Biology subjects

Ball, B.

Publications and source records attributed to Ball, B..

7 recordsLinked to original sources

bioRxiv2026

Systematic Infectome-Phenome Profiling Reveals Cryptococcal Infection-Associated Proteins Driving Immune System Remodeling and Immunization Potential

Mortality and morbidity associated with invasive fungal infections continue to rise, driven by the emergence of new pathogens, increasing antifungal resistance, and expanding immunocompromised populations. Despite this growing threat, fungal biology lacks scalable, unbiased strategies to link infection-responsive fungal proteins to functional outcomes that drive virulence and immune modulation. Here, we present an integrated infectome-phenome discovery platform that combines high resolution mass spectrometry-based proteomics with systematic phenotypic profiling to globally interrogate Cryptococcus neoformans-macrophage interactions. This approach reveals coordinated host immune suppression alongside complementary fungal virulence programs and enables the unbiased prioritization of infection-associated fungal proteins. Systematic phenome fingerprinting of candidate mutant strains resolves two functional classes of putative therapeutic relevance: antifungal and antivirulence, with in vitro characterizations corroborated with a murine model of cryptococcosis. Prioritization of a conserved, previously uncharacterized virulence-associated protein, CipC, uncovers altered extracellular vesicle composition and enhanced antigenic properties. Immunization with CipC-derived vesicles elicits a robust and diversified host immune response, implicating fungal extracellular vesicles in immune remodeling and host priming. Together, these findings establish a broadly applicable framework for systematically identifying and functionally characterizing fungal drivers of infection for therapeutic and immunological target discovery with relevance across diverse human fungal pathogens.

microbiology↗

bioRxiv2025

Spatiotemporal dynamics of cryptococcal infection reveal novel immune modulatory mechanisms and antifungal targets

The threat and incidence of fungal diseases are increasing, as is the severity and mortality rates associated with these infections. New strategies to combat fungal infections are urgently needed to overcome rising rates of resistance and the emergence of new pathogens. To promote invasion within a host, fungi use highly adapted and regulated virulence factors, and, in turn, the host adopts an active and dynamic immune response to suppress infection. Understanding the interplay between these processes is crucial to move fungal disease management and treatment forward and improve global health outcomes. Within the present study, we tackle these challenges using state-of-the-art mass spectrometry instrumentation to explore proteome remodeling during active infection of Cryptococcus neoformans at an unprecedented depth with spatiotemporal resolution. Our prioritization of three host organs (i.e., lungs, brain, spleen) critical to initiation, progression, and response of disease discovers tissue-specific remodeling across time. Within the lungs, we revealed early and sustained activation of the host immune response integrated with characterization of a promising new antifungal target, and we propose the discovery of a competitive inhibitor for functional target disruption. Within the brain, proteome remodeling aligns with disease progression, and we define a new mechanistic role for haptoglobin in fungal cell modulation, as well as showcasing an adaptive survival response of C. neoformans within an hypoxic environment. Within the spleen, we reveal new dynamics of immune system activation upon cryptococcal infection. Overall, we provide the deepest integrated view of cryptococcal disease dynamics across temporal and spatial scales, revealing unrecognized mechanisms of host immunity and fungal pathogenesis that offer new avenues for targeted therapeutic intervention and disease management.

microbiology↗

bioRxiv2023

Integration of homeostatic and adaptive oxidative responses by a putative co-chaperone, Wos2, drives fungal virulence in cryptococcosis

The increasing prevalence of invasive fungal pathogens are dramatically changing the clinical landscape of infectious diseases and are an imminent burden to public health that lack the resources (i.e., robust antifungals) to tackle this threat. Specifically, the human opportunistic pathogen, Cryptococcus neoformans, expresses elaborate virulence mechanisms and is equipped with sophisticated adaptation strategies to survive in harsh host environments. In this study, we extensively characterize Wos2, an Hsp90 co-chaperone homologue, featuring bilateral functioning for both cryptococcal adaptation and virulence strategies. Here, we evaluated the proteome and secretome signatures of Wos2 in enriched and infection-mimicking conditions to reveal a Wos2-dependent regulation of oxidative stress response. The wos2{Delta} strain reports defective intracellular and extracellular antioxidant protection systems measurable through a decreased abundance of critical antioxidant enzymes and reduced growth in the presence of peroxide stress. Additional Wos2-associated stress phenotypes were observed upon fungal challenge with heat shock, osmotic, and cell wall stressors. We demonstrate the importance of Wos2 for C. neoformans intracellular lifestyle during in vitro macrophage infection and provide evidence for wos2{Delta} reduced phagosomal replication levels. Accordingly, wos2{Delta} featured significantly reduced virulence in a murine model of cryptococcosis. Our study highlights a vulnerable point in the fungal chaperone network that offers a powerful druggable opportunity to interfere with both virulence and fitness. Author SummaryThe global impact of fungal pathogens, both emerging and emerged, is undeniable and the alarming increase in antifungal resistance rates hampers our ability to protect the global population from deadly infections. For cryptococcal infections, a limited arsenal of antifungals and resistance demands alternative therapeutic strategies, including an anti-virulence approach, which disarms the pathogen of critical virulence factors, empowering the host to remove the pathogen and clear the infection. To this end, we apply state-of-the-art mass spectrometry-based proteomics to interrogate the impact of a recently defined novel co-chaperone, Wos2, towards cryptococcal virulence using in vitro and in vivo models of infection. We defined global proteome and secretome remodeling driven by the protein and uncovered a novel role in modulating the fungal oxidative stress response. Complementation of the proteome findings with in vitro infectivity assays demonstrated a protective role for Wos2 within the macrophage phagosome, influencing fungal replication and survival. These results underscore differential cryptococcal survivability and weakened patterns of dissemination in the absence of wos2. Overall, our study establishes Wos2 as an important contributor to fungal pathogenesis and warrants further research into critical proteins within global stress response networks as potential druggable targets to reduce fungal virulence and clear the infection.

microbiology↗

bioRxiv2021

Expansion of tissue-resident CD8+ T cells and CD4+ Th17 cells in the nasal mucosa following mRNA COVID-19 vaccination

Vaccines against SARS-CoV-2 have shown high efficacy in clinical trials, yet a full immunologic characterization of these vaccines, particularly within the upper respiratory tract, remains lacking. We enumerated and phenotyped T cells in nasal mucosa and blood before and after vaccination with the Pfizer-BioNTech COVID-19 vaccine (n =21). Tissue-resident memory (Trm) CD8+ T cells expressing CD69+CD103+ expanded [~]12 days following the first and second doses, by 0.31 and 0.43 log10 cells per swab respectively (p=0.058 and p=0.009 in adjusted linear mixed models). CD69+CD103+CD8+ T cells in the blood decreased post-vaccination. Similar increases in nasal CD8+CD69+CD103-T cells were observed, particularly following the second dose. CD4+ Th17 cells were also increased in abundance following both doses. Following stimulation with SARS-CoV-2 spike peptides, CD8+ T cells increased expression of CD107a and CD154. These data suggest that nasal T cells may be induced and contribute to the protective immunity afforded by this vaccine.

immunology↗

bioRxiv2019

Environmental (e)DNA detection of the invasive pink salmon Oncorhynchus gorbuscha during the 2017 Norwegian invasion

The pink salmon Oncorhynchus gorbuscha was introduced from its native range in the Pacific to Northwest Russia several times since the 1950s. While this species has been regularly observed in rivers in Northern Norway since that time, there has been an upsurge in the numbers of odd-year O. gorbuscha individuals observed in rivers in southern Norway in recent years, and particularly in 2017. Although the wide-scale effects of this species presence are currently uncertain, there are concerns regarding potential competition between O. gorbuscha and native species - most notably the Atlantic salmon Salmo salar. Environmental (e)DNA is becoming a widely used tool to monitor rare and invasive species in aquatic environments. In the present pilot study, primers and a probe were developed to detect O. gorbuscha from eDNA samples taken from a Norwegian river system where the species was observed. Water samples were taken at both upstream and downstream locations of the Lysakerelva river during Autumn 2017 (to coincide with spawning) and during late Spring 2018. Autumn samples were positive for O. gorbuscha at both sampling locations, whereas Spring samples showed positive detection of this species in the upstream region of the river, when smolt should have left, or be in the process of leaving the river. These findings reveal that eDNA-based methods can be used detect the presence of O. gorbuscha during their spawning season. This suggests that odd-year populations have the potential to become established in the studied river system. We recommend that eDNA sampling is repeated to determine whether individuals of this odd-year population have survived at sea and return to spawn. Our assay specificity tests indicate that the tools developed in the present study can be used for detection of O. gorbuscha in both Norwegian and other European river systems where presence/absence data is required. We also suggest some modifications to our methodology that may improve upon the detection capabilities of O. gorbuscha using eDNA.

genetics↗

bioRxiv2019

Field application of an eDNA assay for the threatened white-clawed crayfish Austropotamobius pallipes

The white-clawed crayfish Austropotamobius pallipes has undergone extensive declines within its native range in the last century. Because of its threatened status, European legislation requires the species to be regularly monitored and that Special Areas of Conservation (SACs) be designated for it. Knowledge on the distribution of this species is vital for addressing these needs. This study presents an environmental (e)DNA assay to detect A. pallipes in water samples, based on the mitochondrial cytochrome oxidase I (COI) gene, utilizing species-specific primers, a minor groove binding (MGB) probe and quantitative PCR. The results of this study indicate that eDNA is an effective tool for detecting A. pallipes in a lotic system, and could provide a valuable, non-invasive method for determining the distribution of this species.

genetics↗

bioRxiv2017

A quantitative PCR based environmental DNA assay for detecting Atlantic salmon (Salmo salar L.)

O_LIThe Atlantic salmon (Salmo salar L.) has worldwide ecological, cultural and economic importance. The species has undergone extensive decline across its native range, yet concerns have been raised about its invasive potential in the Pacific. Knowledge on the distribution of this species is vital for addressing conservation goals.\nC_LIO_LIThis study presents an eDNA assay to detect S. salar in water samples, using quantitative PCR (qPCR) technology. Species-specific primers and a minor groove binding (MGB) probe were designed for the assay, based on the mitochondrial cytochrome oxidase I (COI) gene.\nC_LIO_LIThe results of this study indicate that eDNA is a highly sensitive tool for detecting S. salar in situ, and could potentially provide an alternative, non-invasive method for determining the distribution of this species.\nC_LI

genetics↗