Murine infection models are widely used to study systemic candidiasis caused by C. albicans. Whole-blood models can help to elucidate host-pathogens interactions and have been used for several Candida species in human blood. We adapted the human whole-blood model to murine blood. Unlike human blood, murine blood was unable to reduce fungal burden and more substantial filamentation of C. albicans was observed. This coincided with less fungal association with leukocytes, especially neutrophils. The lower neutrophil number in murine blood only partially explains insufficient infection and filamentation control, as spiking with murine neutrophils had only limited effects on fungal killing. Furthermore, increased fungal survival is not mediated by enhanced filamentation, as a filament-deficient mutant was likewise not eliminated. We also observed host-dependent differences for interaction of platelets with C. albicans, showing enhanced platelet aggregation, adhesion and activation in murine blood. For human blood, opsonization was shown to decrease platelet interaction suggesting that complement factors interfere with fungus-to-platelet binding. Our results reveal substantial differences between murine and human whole-blood models infected with C. albicans and thereby demonstrate limitations in the translatability of this ex vivo model between hosts.
Copyright © 2021 Machata, Sreekantapuram, Hünniger, Kurzai, Dunker, Schubert, Krüger, Schulze-Richter, Speth, Rambach and Jacobsen.

There is an urgent need for a vaccine to combat the hepatitis C virus (HCV) pandemic, and induction of broadly neutralizing monoclonal antibodies (bNAbs) against HCV is a major goal of vaccine development. Even within HCV genotype 1, no single bNAb effectively neutralizes all viral strains, so induction of multiple neutralizing monoclonal antibodies (NAbs) targeting distinct epitopes may be necessary for protective immunity. Therefore, identification of optimal NAb combinations and characterization of NAb interactions can guide vaccine development. We analyzed neutralization profiles of 12 human NAbs across diverse HCV strains, assigning the NAbs to two functionally distinct clusters. We then measured neutralizing breadth of 35 NAb combinations against genotype 1 isolates, with each combination including one NAb from each neutralization cluster. Many NAbs displayed complementary neutralizing breadth, forming combinations with greater neutralization across diverse strains than any individual bNAb. Remarkably, one of the most broadly neutralizing combinations of two NAbs, designated HEPC74/HEPC98, also displayed enhanced potency, with interactions matching the Bliss independence model, suggesting that these NAbs inhibit HCV infection through independent mechanisms. Subsequent experiments showed that HEPC74 primarily blocks HCV envelope protein binding to CD81, while HEPC98 primarily blocks binding to scavenger receptor B1 and heparan sulfate. Together, these data identify a critical vulnerability resulting from the reliance of HCV on multiple cell surface receptors, suggesting that vaccine induction of multiple NAbs with distinct neutralization profiles is likely to enhance the breadth and potency of the humoral immune response against HCV.

Herpes zoster (shingles) causes significant morbidity in immune compromised hosts and older adults. Whereas a vaccine is available for prevention of shingles, its efficacy declines with age. To help to understand the mechanisms driving vaccinal responses, we constructed a multiscale, multifactorial response network (MMRN) of immunity in healthy young and older adults immunized with the live attenuated shingles vaccine Zostavax. Vaccination induces robust antigen-specific antibody, plasmablasts, and CD4+ T cells yet limited CD8+ T cell and antiviral responses. The MMRN reveals striking associations between orthogonal datasets, such as transcriptomic and metabolomics signatures, cell populations, and cytokine levels, and identifies immune and metabolic correlates of vaccine immunity. Networks associated with inositol phosphate, glycerophospholipids, and sterol metabolism are tightly coupled with immunity. Critically, the sterol regulatory binding protein 1 and its targets are key integrators of antibody and T follicular cell responses. Our approach is broadly applicable to study human immunity and can help to identify predictors of efficacy as well as mechanisms controlling immunity to vaccination.
Copyright © 2017 Elsevier Inc. All rights reserved.