Neutrophils Turn Plasma Proteins into Weapons against HIV-1

As a consequence of innate immune activation granulocytes and macrophages produce hypochlorite/hypochlorous acid (HOCl) via secretion of myeloperoxidase (MPO) to the outside of the cells, where HOCl immediately reacts with proteins. Most proteins that become altered by this system do not belong to the invading microorganism but to the host. While there is no doubt that the myeloperoxidase system is capable of directly inactivating HIV-1, we hypothesized that it may have an additional indirect mode of action. We show in this article that HOCl is able to chemically alter proteins and thus turn them into Idea-Ps (Idea-P = immune defence-altered protein), potent amyloid-like and SH-groups capturing antiviral weapons against HIV-1. HOCl-altered plasma proteins (Idea-PP) have the capacity to bind efficiently and with high affinity to the HIV-1 envelope protein gp120, and to its receptor CD4 as well as to the protein disulfide isomerase (PDI). Idea-PP was able to inhibit viral infection and replication in a cell culture system as shown by reduced number of infected cells and of syncytia, resulting in reduction of viral capsid protein p24 in the culture supernatant. The unmodified plasma protein fraction had no effect. HOCl-altered isolated proteins antithrombin III and human serum albumin, taken as representative examples of the whole pool of plasma proteins, were both able to exert the same activity of binding to gp120 and inhibition of viral proliferation. These data offer an opportunity to improve the understanding of the intricacies of host-pathogen interactions and allow the generation of the following hypothetical scheme: natural immune defense mechanisms generate by posttranslational modification of plasma proteins a potent virucidal weapon that immobilizes the virus as well as inhibits viral fusion and thus entry into the host cells. Furthermore simulation of this mechanism in vitro might provide an interesting new therapeutic approach against microorganisms

Candida albicans Factor H Binding Molecule Hgt1p – A Low Glucose-Induced Transmembrane Protein Is Trafficked to the Cell Wall and Impairs Phagocytosis and Killing by Human Neutrophils

Complement is a tightly controlled arm of the innate immune system, facilitating phagocytosis and killing of invading pathogens. Factor H (FH) is the main fluid-phase inhibitor of the alternative pathway. Many pathogens can hijack FH from the host and protect themselves from complement-dependent killing. Candida albicans is a clinically important opportunistic yeast, expressing different FH binding molecules on its cell surface, which allow complement evasion. One such FH binding molecule is the transmembrane protein “High affinity glucose transporter 1” (Hgt1p), involved in glucose metabolism. This study demonstrated that Hgt1p transcription and expression is induced and highest at the low, but physiological glucose concentration of 0.1%. Thus, this concentration was used throughout the study. We also demonstrated the transport of Hgt1p to the fungal cell wall surface by vesicle trafficking and its release by exosomes containing Hgt1p integrated in the vesicular membrane. We corroborated Hgt1p as FH binding molecule. A polyclonal anti-Hgt1p antibody was created which interfered with the binding of FH, present in normal human serum to the fungal cell wall. A chimeric molecule consisting of FH domains 6 and 7 fused to human IgG1 Fc (FH6.7/Fc) even more comprehensively blocked FH binding, likely because FH6.7/Fc diverted FH away from fungal FH ligands other than Hgt1p. Reduced FH binding to the yeast was associated with a concomitant increase in C3b/iC3b deposition and resulted in significantly increased in vitro phagocytosis and killing by human neutrophils. In conclusion, Hgt1p also exhibits non-canonical functions such as binding FH after its export to the cell wall. Blocking Hgt1p-FH interactions may represent a tool to enhance complement activation on the fungal surface to promote phagocytosis and killing of C. albicans

Molecular mechanisms for mediating light-dependent nucleo/cytoplasmic partitioning of phytochrome photoreceptors

The photoreceptors phytochromes monitor the red/far-red part of the spectrum, exist in the biologically active Pfr (far-red absorbing) or inactive Pr (red absorbing) forms, and function as red/far-red light-regulated molecular switches to modulate plant development and growth. Phytochromes are synthesized in the cytoplasm, and light induces translocation of the Pfr conformer into the nucleus. Nuclear import of phytochromes is a highly regulated process and is fine-tuned by the quality and quantity of light. It appears that phytochrome A (phyA) and phytochrome B (phyB) do not possess active endogenous nuclear import signals (NLSs), thus light-induced translocation of these photoreceptors into the nucleus requires direct protein–protein interactions with their NLS-containing signaling partners. Sub-cellular partitioning of the various phytochrome species is mediated by different molecular machineries. Translocation of phyA into the nucleus is promoted by FAR-RED ELONGATED HYPOCOTYL 1 (FHY1) and FHY1-LIKE (FHL), but the identity of nuclear transport facilitators mediating the import of phyB-E into the nucleus remains elusive. Phytochromes localized in the nucleus are associated with specific protein complexes, termed photobodies. The size and distribution of these structures are regulated by the intensity and duration of irradiation, and circumstantial evidence indicates that they are involved in fine-tuning phytochrome signaling

Complement Attack against Aspergillus and Corresponding Evasion Mechanisms

Invasive aspergillosis shows a high mortality rate particularly in immunocompromised patients. Perpetually increasing numbers of affected patients highlight the importance of a clearer understanding of interactions between innate immunity and fungi. Innate immunity is considered to be the most significant host defence against invasive fungal infections. Complement represents a crucial part of this first line defence and comprises direct effects against invading pathogens as well as bridging functions to other parts of the immune network. However, despite the potency of complement to attack foreign pathogens, the prevalence of invasive fungal infections is increasing. Two possible reasons may explain that phenomenon: First, complement activation might be insufficient for an effective antifungal defence in risk patients (due to, e.g., low complement levels, poor recognition of fungal surface, or missing interplay with other immune elements in immunocompromised patients). On the other hand, fungi may have developed evasion strategies to avoid recognition and/or eradication by complement. In this review, we summarize the most important interactions between Aspergillus and the complement system. We describe the various ways of complement activation by Aspergillus and the antifungal effects of the system, and also show proven and probable mechanisms of Aspergillus for complement evasion

Galactosaminogalactan (GAG) and its multiple roles in Aspergillus pathogenesis

Aspergillus spp and particularly the species Aspergillus fumigatus are the causative agents of invasive aspergillosis, a progressive necrotizing pneumonia that occurs in immunocompromised patients. The limited efficacy of currently available antifungals has led to interest in a better understanding of the molecular mechanisms underlying the pathogenesis of invasive aspergillosis in order to identify new therapeutic targets for this devastating disease. The Aspergillus exopolysaccharide galactosaminogalactan (GAG) plays an important role in the pathogenesis of experimental invasive aspergillosis. The present review article summarizes our current understanding of GAG composition and synthesis and the molecular mechanisms whereby GAG promotes virulence. Promising directions for future research and the prospect of GAG as both a therapy and therapeutic target are reviewed

In Vitro Activities of Amphotericin B and Voriconazole against Aleurioconidia from Aspergillus terreus

This study used aleurioconidia as inoculum and compared the MICs of amphotericin B and voriconazole to those obtained for conidia of 31 Aspergillus terreus strains. For conidia and aleurioconidia, the MIC at which 90% of strains were inhibited was 2.5 μg/ml and 5 μg/ml with amphotericin B and 1 μg/ml and 2 μg/ml with voriconazole

Micro- and Mycobiota Dysbiosis in Pancreatic Ductal Adenocarcinoma Development

Background: Dysbiosis of the intestinal flora has emerged as an oncogenic contributor in different malignancies. Recent findings suggest a crucial tumor-promoting role of micro- and mycobiome alterations also in the development of pancreatic ductal adenocarcinoma (PDAC). Methods: To summarize the current knowledge about this topic, a systematic literature search of articles published until October 2020 was performed in MEDLINE (PubMed). Results: An increasing number of publications describe associations between bacterial and fungal species and PDAC development. Despite the high inter-individual variability of the commensal flora, some studies identify specific microbial signatures in PDAC patients, including oral commensals like Porphyromonas gingivalis and Fusobacterium nucleatum or Gram-negative bacteria like Proteobacteria. The role of Helicobacter spp. remains unclear. Recent isolation of Malassezia globosa from PDAC tissue suggest also the mycobiota as a crucial player of tumorigenesis. Based on described molecular mechanisms and interactions between the pancreatic tissue and the immune system this review proposes a model of how the micro- and the mycobial dysbiosis could contribute to tumorigenesis in PDAC. Conclusions: The presence of micro- and mycobial dysbiosis in pancreatic tumor tissue opens a fascinating perspective on PDAC oncogenesis. Further studies will pave the way for novel tumor markers and treatment strategies