PLoS Pathogens

Journal: PLoS Pathogens

Abbreviation

PLoS Pathog

Publisher

PLOS

ISSN

1553-7374
1553-7366

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Publications 1 - 10 of 124

Predicting HIV-1 transmission and antibody neutralization efficacy in vivo from stoichiometric parameters
Brandenberg, Oliver F.; Magnus, Carsten; Rusert, Peter; et al. (2017)
PLoS Pathogens
The potential of broadly neutralizing antibodies targeting the HIV-1 envelope trimer to prevent HIV-1 transmission has opened new avenues for therapies and vaccines. However, their implementation remains challenging and would profit from a deepened mechanistic understanding of HIV-antibody interactions and the mucosal transmission process. In this study we experimentally determined stoichiometric parameters of the HIV-1 trimer-antibody interaction, confirming that binding of one antibody is sufficient for trimer neutralization. This defines numerical requirements for HIV-1 virion neutralization and thereby enables mathematical modelling of in vitro and in vivo antibody neutralization efficacy. The model we developed accurately predicts antibody efficacy in animal passive immunization studies and provides estimates for protective mucosal antibody concentrations. Furthermore, we derive estimates of the probability for a single virion to start host infection and the risks of male-to-female HIV-1 transmission per sexual intercourse. Our work thereby delivers comprehensive quantitative insights into both the molecular principles governing HIV-antibody interactions and the initial steps of mucosal HIV-1 transmission. These insights, alongside the underlying, adaptable modelling framework presented here, will be valuable for supporting in silico pre-trial planning and post-hoc evaluation of HIV-1 vaccination or antibody treatment trials.
High Heritability Is Compatible with the Broad Distribution of Set Point Viral Load in HIV Carriers
Bonhoeffer, Sebastian; Fraser, Christophe; Leventhal, Gabriel E. (2015)
PLoS Pathogens
Set point viral load in HIV patients ranges over several orders of magnitude and is a key determinant of disease progression in HIV. A number of recent studies have reported high heritability of set point viral load implying that viral genetic factors contribute substantially to the overall variation in viral load. The high heritability is surprising given the diversity of host factors associated with controlling viral infection. Here we develop an analytical model that describes the temporal changes of the distribution of set point viral load as a function of heritability. This model shows that high heritability is the most parsimonious explanation for the observed variance of set point viral load. Our results thus not only reinforce the credibility of previous estimates of heritability but also shed new light onto mechanisms of viral pathogenesis.
Strain-specific galactose utilization by commensal E. coli mitigates Salmonella establishment in the gut
Schubert, Christopher; Näf, Jana; Petukhov, Lisa; et al. (2025)
PLoS Pathogens
Salmonella enterica serovar Typhimurium (S. Tm) is a major cause of gastrointestinal diseases worldwide. To date, options for prevention or curative therapy remain limited. The gut microbiota plays a protective role against enteric diseases, particularly in preventing establishment and proliferation of S. Tm. While most research has focused on microbiota-mediated pathogen exclusion during the later, inflammation-dominated stages of infection, little is known about how microbiota members mitigate S. Tm early gut colonization. To address this gap, we conducted 24 h in vivo competitive experiments using S. Tm and different commensal E. coli strains. We observed a significant reduction in pathogen load, which was strain-specific and particularly evident with E. coli 8178. To investigate the underlying molecular mechanisms, we performed an in vivo screen using a rationally designed S. Tm library—which includes a wide range of carbohydrate utilization mutants—both in the absence and presence of E. coli strains. Our findings revealed that E. coli 8178-mediated S. Tm competition was driven by the exploitation of galactose during the early stage of infection. Identifying galactose as a key metabolite in pathogen exclusion by gut microbiota members enhances our mechanistic understanding of microbiota-mediated protection and opens new avenues for developing microbiota- and dietary-based strategies to better control intestinal infections.
TTSS-2 virulence drives inflammatory destruction of the gut epithelial barrier and modulates inflammatory response profiles in the Salmonella-infected mouse gut
Enz, Ursina; Gül, Ersin; Maurer, Luca; et al. (2025)
PLoS Pathogens
Salmonella enterica serovar Typhimurium (S. Tm) employs type III secretion system 1 and 2 (TTSS-1 and TTSS-2) to infect host tissues. In orogastric infections, both TTSSs manipulate host responses, increasing mucosal pathogen loads and eliciting inflammation. However, we still do not fully understand how virulence and inflammatory enteropathy are interconnected. Here, we investigate whether TTSS-2-dependent virulence contributes to epithelial barrier disruption and delineate its role in shaping inflammatory response profiles in the mouse gut. Using wild-type and TTSS-2 mutant S. Tm strains in antibiotic-pretreated mouse models, we demonstrate that intestinal epithelial destruction is promoted by TTSS-2 virulence. This effect is observed in both wild-type and immune-deficient C57BL/6J mice. Transcriptomic profiling together with immunofluorescence microscopy analysis reveals that wild-type S. Tm triggers a distinct, yet amplified immune response compared to a TTSS-2 mutant which is characterized by enhanced phagocyte recruitment and a unique transcriptional signature. These findings underscore the role of TTSS-2-mediated virulence in S. Tm gut infection, shaping distinct inflammatory microenvironments with potential implications for host-pathogen interaction studies.
Zoonotic hepatitis E virus spreads through environmental routes in pig herds–A phylodynamic analysis
Meester , Marina; Valenzuela Agüí, Cecilia; Tobias , Tijs J.; et al. (2025)
PLoS Pathogens
Worldwide, many pig farms are affected by hepatitis E virus (HEV) genotype 3, a zoonotic virus that causes hepatitis in humans. People can become infected after eating contaminated pork, making HEV control in pig farms crucial for public health. However, knowledge of HEV transmission dynamics and control options within farms is limited. Our findings reveal that HEV persists in the farm environment, enabling transmission between pigs separated in space and time. We investigated HEV transmission on two Dutch finishing farms for nine months in 2022. In both farms, samples from three compartments (confined rooms), holding 12 pens with pigs each, were collected and tested weekly across three batches (consecutively housed groups of pigs). Additionally, at least one sample per HEV-positive pen was sequenced per batch, retrieving 89 near-complete sequences. We integrated epidemiological data on duration and timing of infection with phylogenetic data to quantify transmission. We observed phylogenetic clustering of pens per compartment in both farms. In farm A, some sequences from different compartments and different batches also clustered, suggesting transmission between pigs housed separately. In farm B, only one compartment became HEV-positive during one batch. Within that compartment, between-pen transmission was efficient, with an effective reproduction number (Re) of 3.6 (95% HPD interval 1.3–6.7). The other compartments and batch may have remained HEV-negative thanks to stringent biosecurity measures applied on that farm. In farm A, the Re’s for transmission between pens within and across compartments were not significantly above 1, yet all sampled pens became positive in all batches. A combination of transmission routes, in conjunction with persistence of HEV in the environment, is required to explain why all pens tested positive. These findings show not only how HEV effectively spreads without pigs sharing housing, yet also that reduction of HEV’s zoonotic risk may be achieved by improved biosecurity within farms.
Capacity of Broadly Neutralizing Antibodies to Inhibit HIV-1 Cell-Cell Transmission Is Strain- and Epitope-Dependent
Reh, Lucia; Magnus, Carsten; Schanz, Merle; et al. (2015)
PLoS Pathogens
An increasing number of broadly neutralizing antibodies (bnAbs) are considered leads for HIV-1 vaccine development and novel therapeutics. Here, we systematically explored the capacity of bnAbs to neutralize HIV-1 prior to and post-CD4 engagement and to block HIV-1 cell-cell transmission. Cell-cell spread is known to promote a highly efficient infection with HIV-1 which can inflict dramatic losses in neutralization potency compared to free virus infection. Selection of bnAbs that are capable of suppressing HIV irrespective of the transmission mode therefore needs to be considered to ascertain their in vivo activity in therapeutic use and vaccines. Employing assay systems that allow for unambiguous discrimination between free virus and cell-cell transmission to T cells, we probed a panel of 16 bnAbs for their activity against 11 viruses from subtypes A, B and C during both transmission modes. Over a wide range of bnAb-virus combinations tested, inhibitory activity against HIV-1 cell-cell transmission was strongly decreased compared to free virus transmission. Activity loss varied considerably between virus strains and was inversely associated with neutralization of free virus spread for V1V2- and V3-directed bnAbs. In rare bnAb-virus combinations, inhibition for both transmission modes was comparable but no bnAb potently blocked cell-cell transmission across all probed virus strains. Mathematical analysis indicated an increased probability of bnAb resistance mutations to arise in cell-cell rather than free virus spread, further highlighting the need to block this pathway. Importantly, the capacity to efficiently neutralize prior to CD4 engagement correlated with the inhibition efficacy against free virus but not cell-cell transmitted virus. Pre-CD4 attachment activity proved strongest amongst CD4bs bnAbs and varied substantially for V3 and V1V2 loop bnAbs in a strain-dependent manner. In summary, bnAb activity against divergent viruses varied depending on the transmission mode and differed depending on the window of action during the entry process, underscoring that powerful combinations of bnAbs are needed for in vivo application.
Galactosaminogalactan, a New Immunosuppressive Polysaccharide of Aspergillus fumigatus
Fontaine, Thierry; Delangle, Aurélie; Simenel, Catherine; et al. (2011)
PLoS Pathogens
A new polysaccharide secreted by the human opportunistic fungal pathogen Aspergillus fumigatus has been characterized. Carbohydrate analysis using specific chemical degradations, mass spectrometry, 1H and 13C nuclear magnetic resonance showed that this polysaccharide is a linear heterogeneous galactosaminogalactan composed of α1-4 linked galactose and α1-4 linked N-acetylgalactosamine residues where both monosacharides are randomly distributed and where the percentage of galactose per chain varied from 15 to 60%. This polysaccharide is antigenic and is recognized by a majority of the human population irrespectively of the occurrence of an Aspergillus infection. GalNAc oligosaccharides are an essential epitope of the galactosaminogalactan that explains the universal antibody reaction due to cross reactivity with other antigenic molecules containing GalNAc stretches such as the N-glycans of Campylobacter jejuni. The galactosaminogalactan has no protective effect during Aspergillus infections. Most importantly, the polysaccharide promotes fungal development in immunocompetent mice due to its immunosuppressive activity associated with disminished neutrophil infiltrates.
Immunogenetic Mechanisms Driving Norovirus GII.4 Antigenic Variation
Lindesmith, Lisa C.; Beltramello, Martina; Donaldson, Eric F.; et al. (2012)
PLoS Pathogens
Noroviruses are the principal cause of epidemic gastroenteritis worldwide with GII.4 strains accounting for 80% of infections. The major capsid protein of GII.4 strains is evolving rapidly, resulting in new epidemic strains with altered antigenic potentials. To test if antigenic drift may contribute to GII.4 persistence, human memory B cells were immortalized and the resulting human monoclonal antibodies (mAbs) characterized for reactivity to a panel of time-ordered GII.4 virus-like particles (VLPs). Reflecting the complex exposure history of the volunteer, human anti-GII.4 mAbs grouped into three VLP reactivity patterns; ancestral (1987–1997), contemporary (2004–2009), and broad (1987–2009). NVB 114 reacted exclusively to the earliest GII.4 VLPs by EIA and blockade. NVB 97 specifically bound and blocked only contemporary GII.4 VLPs, while NBV 111 and 43.9 exclusively reacted with and blocked variants of the GII.4.2006 Minerva strain. Three mAbs had broad GII.4 reactivity. Two, NVB 37.10 and 61.3, also detected other genogroup II VLPs by EIA but did not block any VLP interactions with carbohydrate ligands. NVB 71.4 cross-neutralized the panel of time-ordered GII.4 VLPs, as measured by VLP-carbohydrate blockade assays. Using mutant VLPs designed to alter predicted antigenic epitopes, two evolving, GII.4-specific, blockade epitopes were mapped. Amino acids 294–298 and 368–372 were required for binding NVB 114, 111 and 43.9 mAbs. Amino acids 393–395 were essential for binding NVB 97, supporting earlier correlations between antibody blockade escape and carbohydrate binding variation. These data inform VLP vaccine design, provide a strategy for expanding the cross-blockade potential of chimeric VLP vaccines, and identify an antibody with broadly neutralizing therapeutic potential for the treatment of human disease. Moreover, these data support the hypothesis that GII.4 norovirus evolution is heavily influenced by antigenic variation of neutralizing epitopes and consequently, antibody-driven receptor switching; thus, protective herd immunity is a driving force in norovirus molecular evolution.
IL-21 Restricts Virus-driven Treg Cell Expansion in Chronic LCMV Infection
Schmitz, Iwana; Schneider, Christoph; Fröhlich, Anja; et al. (2013)
PLoS Pathogens
Foxp3+ regulatory T (Treg) cells are essential for the maintenance of immune homeostasis and tolerance. During viral infections, Treg cells can limit the immunopathology resulting from excessive inflammation, yet potentially inhibit effective antiviral T cell responses and promote virus persistence. We report here that the fast-replicating LCMV strain Docile triggers a massive expansion of the Treg population that directly correlates with the size of the virus inoculum and its tendency to establish a chronic, persistent infection. This Treg cell proliferation was greatly enhanced in IL-21R−/− mice and depletion of Treg cells partially rescued defective CD8+ T cell cytokine responses and improved viral clearance in some but not all organs. Notably, IL-21 inhibited Treg cell expansion in a cell intrinsic manner. Moreover, experimental augmentation of Treg cells driven by injection of IL-2/anti-IL-2 immune complexes drastically impaired the functionality of the antiviral T cell response and impeded virus clearance. As a consequence, mice became highly susceptible to chronic infection following exposure to low virus doses. These findings reveal virus-driven Treg cell proliferation as potential evasion strategy that facilitates T cell exhaustion and virus persistence. Furthermore, they suggest that besides its primary function as a direct survival signal for antiviral CD8+ T cells during chronic infections, IL-21 may also indirectly promote CD8+ T cell poly-functionality by restricting the suppressive activity of infection-induced Treg cells.
NK cells negatively regulate CD8 T cells via natural cytotoxicity receptor (NCR) 1 during LCMV infection
Pallmer, Katharina; Barnstorf, Isabel; Baumann, Nicolas S.; et al. (2019)
PLoS Pathogens
Besides their function in recognizing cancerous and virally infected cells, natural killer (NK) cells have the potential to shape adaptive immune responses. However, the mechanisms employed by NK cells to negatively regulate virus-specific CD8 T cell responses remain to be fully defined. Using activating receptor natural cytotoxicity receptor (NCR) 1 deficient (NCR1gfp/gfp) mice, we found increased numbers of virus-specific CD8 T cells, leading to enhanced virus control during acute LCMV infection. Furthermore, virus-specific CD8 T cells were more activated in the absence of NCR1, resulting in exacerbated immunopathology, documented by weight loss, and superior virus control early during chronic LCMV infection. Transfer experiments of virus-specific CD8 T cells into NCR1 deficient hosts revealed a direct cross talk between NK and CD8 T cells. Studies on the splenic microarchitecture revealed pronounced disorganization of T cells in infected NCR1gfp/gfp mice, resulting in enhanced immunopathology and disruption of the T cell niche upon chronic LCMV infection. Our data show a novel pathway employed by NK cells to regulate antiviral CD8 T cell responses, namely direct recognition and elimination of activated CD8 T cells via NCR1 early during infection to protect the host from an overshooting T cell response.

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