Medical Microbiology and Immunology最新文献

Guanylate binding proteins (GBPs) represent an evolutionary ancient protein family widely distributed among eukaryotes. They are interferon (IFN)-inducible guanosine triphosphatases that belong to the dynamin superfamily. GBPs are known to have a major role in the cell-autonomous innate immune response against bacterial, parasitic and viral infections and are also involved in inflammasome activation. Evolutionary studies depicted that GBPs present a pattern of gain and loss of genes in each family with several genes pseudogenized and some genes more divergent, indicative for the birth-and-death evolution process. Most species harbor large GBP gene clusters encoding multiple paralogs. Previous functional studies mainly focused on mouse and human GBPs, but more data are becoming available, broadening the understanding of this multifunctional protein family. In this review, we will provide new insights and give a broad overview about GBP evolution, conservation and their roles in all studied species, including plants, invertebrates and vertebrates, revealing how far the described features of GBPs can be transferred to other species.

Infection with the pandemic human coronavirus SARS-CoV-2 elicits a respiratory tract disease, termed Coronavirus disease 2019 (COVID-19). While a variable degree of disease-associated symptoms may emerge, severe COVID-19 is commonly associated with respiratory complications such as acute respiratory distress syndrome (ARDS), the necessity for mechanical ventilation or even extracorporeal membrane oxygenation (ECMO). Amongst others, disease outcome depends on age and pre-existing conditions like cardiovascular diseases, metabolic disorders but also age and biological sex. Intriguingly, increasing experimental and clinical evidence suggests that an exacerbated inflammatory response and in particular IgG immune complexes (ICs), significantly contribute to severe and prolonged COVID-19 disease progression. Vast amounts of deposited, unresolved ICs in tissue are capable to initiate an exaggerated Fc gamma receptor (FcγR) mediated signalling cascade which eventually results in common IC-associated organ diseases such as vasculitis, glomerulonephritis and arthritis, comorbidities that have been frequently reported for COVID-19. Moreover and independent of deposited ICs, very recent work identified soluble ICs (sIC) to be also present in the circulation of a majority of severely ill patients, where their systemic abundance correlated with disease severity. Thus, detection of circulating sICs in patients represents a potential marker for critical COVID-19 disease progression. Their detection early after clinical deterioration might become an indicator for the requirement of prompt anti-inflammatory treatment. Here, we review the role of ICs in COVID-19 progression, their possible origins and potential intervention strategies.

Serine incorporator 5 (SERINC5 or SER5) is a multipass transmembrane protein with ill-defined cellular activities. SER5 was recently described as a human immunodeficiency virus 1 (HIV-1) restriction factor capable of inhibiting HIV-1 that does not express its accessory protein Nef (Δ Nef). SER5 incorporated into the viral membrane impairs the entry of HIV-1 by disrupting the fusion between the viral and the plasma membrane after envelope receptor interaction induced the first steps of the fusion process. The mechanisms of how SER5 prevents membrane fusion are not fully understood and viral envelope proteins were identified that escape the SER5-mediated restriction. Primate lentiviruses, such as HIV-1 and simian immunodeficiency viruses (SIVs), use their accessory protein Nef to downregulate SER5 from the plasma membrane by inducing an endocytic pathway. In addition to being directly antiviral, recent data suggest that SER5 is an important adapter protein in innate signaling pathways leading to the induction of inflammatory cytokines. This review discusses the current knowledge about HIV-1 restriction by SER5.

The innate immune system is a powerful barrier against invading pathogens. Interferons (IFNs) are a major part of the cytokine-mediated anti-viral innate immune response. After recognition of a pathogen by immune sensors, signaling cascades are activated that culminate in the release of IFNs. These activate cells in an autocrine or paracrine fashion eventually setting cells in an anti-viral state via upregulation of hundreds of interferon-stimulated genes (ISGs). To evade the anti-viral effect of the IFN system, successful viruses like the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolved strategies to counteract both IFN induction and signaling. In fact, more than half of the about 30 proteins encoded by SARS-CoV-2 target the IFN system at multiple levels to escape IFN-mediated restriction. Here, we review recent insights into the molecular mechanisms used by SARS-CoV-2 proteins to suppress IFN production and the establishment of an anti-viral state.

The emergence of SARS-CoV-2, the severe acute respiratory syndrome coronavirus type 2 causing the COVID-19 pandemic, resulted in a major necessity for scientific countermeasures. Investigations revealing the exact mechanisms of the SARS-CoV-2 pathogenesis provide the basis for the development of therapeutic measures and protective vaccines against COVID-19. Animal models are inevitable for infection and pre-clinical vaccination studies as well as therapeutic testing. A well-suited animal model, mimicking the pathology seen in human COVID-19 patients, is an important basis for these investigations. Several animal models were already used during SARS-CoV-2 studies with different clinical outcomes after SARS-CoV-2 infection. Here, we give an overview of different animal models used in SARS-CoV-2 infection studies with a focus on the mouse model. Mice provide a well-established animal model for laboratory use and several different mouse models have been generated and are being used in SARS-CoV-2 studies. Furthermore, the analysis of SARS-CoV-2-specific T cells during infection and in vaccination studies in mice is highlighted.

Conflicting hallmarks are attributed to cytomegalovirus (CMV) infections. CMVs are viewed as being master tacticians in "immune evasion" by subverting essentially all pathways of innate and adaptive immunity. On the other hand, CMV disease is undeniably restricted to the immunologically immature or immunocompromised host, whereas an intact immune system prevents virus spread, cytopathogenic tissue infection, and thus pathological organ manifestations. Therefore, the popular term "immune evasion" is apparently incongruous with the control of CMV infections in the immunocompetent human host as well as in experimental non-human primate and rodent models. Here, we review recent work from the mouse model that resolves this obvious discrepancy for the example of the virus-specific CD8 T-cell response. Immune evasion proteins encoded by murine CMV (mCMV) interfere with the cell surface trafficking of antigenic peptide-loaded MHC class-I (pMHC-I) complexes and thereby reduce their numbers available for interaction with T-cell receptors of CD8 T cells; but this inhibition is incomplete. As a consequence, while CD8 T cells with low interaction avidity fail to receive sufficient signaling for triggering their antiviral effector function in the presence of immune evasion proteins in infected cells, a few pMHC-I complexes that escape to the cell surface are sufficient for sensitizing high-avidity CD8 T cells. It is thus proposed that the function of immune evasion proteins is to raise the avidity threshold for activation, so that in the net result, only high-avidity cells can protect. An example showing that immune evasion proteins can make the difference between life and death is the lacking control of infection in a mouse model of MHC-I histoincompatible hematopoietic cell transplantation (allogeneic-HCT). In this model, only low-avidity CD8 T cells become reconstituted by HCT and almost all infected HCT recipients die of multiple-organ CMV disease when immune evasion proteins are expressed. In contrast, lowering the avidity threshold for antigen recognition by deletion of immune evasion proteins allowed control of infection and rescued from death.

Human cytomegalovirus (CMV) is a widespread persistent herpes virus requiring lifelong immune surveillance to maintain latency. Such long-term interactions with the immune system may be associated with deleterious effects including immune exhaustion and senescence. Regarding the COVID-19 pandemic, we asked whether CMV-specific cellular and humoral activity could influence immune responses toward SARS-CoV-2 and/or disease severity. All adults with mild (n = 15) and severe (n = 14) COVID-19 were seropositive for anti-CMV IgG, but negative for IgM antibodies. Antibody titers did not correlate with COVID-19 severity. Six patients presented elevated frequencies of CMV-specific CD4 + and CD8 + T cells producing IFNγ, IL-17, and TNFα, designated as CMV high responders (hiT CMV). In comparison to low CMV responders, hiT CMV individuals exhibited higher frequencies of SARS-CoV-2-specific CD4 + IL-17 + and CD8 + IFNγ + , IL-17 + or TNFα + T cells. These results indicate that high frequencies of CMV-specific T cells may be associated with a SARS-CoV-2-reactive profile skewed toward Th17-dominated immunity.

The SARS-CoV-2 virus has been rapidly evolving over the time and the genetic variation has led to the generation of Variants of Concerns (VoC), which have shown increased fitness. These VoC viruses contain the key mutations in the spike protein which have allowed better survival and evasion of host defense mechanisms. The D614G mutation in the spike domain is found in the majority of VoC; additionally, the P681R/H mutation at the S1/S2 furin cleavage site junction is also found to be highly conserved in major VoCs; Alpha, Delta, Omicron, and its' current variants. The impact of these genetic alterations of the SARS-CoV-2 VoCs on the host cell entry, transmissibility, and infectivity has not been clearly identified. In our study, Delta and D614G + P681R synthetic double mutant pseudoviruses showed a significant increase in the cell entry, cell-to-cell fusion and infectivity. In contrast, the Omicron and P681H synthetic single mutant pseudoviruses showed TMPRSS2 independent cell entry, less fusion and infectivity as compared to Delta and D614G + P681R double mutants. Addition of exogenous trypsin further enhanced fusion in Delta viruses as compared to Omicron. Furthermore, Delta viruses showed susceptibility to both E64d and Camostat mesylate inhibitors suggesting, that the Delta virus could exploit both endosomal and TMPRSS2 dependent entry pathways as compared to the Omicron virus. Taken together, these results indicate that the D614G and P681R/H mutations in the spike protein are pivotal which might be favoring the VoC replication in different host compartments, and thus allowing a balance of mutation vs selection for better long-term adaptation.