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Pathogenesis of viral hemorrhagic fevers: Rift Valley fever and Lassa fever contrasted.

Although many viral infections have on occasion been associated with hemorrhagic complications, infection with any of several RNA viruses regularly results in vascular involvement and the syndrome called viral hemorrhagic fever (VHF). In spite of clinically useful similarities among various VHFs, there are significant differences in their pathogenesis and clinical evolution; these are often related to characteristics of their viral taxon. Infection with Rift Valley fever (RVF) virus, a phlebovirus, appears to be regulated by interferon and terminated by neutralizing antibody. In contrast, Lassa fever (LF) virus, an arenavirus, is resistant to interferon, and LF is terminated by cellular immune effector mechanisms. The lytic virus-cell interaction typical of RVF virus suggests its major effects occur by direct, virus-induced cellular necrosis, particularly in the liver. In the primate RVF model, disseminated intravascular coagulation (DIC) may be important. LF virus--characteristically noncytopathic--may exert its effects through induction of mediator secretion from infected macrophages. DIC does not appear to be a central pathogenetic mechanism in LF. Pichinde virus, which is not pathogenic for humans, provides an alternate model for study of LF. Infected guinea pigs do not show histologic lesions that could explain their body wasting, cardiovascular deterioration, and pulmonary edema. In the heart, for example, loss of tissue mass, protein, and contractile function proceed without direct viral involvement or myocarditis. Sulfidopeptide leukotrienes have been implicated as one relevant soluble mediator participating in the disease state.

Animals↗
PubMed2025

Adaptation of the Cyst Nematode Globodera pallida to the Colinear Potato Resistant QTLs GpaVvrn and GpaVspl Involved Distinct Genomic Regions and Absence of Cross-Virulence.

The use of alternative methods to control cyst nematode populations has accelerated since the ban of chemical nematicides in Europe. The resistant QTL GpaVvrn, derived from the wild species Solanum vernei, is widely present in resistant European potato cultivars and provides strong protection against Globodera pallida populations although a risk of resistance breakdown has already been demonstrated in both experimental evolution studies and field populations. The wild relative S. sparsipilum, harbouring the resistant QTL GpaVspl, would be an interesting alternative source of resistance to control virulent G. pallida. The goal of the present study was to understand the genomics of adaptation of the nematode to these two colinear resistant QTLs. Starting with two natural populations, an experimental evolution approach allowed, after 10 generations on resistant potato genotypes, selecting independent nematode lineages adapted to each QTL. These virulent lineages were analysed through a combination of phenotyping and genome scans approaches. Phenotyping enabled the quantification of virulence levels and confirmed resistance breakdowns. Pool-Seq whole genome sequencing followed by genome scan analyses identified genomic regions under selection, potentially involved in the adaptive mechanisms to each resistance factor. Candidate genes within these regions provided insights into the genetic basis of adaptation, revealing effectors known to suppress plant immunity. As genome scans highlighted distinct genomic regions for the adaptation to both resistant factors, we were able to predict and phenotypically confirm the absence of cross-virulence between nematode lineages evolving on GpaVvrn and GpaVspl. These findings have significant implications for the design of effective and sustainable resistance management strategies.

Animals↗
PubMed1986

Domain structure of rat liver carbamoyl phosphate synthetase I.

Independently folded structural domains of rat liver carbamoyl phosphate synthetase I have been identified by partial proteolytic cleavage under nondenaturing conditions. The pattern of fragments produced was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The NH2-terminal sequences of the fragments were determined by automated Edman degradation. Comparison of these fragment sequences with the sequence of the intact protein allowed alignment of the fragments. The hydrolysis of carbamoyl phosphate synthetase I (Mr 160,000) by either trypsin or elastase proceeded in two stages, with two alternative routes of degradation for elastase. The alignment of the final tryptic fragments from the NH2 terminus to the COOH terminus was: Mr 87,000 fragment-Mr 62,000 fragment-group of small peptides. The alignment of the final elastase fragments was: Mr 37,000 fragment-Mr 108,000 fragment-group of small peptides. The rates of cleavage were affected by the presence of the substrate ATP or the positive allosteric effector N-acetylglutamate; the preferred route of elastase cleavage was also affected. In addition to providing a map of the carbamoyl phosphate synthetase I domains and preliminary information on the interaction of substrates with these domains, the present studies provide further support for the proposal that domains serve as units of protein evolution since the 37-kDa fragment encompasses the region of the rat liver synthetase that is homologous to the 40-kDa subunit of the Escherichia coli synthetase.

Adenosine Triphosphate↗
PubMed1991

Atopic dermatitis: new therapeutic considerations.

Atopic dermatitis is a genetically determined inflammatory condition in which the primary defect is expressed in one or more hematopoietic cells that infiltrate the skin. It is a multifactorial disease with inflammation triggered by a variety of factors. Among these, atopic dermatitis has been experimentally induced and reproduced by emotional-stress interviews and food challenges only. The inflammatory events of atopic dermatitis appear to initiated by mast cells, but eosinophils, monocytes, and T lymphocytes (predominantly CD4) also are present in lesions. The secondary effects of inflammation are a dry, brittle stratum corneum and pruritus, causing excoriation and a lichenified epidermal layer resulting from chronic rubbing. Therapeutic approaches to atopic dermatitis may be directed at several points in the evolution of the disease. Agents including emollients are needed to preserve and restore the stratum corneum barrier, and effective antipruritics are required to reduce the self-inflicted damage to the involved skin. Various other agents may be needed to antagonize mediators or cytokines and to inhibit cytokine expression and release from lesional, immune-effector cells. Likewise, new phosphodiesterase inhibitors, calcium-active agents, and antiallergic drugs may be used to reduce the quantity and pathologic functioning of inflammatory infiltrating cells in the skin.

Dermatitis, Atopic↗
PubMed2026

Virome-wide ubiquitin ligase discovery reveals diverse mechanisms of immune evasion.

Viruses are intracellular parasites that reprogram the host proteome to promote replication and evade immune recognition. We applied a virome-wide library of ~10,000 open reading frames to discover viral ubiquitin ligases, mapping their mechanisms of degradation and host substrates using targeted CRISPR screens and proteomics. These viral effectors could be classified as canonical ligases that mimic host E3s, hijackers that redirect host E3s, and noncanonical ligases that rewire cullin-RING ligase machinery. These diverse strategies of virus-mediated degradation converged on immune-related substrates, including JAK1 and CUL1β-TrCP, underscoring immune evasion as a major driver of viral ubiquitin ligase evolution. Our findings elucidate viral strategies for exploiting the ubiquitin-proteasome system with potential for therapeutic targeting.

Humans↗
PubMed1988

Evolution of the rat immunoglobulin gamma heavy-chain gene family.

The sequences of the four immunoglobulin gamma heavy chains of the rat (gamma 1, gamma 2a, gamma 2b, gamma 2c) have been determined. These sequences reveal that the rat genes have evolved differently from the closely related mouse gamma genes (gamma 1, gamma 2a, gamma 2b, gamma 3): in rat two of the four genes (gamma 2a and gamma 1) are 94% homologous to each other and best resemble the single mouse gamma 1 gene. Rat gamma 2b is equivalent to the mouse gamma 2a/gamma 2b pair as regards both nucleotide sequence and antibody effector functions whilst rat gamma 2c resembles mouse gamma 3. In evolutionary terms this suggests the existence of a set of three common C gamma genes before separation of rat and mouse as individual species. In addition, two independent duplication events must have occurred after species separation affecting different constant regions; this yielded rat gamma 2a and gamma 1 as a recently evolved pair and mouse gamma 2a and gamma 2b as a different pair. Furthermore, the sequence comparisons reveal several other features of interest; rat IgG2b lacks two amino acids in CH1 which are conserved in all other sequenced gamma chains. Residues believed to be essential for monocyte interaction (FcRI) are retained only in rat gamma 2b and not in the other rat gamma genes whilst a particular motif involved in C1q interaction shows a variation in both rat IgG1 and rat IgG2a which has not been observed previously.

Amino Acid Sequence↗
PubMed1990

An evolutionary perspective of endotoxin: a signal for a well-adapted defense system.

In the evolutionary view of endotoxin presented here, endotoxin is the primary signal animals use to detect gram negative (Gr-) bacteria. Since endotoxin, or lipopolysaccharide (LPS), is an integral part of the surface of all Gr- bacteria, it was excellent evolutionary 'choice' for the signal. The concept of an 'endotoxin response system' (ERS) is introduced. The ERS protects against Gr- bacteria by employing many of the body's defenses to both detect and react against LPS. The intensity of the response has evolved to maximize protection while minimizing the biological cost and self-damaging effects. The setting of the response, here termed the 'endostat', is programmed by natural selection and fine tuned by feedback mechanisms. Other potentially invasive organisms are detected by different signals, but the effector components of the defenses are similar. This evolutionary view of LPS offers a framework for the seemingly contradictory findings on endotoxin and suggests new avenues of productive research.

Adaptation, Physiological↗
PubMed2025

Understanding Mycobacterium tuberculosis through its genomic diversity and evolution.

Pathogen evolution and genomic diversity are shaped by specific host immune pressures and therapeutic interventions. Analysis of the extant genomes of circulating strains of Mycobacterium tuberculosis, a leading cause of infectious mortality that has co-evolved with humans for thousands of years, can provide new insights into host-pathogen interactions that underlie specific aspects of pathogenesis and onward transmission. With the explosion in the number of fully sequenced M. tuberculosis strains that are now paired with detailed clinical data, there are new opportunities to understand the evolutionary basis for and consequences of M. tuberculosis strain diversity. This review examines mechanistic findings that have emerged from pairing whole genome sequencing data and evolutionary analysis with functional dissection of specific bacterial variants. These include improved understanding of secreted effectors that modulate the properties and migratory behavior of infected macrophages as well as bacterial genetic alterations important for survival within hypoxic microenvironments. Genomic, evolutionary, and functional analyses across diverse M. tuberculosis strains will identify prominent bacterial adaptations to their human hosts and shape our understanding of TB disease biology and the host immune response.

Mycobacterium tuberculosis↗
PubMed1986

A computational frame to study social behaviour in animals.

This paper presents new methods and procedures for studying collective behaviour in rats. The animals are assumed to be indistinguishable one from another and the behaviour of the group is represented analysed and interpreted in terms of the temporal evolution of a finite state probabilistic automaton. The automaton states are defined by measures on the clustering degree considered as a social response variable. The electronic system developed to carry out the cluster analysis and the automatic control of the social behaviour in the experimental environment includes a multimicroprocessor interacting with a 'social box' in which, together with classical sensors and effectors, a phototransistor based position sensor is included. Preliminary experiments show the discriminative power of the cluster automaton concerning sexual differences and emotivity, as well as the extensive of a basic mechanism of clustering as a collective response to stress. Pharmacologically, the new experimental medium proposed in this paper may be used to detect a new range of products affecting social but not individual behaviour. Also, well-known products, which in normal doses produce no detectable modification of individual behaviour, might have detectable effects on the collective level. Be this as it may, the experimental environment described constitutes a further experimental facility for the analysis and control of animal behaviour.

Animals↗
PubMed1991

Cooperativity and allosteric regulation in non-mammalian vertebrate haemoglobins.

1. This review illustrates the vast range of molecular functions expressed in non-mammalian vertebrate haemoglobins; with particular reference to the degree of aggregation of haemoglobin subunits and their interactions with allosteric effectors. 2. In at least the broadest sense, these properties suggest that haemoglobin function in non-mammalian vertebrates can be viewed against the evolutionary hierarchy of organisms rather than from a purely adaptive perspective.

Allosteric Regulation↗
PubMed2026

Building CRISPR immunity: evolution and mechanisms of spacer acquisition.

CRISPR-Cas systems in prokaryotes serve as adaptive immune systems that neutralize phage infections through RNA-guided nucleases. Immunization is achieved during the adaptation stage through Cas1-Cas2 integrase-mediated insertion of short foreign DNA snippets, termed spacers, into a CRISPR array in the host genome. This review examines the evolutionary origins of Cas1-Cas2 and the mechanisms of spacer acquisition in DNA-targeting CRISPR-Cas systems. Particular emphasis is placed on the recently characterized effector-assisted adaptation pathways, in which CRISPR effector proteins, such as Cascade and Cas9, typically involved in target interference, are repurposed for prespacer capture and integration into a CRISPR array.

CRISPR–Cas spacer acquisition↗
PubMed1989

Cell-mediated suppression of HIV-specific cytotoxic T lymphocytes.

CTL specific for HIV have been described in lungs of infected patients at early stages of HIV disease. In order to characterize the evolution over time of HIV-specific CTL, we have analyzed the cytotoxic function and the cell surface phenotype of the alveolar lymphocytes from 41 patients at various stages of HIV disease. We demonstrated a progressive decline of alveolar anti-HIV CTL activity and detected Ts cells from the lungs of patients with advanced HIV disease. These alveolar T cells strongly suppressed the effector phase of anti-HIV CTL lysis. They lacked a marked specificity of function because they also block anti-HLA CTL response and were not restricted by the HLA-class-I transplantation Ag. They displayed the CD3, CD8, and HNK1 markers, were CD4 and CD16 negative, and lacked NK activity. The presence of Ts cells at late stages of HIV disease could thus partly explain the inefficiency of host defenses against HIV.

AIDS-Related Complex↗
PubMed1992

On the kinetics and optimal specificity of cytotoxic reactions mediated by T-lymphocyte clones.

Using the chromium release assay and the single cell assay in agarose, we study the cytotoxic reaction of the MHC-restricted T lymphocyte clones P89:15 and P1:3, which recognize distinct but specific tumour antigens on the surface of syngeneic P815 mastocytoma cells. We propose a mathematical model which describes these experiments, accounts for the strongly non-Michaelian behaviour of the reaction and permits us to estimate the kinetic parameters characterizing effector-target conjugation and lethal hit delivery. The results show that the binding and lytic activity of effector cells is modulated by the number of targets bound to them. The binding of a second target by an effector having already a target bound is facilitated; on the other hand, an effector having bound two targets delivers a lethal hit more slowly than one with a single target bound. We investigate the role of these kinetic properties in the competition between the process of tumour progression due to cancer cell replication and the process of tumour regression due to T lymphocyte cytotoxic activity. For both clones, we estimate the effector-target ratio beyond which rejection prevails. This ratio is nine times larger for P1:3 than for P89:15. Furthermore, our analysis suggests that there exists an optimal specificity minimizing this ratio. Deviations from this optimum, be it in the sense of an increase or decrease of specificity, tends to stabilize the tumoural state: a situation which in the broader context of the immune response evolution and regulation can be viewed as an immune response dilemma.

Animals↗
PubMed1983

Inhibiton of IL 2 production after human allogeneic bone marrow transplantation.

Bone marrow transplantation (BMT) is currently used to treat patients with severe aplastic anemia or leukemia. Despite the use of an HLA identical sibling donor, however, the survival after BMT is reduced by the occurrence of two major immunologic complications: graft-vs-host disease and a long-lasting immune deficiency responsible for late infections. This immune deficiency could be explained by an imbalance of lymphocyte subpopulations reconstituted after transplant. The aim of the present work was to study the helper function by measuring the production of interleukin 2 (IL 2). This lymphokine is responsible for the amplification of the effector phase of immunity. A consecutive series of 34 patients was tested for IL 2 production after BMT. This production was absent or low in 32 of 34 patients for at least 2 yr after BMT. The mechanism of this low IL 2 production was investigated. Irradiation of patients' lymphocytes in vitro with low dose gamma-rays partially restored the IL 2 production after 6 mo of evolution. The IL 2 production was not restored or was slightly affected by irradiation early after BMT. These results suggest that the lack of immune reconstitution after BMT may be caused by the lack of IL 2-producing cells and/or the increased activity of suppressor cells of the helper function. This suppression is radiosensitive.

Bone Marrow Transplantation↗
PubMed1983

pH feedback control of enzyme membranes.

pH feedback on immobilized enzymes is theoretically examined with respect to substrate and pH levels, strength of acids produced by the reaction, buffering and asymmetry of the system. All the productions of proton by the different reactions are taken into account by using a 'symbolic species' H. The system of differential diffusion-reaction equations is then integrated using numerical methods. The local 'effective enzyme activity' modulated by an acidity factor enables us to predict and quantify evolutions of the systems: NonMichaelian behavior of an immobilized Michaelis-Menten-type enzyme is shown, even when pH back-actions are excluded; the analysis of intramembrane pH profiles shows that the shift of the optimal pH is a complex function of the substrate and pH levels, the intrinsic pH dependence of the enzyme, and the membrane characteristics. This study may easily be transposed to other types of effector such as divalent cations and used in examining self-regulations of multienzyme systems where pH-active reactions are involved.

Buffers↗
PubMed1983

[Computer bank of amino acid sequences of protein hormones. Comparative analysis of the sequences in pro-opio-melanocortin, proenkephalin and prodynorphin: detection of phorphin--the 4th repeating peptide in prodynorphin].

Using a BESM-6 computer, a computer system for accumulation and comparative analysis of amino acid sequences (AS) of protein-peptide hormones and their precursors (the so-called computer bank of protein hormone AS) was developed. A Fortran-based program designed for construction of correspondence schemes of AS and their local similarity profiles was elaborated. In combination with the previous programs this system allows a rapid inclusion of the newly deciphered sequences into the corresponding homologous groups, thus complementing the correspondence scheme and specifying the evolution profiles. A comparative analysis of AS in proopiomelanocortin (POMC), proenkephalin (PENK) and prodynorphin (PDIN) revealed evolutionary-conservative and variable sites. The conservative sites of AS are active centers of the hormones. The leu-enkephalin analog, phorphin, the fourth repeating peptide of this precursor, was detected in prodynorphin, which, similar to beta-neo-endorphin, dynorphin and rimorphin may possess a biological activity. The similarity of the effector sites of the melanotropin sequence from POMC to the met-enkephalin sequence from PENK and leu-enkephalin sequence from PDIN as well as to gastrin and cholecystokinin was established. This may suggest that the hormone-receptor complexes in target organs of these hormones are also similar.

Amino Acid Sequence↗
PubMed1989

The sympatho-adrenal tone and reactivity in human hypertension.

In the last two decades, remarkable advances have permitted a better understanding of the modulation of sympathetic tone and reactivity at the sympathetic nerve and at the effector cell levels. In man, several indirect approaches have permitted to suggest the possibility of increased sympathetic nerve activity and reactivity in an important subgroup of essential hypertensive patients. The demonstration of significant correlations between circulating levels of sympathetic transmitters and various parameters of cardiovascular functions supports the hypothesis of a participation of the sympathetic system in the maintenance of an elevated blood pressure in those patients. Moreover, several experimental evidences have indicated that the sensitivity of cardiovascular effector cells may be altered in hypertensive patients. The blunted beta receptor responsiveness and the normal or enhanced alpha receptor responsiveness which were observed suggest the possibility of an imbalance between adrenergic receptor functions in hypertension, which may explain the preferential alpha 1 modulation of blood pressure through changes in peripheral resistance in hypertensive patients. Such an abnormality could contribute to the development of cardiac and vascular wall hypertrophy during the evolution of hypertension. These studies therefore suggest that a variety of sympathetic dysfunctions could play a role in the development, maintenance and evolution of human essential hypertension.

Adrenal Glands↗
PubMed1981

Phylogeny of NK cell reactivity against human and nonhuman primate lymphoblastoid cell lines: evolving and conserved target antigens.

Both human and nonhuman primate natural killer (NK) cells display little or no killing against allogeneic B lymphoblastoid cell lines. However, the same B cell lines are killed in baboon-human (B alpha H) or human-baboon (H alpha B) xenogeneic combinations. Competition-inhibition experiments indicate that the xenogeneic determinants recognized by NK cells are found principally if not exclusively on B rather than T target cells. Cell lines from closely related chimpanzee or orang-utan species can block some killing of human target cells, but lines from more distantly related species including gibbon, macaque, baboon, and marmoset do not inhibit cytotoxicity. This suggests that some NK target structures are susceptible to evolutionary change. Gibbon or marmoset lines infected with Epstein Barr virus (EBV) do not block killing, suggesting that host rather than viral determinants are being recognized. In contrast to the foregoing pattern, 2 cell lines derived from the same baboon differed in susceptibility to NK lysis irrespective of the effector cell species. The viral producer line 13CB-1 was more susceptible to lysis than its viral nonproducer partner 26CB-1. Thus, some NK target antigens may be highly conserved whereas others evolve with the species.

Animals↗