The longer-than-average wait for this tRNA to be recruited to the ribosome makes a frameshift mutation more probable. READ MORE »
There have been claims that variations in the composition of the intestinal flora influence individual health going back at least to the early years of the 1900s. Late in his career, Ilya Mechnikov, co-receipient of the Nobel Prize for Physiology or Medicine in 1908 (along with Paul Ehrlich) and a pioneer in the study of what we now call innate immune mechanisms, promoted a diet based on fermented milk containing live bacterial cultures of lactobacilli (i.e., yogurt) (1). Mechnikov apparently believed that the bacteria in the yogurt would compete with bacterial species that he thought were, on balance, harmful to human health. In other words, Mechnikov recognized the potential relevance of gastrointestinal ecology to human health a century ago. READ MORE »
The new tools for determining nucleotide sequences for whole genomes can sometimes present a problem of data analysis: How can mutations that influence important phenotypes be distinguished from mutations that may be of minimal or no impact on fitness, so-called passenger mutations that arise and persist primarily by chance and can greatly outnumber adaptive genetic variants? Merely finding nucleotide substitutions or larger genomic differences in comparing independent isolates of a microbial pathogen does not automatically reveal which genetic variants are responsible for the medically-relevant differences in pathogen attributes.
Lieberman et al. (2011) have approached this problem by determining the whole genome sequences for 112 isolates of an opportunistic bacterial pathogen, Burkholderia dolosa, obtained from 14 cystic fibrosis (CF) patients, including the initial patient infected, who were all part of an epidemic of small scale in the Boston area. A total of 39 individuals were infected in the course of the outbreak, and the patient samples were taken over a period of 16 years. Bacterial samples were obtained primarily from the airways and from blood. For these genome sequences, the average read depth was 37x, and the genomes were aligned based on a B. dolosa reference genome. READ MORE »