Quantitative fragmentomics allow affinity mapping of interactomes

Human protein networks have been widely explored but most binding affinities remain unknown, hindering quantitative interactome-function studies. Yet interactomes rely on minimal interacting fragments displaying quantifiable affinities. Here we measured the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer. We calculate interactomic distances, identify hot spots for viral interference, generate binding profiles and specificity logos, and explain selected cases by crystallographic studies. Mass spectrometry experiments on cell extracts and literature surveys show that quantitative fragmentomics effectively complement protein interactomics by providing affinities and completeness of coverage, putting a full human interactome affinity survey within realistic reach. Finally, we show that interactome hijacking by the viral PBM of human papillomavirus (HPV) E6 oncoprotein deeply impacts the host cell proteome way beyond immediate E6 binders, illustrating the complex system-wide relationship between interactome and function.

Influenza vaccine during the 2019–2020 season and COVID-19 risk: A case-control study in Québec

Background: We carried out a case-control study that examined whether receipt of the inactivated influenza vaccine during the 2019–2020 season impacted on the risk of coronavirus disease 2019 (COVID-19), as there was a concern that the vaccine could be detrimental through viral interference. Methods: A total of 920 cases with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (diagnosed between March and October 2020) and 2,123 uninfected controls were recruited from those who were born in Québec between 1956 and 1976 and who had received diagnostic services at two hospitals (Montréal and Sherbrooke, Québec). After obtaining consent, a questionnaire was administered by phone. Data were analyzed by logistic regression. Results: Among healthcare workers, inactivated influenza vaccine received during the previous influenza season was not associated with increased COVID-19 risk (AOR: 0.99, 95% CI: 0.69–1.41). Among participants who were not healthcare workers, influenza vaccination was associated with lower odds of COVID-19 (AOR: 0.73, 95% CI 0.56–0.96). Conclusion: We found no evidence that seasonal influenza vaccine increased the risk of developing COVID-19.

Virus-Induced Tumorigenesis and IFN System

Oncogenic viruses favor the development of tumors in mammals by persistent infection and specific cellular pathways modifications by deregulating cell proliferation and inhibiting apoptosis. They counteract the cellular antiviral defense through viral proteins as well as specific cellular effectors involved in virus-induced tumorigenesis. Type I interferons (IFNs) are a family of cytokines critical not only for viral interference but also for their broad range of properties that go beyond the antiviral action. In fact, they can inhibit cell proliferation and modulate differentiation, apoptosis, and migration. However, their principal role is to regulate the development and activity of most effector cells of the innate and adaptive immune responses. Various are the mechanisms by which IFNs exert their effects on immune cells. They can act directly, through IFN receptor triggering, or indirectly by the induction of chemokines, the secretion of further cytokines, or by the stimulation of cells useful for the activation of particular immune cells. All the properties of IFNs are crucial in the host defense against viruses and bacteria, as well as in the immune surveillance against tumors. IFNs may be affected by and, in turn, affect signaling pathways to mediate anti-proliferative and antiviral responses in virus-induced tumorigenic context. New data on cellular and viral microRNAs (miRNAs) machinery, as well as cellular communication and microenvironment modification via classical secretion mechanisms and extracellular vesicles-mediated delivery are reported. Recent research is reviewed on the tumorigenesis induced by specific viruses with RNA or DNA genome, belonging to different families (i.e., HPV, HTLV-1, MCPyV, JCPyV, Herpesviruses, HBV, HCV) and the IFN system involvement.

Coinfection and Interference Phenomena Are the Results of Multiple Thermodynamic Competitive Interactions

Biological, physical and chemical interaction between one (or more) microorganisms and a host organism, causing host cell damage, represents an infection. Infection of a plant, animal or microorganism with a virus can prevent infection with another virus. This phenomenon is known as viral interference. Viral interference is shown to result from two types of interactions, one taking place at the cell surface and the other intracellularly. Various viruses use different receptors to enter the same host cell, but various strains of one virus use the same receptor. The rate of virus–receptor binding can vary between different viruses attacking the same host, allowing interference or coinfection. The outcome of the virus–virus–host competition is determined by the Gibbs energies of binding and growth of the competing viruses and host. The virus with a more negative Gibbs energy of binding to the host cell receptor will enter the host first, while the virus characterized by a more negative Gibbs energy of growth will overtake the host metabolic machine and dominate. Once in the host cell, the multiplication machinery is shared by the competing viruses. Their potential to utilize it depends on the Gibbs energy of growth. Thus, the virus with a more negative Gibbs energy of growth will dominate. Therefore, the outcome can be interference or coinfection, depending on both the attachment kinetics (susceptibility) and the intracellular multiplication machinery (permittivity). The ratios of the Gibbs energies of binding and growth of the competing viruses determine the outcome of the competition. Based on this, a predictive model of virus–virus competition is proposed.

Suppression of influenza virus infection by rhinovirus interference at the population, individual and cellular levels

Background: Investigations of the natural viral interference effect between rhinovirus (RV) and influenza virus (IV) were conducted in temperate regions. We conducted an epidemiological study in Hong Kong, a major epicentre of influenza virus in the sub-tropical region. RV is the most prevalent respiratory virus year-round and causes asymptomatic to mild symptoms while IV infection exerts a great burden of public health. We aimed to examine the correlation of RV prevalence against IV activity. Methods: Nasopharyngeal aspirates (NPA) collected from patients hospitalized in the regional hospitals from 2015 to 2019 were examined for the presence of respiratory viruses. The correlation of the monthly prevalence between all pairs of virus infection, the co-infection rate and the temporal interference of RV and IV were tested. The viral interference was validated in vitro by conducting sequential RV and IV infection in the well-differentiated primary human airway epithelial cells. Findings: A total of 112,926 NPA were evaluated, and the Enterovirus/RV was the most prevalent respiratory virus detected. The negative correlation between EV/RV and IVs prevalence was independent of age and meteorological factors. Co-infection of EV/RV and IV was significantly less when compared with other virus pairs. Prior exposure to RV inhibited the replication of influenza A, B and oseltamivir-resistance stain in vitro and the inhibition is replication dependent. Interpretation: Epidemiological surveillance and the sequential infection in vitro suggested viral interference between EV/RV and IV operated at the population, individual and cellular levels.

The timing of natural killer cell response in coronavirus infection: a concise model perspective

Coronaviruses, including SARS-CoV, MERS-CoV, and SARS-CoV-2 cause respiratory diseases with remarkably heterogeneous progression. This in part reflects the viral ability to influence the cytokine secretion and thereby the innate immune system. Especially the viral interference of IFN-I signaling and the subsequent deficiency of innate immune response in the early phase have been associated with rapid virus replication and later excessive immune responses. We propose a mathematical framework to analyze IFN-I signaling and its impact on the interaction motif between virus, NK cells and macrophages. The model recapture divergent dynamics of coronavirus infections including the possibility for elevated secretion of IL-6 and IFN-γ as a consequence of exacerbated macrophage activation. Dysfunction of NK cells recruitment increase disease severity by leading to a higher viral load peak, the possibility for excessive macrophage activation, and an elevated risk of the cytokine storm. Thus the model predicts that delayed IFN-I signaling could lead to pathogenicity in the latter stage of an infection. Reversely, in case of strong NK recruitment from infected cells we predict a possible chronic disease state with moderate and potentially oscillating virus/cytokine levels.

COVID-19 Shuts Doors to Flu but Keeps Them Open to Rhinoviruses

It is well known that rhinoviruses are distributed across the globe and are the most common cause of the common cold in all age groups. Rhinoviruses are widely considered to be harmless because they are generally perceived as respiratory viruses only capable of causing mild disease. However, they may also infect the lower respiratory tract, inducing chronic obstructive pulmonary disease and exacerbations of asthma, bronchiolitis, etc. The role of rhinoviruses in pathogenesis and the epidemiological process is underestimated, and they need to be intensively studied. In the light of recent data, it is now known that rhinoviruses could be one of the key epidemiological barriers that may influence the spread of influenza and novel coronaviruses. It has been reported that endemic human rhinoviruses delayed the development of the H1N1pdm09 influenza pandemic through viral interference. Moreover, human rhinoviruses have been suggested to block SARS-CoV-2 replication in the airways by triggering an interferon response. In this review, we summarized the main biological characteristics of genetically distinct viruses such as rhinoviruses, influenza viruses, and SARS-CoV-2 in an attempt to illuminate their main discrepancies and similarities. We hope that this comparative analysis will help us to better understand in which direction research in this area should move.

Strong Replication Interference Between Hepatitis Delta Viruses in Human Liver Chimeric Mice

BackgroundHepatitis D Virus (HDV) is classified into eight genotypes with distinct clinical outcomes. Despite the maintenance of highly conserved functional motifs, it is unknown whether sequence divergence between genotypes, such as HDV-1 and HDV-3, or viral interference mechanisms may affect co-infection in the same host and cell, thus hindering the development of HDV inter-genotypic recombinants. We aimed to investigate virological differences of HDV-1 and HDV-3 and assessed their capacity to infect and replicate within the same liver and human hepatocyte in vivo.MethodsHuman liver chimeric mice were infected with hepatitis B virus (HBV) and with one of the two HDV genotypes or with HDV-1 and HDV-3 simultaneously. In a second set of experiments, HBV-infected mice were first infected with HDV-1 and after 9 weeks with HDV-3, or vice versa. Also two distinct HDV-1 strains were used to infect mice simultaneously and sequentially. Virological parameters were determined by strain-specific qRT-PCR, RNA in situ hybridization and immunofluorescence staining.ResultsHBV/HDV co-infection studies indicated faster spreading kinetics and higher intrahepatic levels of HDV-3 compared to HDV-1. In mice that simultaneously received both HDV strains, HDV-3 became the dominant genotype. Interestingly, antigenomic HDV-1 and HDV-3 RNA were detected within the same liver but hardly within the same cell. Surprisingly, sequential super-infection experiments revealed a clear dominance of the HDV strain that was inoculated first, indicating that HDV-infected cells may acquire resistance to super-infection.ConclusionInfection with two largely divergent HDV genotypes could be established in the same liver, but rarely within the same hepatocyte. Sequential super-infection with distinct HDV genotypes and even with two HDV-1 isolates was strongly impaired, suggesting that virus interference mechanisms hamper productive replication in the same cell and hence recombination events even in a system lacking adaptive immune responses.

In-vitro and in-vivo study of the interference between Rift Valley fever virus (clone 13) and Sheeppox/Limpy Skin disease viruses

Viral interference is a common occurrence that has been reported in cell culture in many cases. In the present study, viral interference between two capripox viruses (sheeppox SPPV and lumpy skin disease virus LSDV in cattle) with Rift Valley fever virus (RVFV) was investigated in vitro and in their natural hosts, sheep and cattle. A combination of SPPV/RVFV and LSDV/RVFV was used to co-infect susceptible cells and animals to detect potential competition. In-vitro interference was evaluated by estimating viral infectivity and copies of viral RNA by a qPCR during three serial passages in cell cultures, whereas in-vivo interference was assessed through antibody responses to vaccination. When lamb testis primary cells were infected with the mixture of capripox and RVFV, the replication of both SPPV and LSDV was inhibited by RVFV. In animals, SPPV/RVFV or LSDV/RVFV combinations inhibited the replication SPPV and LSDV and the antibody response following vaccination. The combined SPPV/RVFV did not protect sheep after challenging with the virulent strain of SPPV and the LSDV/RVFV did not induce interferon Gamma to LSDV, while immunological response to RVFV remain unaffected. Our goal was to assess this interference response to RVFV/capripoxviruses’ coinfection in order to develop effective combined live-attenuated vaccines as a control strategy for RVF and SPP/LSD diseases. Our findings indicated that this approach was not suitable for developing a combined SPPV/LSDV/RVFV vaccine candidate because of interference of replication and the immune response among these viruses.