Novel prime-boost immune-based therapy inhibiting both hepatitis B and D virus infections.

OBJECTIVE: Chronic HBV/HDV infections are a major cause of liver cancer. Current treatments can only rarely eliminate HBV and HDV. Our previously developed preS1-HDAg immunotherapy could induce neutralising antibodies to HBV in vivo and raise HBV/HDV-specific T-cells. Here, we further investigate if a heterologous prime-boost strategy can circumvent T-cell tolerance and preclude HDV superinfection in vivo. DESIGN: A DNA prime-protein boost strategy was evaluated for immunogenicity in mice and rabbits. Its ability to circumvent T-cell tolerance was assessed in immunocompetent hepatitis B surface antigen (HBsAg)-transgenic mice. Neutralisation of HBV and HDV was evaluated both in vitro and in immunodeficient human-liver chimeric mice upon adoptive transfer. RESULTS: The prime-boost strategy elicits robust HBV/HDV-specific T-cells and preS1-antibodies that can effectively prevent HBV and HDV (co-)infection in vitro and in vivo. In a mouse model representing the chronic HBsAg carrier state, active immunisation primes high levels of preS1-antibodies and HDAg-specific T-cells. Moreover, transfer of vaccine-induced antibodies completely protects HBV-infected human-liver chimeric mice from HDV superinfection. CONCLUSION: The herein described preS1-HDAg immunotherapy is shown to be immunogenic and vaccine-induced antibodies are highly effective at preventing HBV and HDV (super)infection both in vitro and in vivo. Our vaccine can complement current and future therapies for the control of chronic HBV and HDV infection.

Otitis media (acute): antimicrobial prescribing

This guideline sets out an antimicrobial prescribing strategy for acute otitis media (ear infection). It aims to limit antibiotic use and reduce antimicrobial resistance. Acute otitis media can be caused by viruses or bacteria. It lasts for about a week, and most children get better in 3 days without antibiotics. Serious complications are rare. In March 2022, we reviewed the evidence and added a recommendation on eardrops containing an anaesthetic and an analgesic because a licensed preparation is now available in the UK. For more information, see update information.

An Embedded Multiscale Modelling to Guide Control and Elimination of Paratuberculosis in Ruminants.

In recent years, multiscale modelling approach has begun to receive an overwhelming appreciation as an appropriate technique to characterize the complexity of infectious disease systems. In this study, we develop an embedded multiscale model of paratuberculosis in ruminants at host level that integrates the within-host scale and the between-host. A key feature of embedded multiscale models developed at host level of organization of an infectious disease system is that the within-host scale and the between-host scale influence each other in a reciprocal (i.e., both) way through superinfection, that is, through repeated infection before the host recovers from the initial infectious episode. This key feature is demonstrated in this study through a multiscale model of paratuberculosis in ruminants. The results of this study, through numerical analysis of the multiscale model, show that superinfection influences the dynamics of paratuberculosis only at the start of the infection, while the MAP bacteria replication continuously influences paratuberculosis dynamics throughout the infection until the host recovers from the initial infectious episode. This is largely because the replication of MAP bacteria at the within-host scale sustains the dynamics of paratuberculosis at this scale domain. We further use the embedded multiscale model developed in this study to evaluate the comparative effectiveness of paratuberculosis health interventions that influence the disease dynamics at different scales from efficacy data.

A Live Olfactory Mouse Cytomegalovirus Vaccine, Attenuated for Systemic Spread, Protects against Superinfection.

Vaccination against the betaherpesvirus, human cytomegalovirus (HCMV) is a public health goal. However, HCMV has proved difficult to vaccinate against. Vaccination against single HCMV determinants has not worked, suggesting that immunity to a wider antigenic profile may be required. Live attenuated vaccines provide the best prospects for protection, but the question remains as to how to balance vaccine virulence with safety. Animal models of HCMV infection provide insights into identifying targets for virus attenuation and understanding how host immunity blocks natural, mucosal infection. Here, we evaluated the vaccine potential of a mouse cytomegalovirus (MCMV) vaccine deleted of a viral G protein-coupled receptor (GPCR), designated M33, that renders it attenuated for systemic spread. A single noninvasive olfactory ΔM33 MCMV vaccine replicated locally, but as a result of the loss of the M33 GPCR, it failed to spread systemically and was attenuated for latent infection. Vaccination did not prevent host entry of a superinfecting MCMV but spread from the mucosa was blocked. This approach to vaccine design may provide a viable alternative for a safe and effective betaherpesvirus vaccine. IMPORTANCE Human cytomegalovirus (HCMV) is the most common cause of congenital infection for which a vaccine is not yet available. Subunit vaccine candidates have failed to achieve licensure. A live HCMV vaccine may prove more efficacious, but it faces safety hurdles which include its propensity to persist and to establish latency. Understanding how pathogens infect guide rational vaccine design. However, HCMV infections are asymptomatic and thus difficult to capture. Animal models of experimental infection provide insight. Here, we investigated the vaccine potential of a mouse cytomegalovirus (MCMV) attenuated for systemic spread and latency. We used olfactory vaccination and virus challenge to mimic its natural acquisition. We provide proof of concept that a single olfactory MCMV that is deficient in systemic spread can protect against wild-type MCMV superinfection and dissemination. This approach of deleting functional counterpart genes in HCMV may provide safe and effective vaccination against congenital HCMV disease.

Ecological Approach to Understanding Superinfection Inhibition in Bacteriophage.

In microbial communities, viruses compete with each other for host cells to infect. As a consequence of competition for hosts, viruses evolve inhibitory mechanisms to suppress their competitors. One such mechanism is superinfection exclusion, in which a preexisting viral infection prevents a secondary infection. The bacteriophage ΦX174 exhibits a potential superinfection inhibition mechanism (in which secondary infections are either blocked or resisted) known as the reduction effect. In this auto-inhibitory phenomenon, a plasmid containing a fragment of the ΦX174 genome confers resistance to infection among cells that were once permissive to ΦX174. Taking advantage of this plasmid system, we examine the inhibitory properties of the ΦX174 reduction effect on a range of wild ΦX174-like phages. We then assess how closely the reduction effect in the plasmid system mimics natural superinfection inhibition by carrying out phage-phage competitions in continuous culture, and we evaluate whether the overall competitive advantage can be predicted by phage fitness or by a combination of fitness and reduction effect inhibition. Our results show that viral fitness often correctly predicts the winner. However, a phage's reduction sequence also provides an advantage to the phage in some cases, modulating phage-phage competition and allowing for persistence where competitive exclusion was expected. These findings provide strong evidence for more complex dynamics than were previously thought, in which the reduction effect may inhibit fast-growing viruses, thereby helping to facilitate coexistence.

Ligilactobacillus salivarius Strains Isolated From the Porcine Gut Modulate Innate Immune Responses in Epithelial Cells and Improve Protection Against Intestinal Viral-Bacterial Superinfection.

Previously, we constructed a library of Ligilactobacillus salivarius strains from the intestine of wakame-fed pigs and reported a strain-dependent capacity to modulate IFN-ß expression in porcine intestinal epithelial (PIE) cells. In this work, we further characterized the immunomodulatory activities of L. salivarius strains from wakame-fed pigs by evaluating their ability to modulate TLR3- and TLR4-mediated innate immune responses in PIE cells. Two strains with a remarkable immunomodulatory potential were selected: L. salivarius FFIG35 and FFIG58. Both strains improved IFN-ß, IFN-λ and antiviral factors expression in PIE cells after TLR3 activation, which correlated with an enhanced resistance to rotavirus infection. Moreover, a model of enterotoxigenic E. coli (ETEC)/rotavirus superinfection in PIE cells was developed. Cells were more susceptible to rotavirus infection when the challenge occurred in conjunction with ETEC compared to the virus alone. However, L. salivarius FFIG35 and FFIG58 maintained their ability to enhance IFN-ß, IFN-λ and antiviral factors expression in PIE cells, and to reduce rotavirus replication in the context of superinfection. We also demonstrated that FFIG35 and FFIG58 strains regulated the immune response of PIE cells to rotavirus challenge or ETEC/rotavirus superinfection through the modulation of negative regulators of the TLR signaling pathway. In vivo studies performed in mice models confirmed the ability of L. salivarius FFIG58 to beneficially modulate the innate immune response and protect against ETEC infection. The results of this work contribute to the understanding of beneficial lactobacilli interactions with epithelial cells and allow us to hypothesize that the FFIG35 or FFIG58 strains could be used for the development of highly efficient functional feed to improve immune health status and reduce the severity of intestinal infections and superinfections in weaned piglets.

Two simple comments regarding coronavirus.

Two thought provoking comments related to understanding the problems with the coronavirus are presented.

A vector-host model to assess the impact of superinfection exclusion on vaccination strategies using dengue and yellow fever as case studies.

Superinfection exclusion is a phenomenon whereby the co-infection of a host with a secondary pathogen is prevented due to a current infection by another closely-related pathogenic strain. We construct a novel vector-host mathematical model for two pathogens that exhibit superinfection exclusion and simultaneously account for vaccination strategies against them. We then derive the conditions under which an endemic disease will prevent the establishment of another through the action of superinfection exclusion and show that vaccination against the endemic strain can enable the previously suppressed strain to invade the population. Through appropriate parameterisation of the model for dengue and yellow fever we find that superinfection exclusion alone is unlikely to explain the absence of yellow fever in many regions where dengue is endemic, and that the rollout of the recently licensed dengue vaccine, Dengvaxia, is unlikely to enable the establishment of Yellow Fever in regions where it has previously been absent.

Off-target effects of an insect cell-expressed influenza HA-pseudotyped Gag-VLP preparation in limiting postinfluenza Staphylococcus aureus infections.

Clinical and historical data underscore the ability of influenza viruses to ally with Staphylococcus aureus and predispose the host for secondary bacterial pneumonia, which is a leading cause of influenza-associated mortality. This is fundamental because no vaccine for S. aureus is available and the number of antibiotic-resistant strains is alarmingly rising. Hence, this leaves influenza vaccination the only strategy to prevent postinfluenza staphylococcal infections. In the present work, we assessed the off-target effects of a Tnms42 insect cell-expressed BEI-treated Gag-VLP preparation expressing the HA of A/Puerto Rico/8/1934 (H1N1) in preventing S. aureus superinfection in mice pre-infected with a homologous or heterologous H1N1 viral challenge strain. Our results demonstrate that matched anti-hemagglutinin immunity elicited by a VLP preparation may suffice to prevent morbidity and mortality caused by lethal secondary bacterial infection. This effect was observed even when employing a single low antigen dose of 50 ng HA per animal. However, induction of anti-hemagglutinin immunity alone was not helpful in inhibiting heterologous viral replication and subsequent bacterial infection. Our results indicate the potential of the VLP vaccine approach in terms of immunogenicity but suggest that anti-HA immunity should not be considered as the sole preventive method for combatting influenza and postinfluenza bacterial infections.

A possible European origin of the Spanish influenza and the first attempts to reduce mortality to combat superinfecting bacteria: an opinion from a virologist and a military historian.

When we reconsider the virology and history of the Spanish Influenza Pandemic, the science of 2018 provides us with tools which did not exist at the time. Two such tools come to mind. The first lies in the field of 'gain of function' experiments. A potential pandemic virus, such as influenza A (H5N1), can be deliberately mutated in the laboratory in order to change its virulence and spreadability. Key mutations can then be identified. A second tool lies in phylogenetics, combined with molecular clock analysis. It shows that the 1918 pandemic virus first emerged in the years 1915-1916. We have revisited the literature published in Europe and the United States, and the notes left by physicians who lived at the time. In this, we have followed the words of the late Alfred Crosby: who wrote that "contemporary documentary evidence from qualified physicians" is the key to understanding where and how the first outbreaks occurred. In our view, the scientists working in Europe fulfill Crosby's requirement for contemporary evidence of origin. Elsewhere, Crosby also suggested that "the physicians of 1918 were participants in the greatest failure of medical science in the twentieth century". Ours is a different approach. We point to individual pathologists in the United States and in France, who strove to construct the first universal vaccines against influenza. Their efforts were not misdirected, because the ultimate cause of death in nearly all cases flowed from superinfections with respiratory bacteria.

The type I interferon receptor is not required for protection in the Chlamydia muridarum and HSV-2 murine super-infection model.

Chlamydia trachomatis/HSV-2 vaginal co-infections are seen clinically, suggesting that these sexually transmitted pathogens may interact. We previously established an intravaginal Chlamydia muridarum/HSV-2 super-infection model and observed that chlamydial pre-infection protects mice from a subsequent lethal HSV-2 challenge. However, the mechanism of protection remains unknown. The type I interferon, IFN-ß, binds to the type I interferon receptor (IFNR), elicits a host cellular antiviral response and inhibits HSV replication in vitro and in vivo. Previous studies have demonstrated that C. muridarum infection stimulates genital tract (GT) IFN-ß production; therefore, we hypothesized that chlamydial pre-infection protects mice from HSV-2 challenge via the IFN-ß/IFNR-induced antiviral response. To test this prediction, we quantified IFN-ß levels in vaginal swab samples. Detection of IFN-ß in C. muridarum singly infected, but not in mock-infected animals, prompted the use of the super-infection model in IFNR knockout (IFNR-/-) mice. We observed that C. muridarum pre-infection reduces HSV-2-induced mortality by 40% in wild-type mice and by 60% IFNR-/- mice. Severity of HSV-2 disease symptoms and viral shedding was also similarly reduced by C. muridarum pre-infection. These data indicate that, while chlamydial infection induces GT production of IFN-ß, type I IFN-induced antiviral responses are likely not required for the observed protective effect.

Evidence that a primary anti-viral stimulation of the immune response by OM-85 reduces susceptibility to a secondary respiratory bacterial infection in mice.

BACKGROUND: Viral respiratory infections may promote bacterial super-infection decreasing the host immune response efficiency. However, using a mice model we recently demonstrated that preventive treatment with the bacterial extract OM-85 reduces the susceptibility to a secondary Streptococcus (S.) pneumoniae infection after influenza virus (I.V.) challenge. METHODS: To better characterize the efficacy of OM-85 against S. pneumoniae super-infection, a post-hoc analysis was conducted, comparing efficacy (survival) and morbidity signs (clinical score, body temperature and weight loss) in the OM-85 and the control (BLANC) groups of mice after: a) I.V. infection; b) primary S. pneumoniae infection and c) post-I.V. S. pneumoniae super-infection. RESULTS: After a sublethal I.V. dose, all mice stayed alive at day 5 and no differences in morbidity signs were detected between the OM-85 and the BLANC groups. However, OM-85 pretreatment led to a significantly reduction of the viral load in the lung on day 5 post viral infection and, on day 10, reduced neutrophilic inflammation while increasing influenza-specific CD8 + T-cell proportion in the airways. Conversely to viral infection, exposure to S. pneumoniae induced a dramatic reduction of survival, with no mice surviving on day 3 post infection in the BLANC group, whereas a partial protective effect was observed in OM-85 pre-treated mice (20% of mice surviving at day 3, and 10% at day 4 and 5). The morbidity data substantiated the survival results. Interestingly, in the "super-infection" study, when mice were exposed to a sublethal I.V. dose followed by a secondary S. pneumoniae infection, all mice died by day 4 in the BLANC group. In contrast, in the OM-85 treated group, the survival rate was 70% at day 4 and still 50% at day 5, with positive effects on the clinical scores and on the body temperature already detectable at days 1 and 2. CONCLUSIONS: The efficacy of OM-85 pre-treatment against S. pneumoniae super-infection reflects a strong and immediate immune reaction from the host, an event that can be explained in part by a "non-specific" activation of the immune system, a positive "immune effect" of the general OM-85- induced immune response against I.V.

Dermatosis inflamatorias asociadas a radioterapia / Inflammatory skin conditions associated with radiotherapy

La radioterapia es una técnica de uso creciente en el campo de la oncología. Debido al alto recambio celular cutáneo, la radiación ionizante afecta colateralmente a la piel y encontramos de forma frecuente dermatosis inflamatorias asociadas a radioterapia. Algunos de estos cuadros, como la radiodermitis o el fenómeno de recall, son bien conocidos por el dermatólogo. Es importante reconocer otros cuadros cutáneos asociados a radioterapia que aparecen de forma menos frecuente y que en muchas ocasiones son infradiagnosticados

Radiotherapy for cancer is used increasingly. Because skin cells undergo rapid turnover, the ionizing radiation of radiotherapy has collateral effects that are often expressed in inflammatory reactions. Some of these reactions-radiodermatitis and recall phenomenon, for example-are very familiar to dermatologists. Other, less common radiotherapy-associated skin conditions are often underdiagnosed but must also be recognized

Prevention of influenza virus induced bacterial superinfection by standardized Echinacea purpurea, via regulation of surface receptor expression in human bronchial epithelial cells.

Viral infections may predispose the airways to secondary bacterial infections that can lead to unfavorable progression of principally self-limiting illnesses. Such complicated respiratory infections include pneumonia, bronchitis, sinusitis, acute otitis media, and sepsis, which cause high morbidity and lethality. Some of the pathogenic consequences of viral infections, like the expression of bacterial adhesion receptors and the disturbance of physical barrier integrity due to inflammation, may create permissive conditions for co-infections. Influenza virus A (H3N2) is a major pathogen that causes secondary bacterial infections and inflammation that lead to pneumonia. The herbal medicine Echinacea purpurea, on the other hand, has been widely used to prevent and treat viral respiratory infections, and recent clinical data suggest that it may prevent secondary infection complications as well. We investigated the role of standardized E. purpurea (Echinaforce® extract or EF) on H3N2-induced adhesion of live nontypeable Haemophilus influenzae (NTHi) and Staphylococcus aureus, along with the expression of bacterial receptors, intracellular adhesion molecule-1 (ICAM-1), fibronectin, and platelet activating factor receptor (PAFr), by BEAS-2B cells. Inflammatory processes were investigated by determining the cellular expression of IL-6 and IL-8 and the involvement of Toll-like receptor (TLR-4) and NFκB p65. We found that influenza virus A infection increased the adhesion of H. influenzae and S. aureus to bronchial epithelial cells via upregulated expression of the ICAM-1 receptor and, to some extent, of fibronectin and PAFr. Echinaforce (EF) significantly reduced the expression of ICAM-1, fibronectin, and PAFr and consequently the adhesion of both bacterial strains. EF also effectively prevented the super-expression of inflammatory cytokines by suppressing the expression of NFκB and possibly TLR-4. These results indicate that E. purpurea has the potential to reduce the risk of respiratory complications by preventing virus-induced bacterial adhesion and through the inhibition of inflammation super-stimulation (cytokine storms).

Functional effector memory T cells contribute to protection from superinfection with heterologous simian immunodeficiency virus or simian-human immunodeficiency virus isolates in Chinese rhesus macaques.

Many studies have revealed a protective effect of infection of an individual with an immunodeficiency virus against subsequent infection with a heterologous strain. However, the extent of protection against superinfection conferred by the first infection and the biological consequences of superinfection are not well understood. Here, we report that a rhesus monkey model of mucosal superinfection was established to investigate the protective immune response. Protection against superinfection was shown to correlate with the extent of the polyfunctionality of CD4+ effector memory T cells, whereas neutralizing antibody responses did not protect against superinfection in this model. Notably, immunodeficiency-virus-associated effector memory T-cell responses might significantly contribute to the suppression of virus superinfection. This provides a potential theoretical basis for the development of an HIV/AIDS vaccine.

Clinical efficacy of ß-lactam/ß-lactamase inhibitor combinations for the treatment of bloodstream infection due to extended-spectrum ß-lactamase-producing Enterobacteriaceae in haematological patients with neutropaenia: a study protocol for a retrospective observational study (BICAR).

INTRODUCTION: Bloodstream infection (BSI) due to extended-spectrum ß-lactamase-producing Gram-negative bacilli (ESBL-GNB) is increasing at an alarming pace worldwide. Although ß-lactam/ß-lactamase inhibitor (BLBLI) combinations have been suggested as an alternative to carbapenems for the treatment of BSI due to these resistant organisms in the general population, their usefulness for the treatment of BSI due to ESBL-GNB in haematological patients with neutropaenia is yet to be elucidated. The aim of the BICAR study is to compare the efficacy of BLBLI combinations with that of carbapenems for the treatment of BSI due to an ESBL-GNB in this population. METHODS AND ANALYSIS: A multinational, multicentre, observational retrospective study. Episodes of BSI due to ESBL-GNB occurring in haematological patients and haematopoietic stem cell transplant recipients with neutropaenia from 1 January 2006 to 31 March 2015 will be analysed. The primary end point will be case-fatality rate within 30 days of onset of BSI. The secondary end points will be 7-day and 14-day case-fatality rates, microbiological failure, colonisation/infection by resistant bacteria, superinfection, intensive care unit admission and development of adverse events. SAMPLE SIZE: The number of expected episodes of BSI due to ESBL-GNB in the participant centres will be 260 with a ratio of control to experimental participants of 2. ETHICS AND DISSEMINATION: The protocol of the study was approved at the first site by the Research Ethics Committee (REC) of Hospital Universitari de Bellvitge. Approval will be also sought from all relevant RECs. Any formal presentation or publication of data from this study will be considered as a joint publication by the participating investigators and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE). The study has been endorsed by the European Study Group for Bloodstream Infection and Sepsis (ESGBIS) and the European Study Group for Infections in Compromised Hosts (ESGICH).

Understanding superinfection exclusion by complex populations of Citrus tristeza virus.

Superinfection exclusion (SIE) is a phenomenon in which a primary viral infection restricts a secondary infection with the same or closely related virus. Previously we showed that SIE by Citrus tristeza virus (CTV) occurs only between isolates of the same virus genotype. This work, however, was done using single genotype-containing isolates, while most field citrus trees harbor complex populations composed of different virus genotypes. Here we examined SIE in plants simultaneously infected with several CTV genotypes. The experiments showed that exclusion of a secondary infection by a CTV variant was triggered by the presence of another variant of the same genotype in the primary population, even under the conditions of its low-level accumulation, and was not affected by co-occurrence of additional heterologous genotypes. The same rule appeared to be in effect when SIE by mixed populations was tested in a series of different citrus varieties.

Positive Contribution of Adjuvanted Influenza Vaccines to the Resolution of Bacterial Superinfections.

BACKGROUND: Most preclinical studies assess vaccine effectiveness in single-pathogen infection models. This is unrealistic given that humans are continuously exposed to different commensals and pathogens in sequential and mixed infections. Accordingly, complications from secondary bacterial infection are a leading cause of influenza-associated morbidity and mortality. New vaccination strategies are needed to control infections on simultaneous fronts. METHODS: We compared different anti-influenza vaccines for their protective potential in a model of viral infection with bacterial superinfection. Mice were immunized with H1N1/A/California/7/2009 subunit vaccines, formulated with different adjuvants inducing either T-helper type 1 (Th1) (MF59 plus CpG)-, Th1/2 (MF59)-, or Th17 (LTK63)-prone immune responses and were sequentially challenged with mouse-adapted influenza virus H1N1/A/Puerto Rico/8/1934 and Staphylococcus aureus USA300, a clonotype emerging as a leading contributor in postinfluenza pneumonia in humans. RESULTS: Unadjuvanted vaccine controlled single viral infection, yet mice had considerable morbidity from viral disease and bacterial superinfection. In contrast, all adjuvanted vaccines efficiently protected mice in both conditions. Interestingly, the Th1-inducing formulation was superior to Th1/2 or Th17 inducers. CONCLUSIONS: Our studies should help us better understand how differential immunity to influenza skews immune responses toward coinfecting bacteria and discover novel modes to prevent bacterial superinfections in the lungs of persons with influenza.

Febrile Ulceronecrotic Mucha-Habermann Disease: Two Cases with Excellent Response to Methotrexate.

Febrile ulceronecrotic Mucha-Habermann disease (FUMHD), a severe form of pityriasis lichenoides et varioliformis acuta (PLEVA), featuring large, ulcerative, necrotic skin plaques, high fever, and other systemic symptoms, is a rare disorder of unknown etiology. No randomized controlled trials have established treatment guidelines and multiple modalities are often employed, making it difficult to assess the efficacy of any single agent. We report two cases of this condition in which treatment with methotrexate plus antibiotic treatment for superinfection led to rapid improvement.