Biology subjects

Okaa, U. J.

Publications and source records attributed to Okaa, U. J..

4 recordsLinked to original sources

bioRxiv2026

Combination adjuvants drive long lived plastic Th17 cells that convert to multi-functional Th1 cells and protect mice against fungal infection

Th1 cells are viewed as a cornerstone of immunity to fungi and other intracellular pathogens. Despite the widely accepted role of Th1 cells in antifungal resistance, the development of protective strategies harnessing them is stunted by a limited understanding of how best to promote their development. We and others have reported a requisite role for Th17 cells in resistance to fungi. We have long been puzzled about how to reconcile seminal roles for both Th1 and Th17 subsets. Here we report that Th17 cells convert into polyfunctional Th1 cells producing multiple cytokines, including IFN-{gamma}, TNF and GM-CSF when we used adjuvant formulations that include glucopyranosyl lipid adjuvant (GLA) to enhance antifungal immunity. GLA induced plastic Th17 cells that convert into polyfunctional Th1 memory cells.

immunology↗

bioRxiv2025

Endoglucanase-2 (Eng2), a conserved immunodominant antigen in dimorphic fungi that elicits immunity and resistance during infection

Herein, we describe a conserved surface and cell wall protein, Endoglucanase 2 (Eng2), expressed on the etiological agents that cause the endemic systemic mycoses of North America - Blastomyces, Coccidioides and Histoplasma. We demonstrate that despite sequence variation of the protein across these related fungi, exposure to Eng2 vaccinates and protects inbred and humanized HLA-DR4 strains of mice against lethal experimental infections with these fungi by eliciting adaptive immunity mediated by CD4 T cells. We also show that CD4 T cell precursors against Eng2 are detectable in naive individuals and that patients who have recovered from these infections evince a memory and recall CD4 T cell response to Eng2 and its immunodominant epitopes that we have mapped. We create and catalogue new tools and information such as immunodominant peptide epitopes of Eng2 from each fungus recognized by inbred mice and human subjects and we engineer novel peptide-MHC II tetramers for tracking T cells in inbred and HLA-DR4 humanized mice that will be useful for those who study these infections in mice and humans. Lastly, because most patients demonstrate memory and recall responses against Eng2, our work oRers new tools for diagnosis of this collection of infectious diseases across North America.

immunology↗

bioRxiv2021

Aspergillus fumigatus drives tissue damage via iterative assaults upon mucosal integrity and immune homeostasis

The human lung is constantly exposed to Aspergillus fumigatus spores, the most prevalent worldwide cause of fungal respiratory disease. Pulmonary tissue damage is a unifying feature of Aspergillus-related diseases; however, the mechanistic basis of damage is not understood. In the lungs of susceptible hosts A. fumigatus undergoes an obligatory morphological switch involving spore germination and hyphal growth. We modelled A. fumigatus infection in cultured A549 human pneumocytes, capturing phosphoactivation status of five host signalling pathways, nuclear translocation & DNA binding of eight host transcription factors, and expression of nine host response proteins over six time points encompassing exposures to live fungus and the secretome thereof. The resulting dataset, comprised of more than 1000 data points, reveals that pneumocytes mount differential responses to A. fumigatus spores, hyphae and soluble secreted products via the NF-kB, JNK, and JNK + p38 pathways respectively. Importantly, via selective degradation of host pro-inflammatory (IL-6 and IL-8) cytokines and growth factors (FGF-2), fungal secreted products reorchestrate the host response to fungal challenge as well as driving multiparametric epithelial damage, culminating in cytolysis. Dysregulation of NF-kB signalling, involving iterative stimulation of canonical and non-canonical signalling, was identified as a significant feature of host damage both in vitro and in a mouse model of invasive aspergillosis. Our data demonstrate that composite tissue damage results from iterative exposures to different fungal morphotypes and secreted products and suggest that modulation of host responses to fungal challenge might represent a unified strategy for therapeutic control of pathologically distinct types of Aspergillus-related disease. IMPORTANCEPulmonary aspergillosis is a spectrum of diseases caused primarily by Aspergillus fumigatus. This fungus is ubiquitous in the environment and grows as a mold, which harbors and disperses spores into the environment. Like other airborne pathogens, the lung mucosa is the first point of contact with the fungus post inhalation. The outcome and severity of disease depends on the host-fungal interaction at the lung interface. We studied how the human lung interacts with spore, germ tube and hyphae growth forms to understand the sequence and dynamics of the early events, which are critical drivers of disease development and progression. Our work is significant in identifying, in response to fungal secreted products, non-canonical NF-kB activation via RelB as being a driving factor in fungus-mediated lung damage. This process could be modulated therapeutically to protect the integrity of infected lung mucosae.

microbiology↗

bioRxiv2021

Combination adjuvants enhance recombinant protein vaccine protection against fungal infection

The development of effective vaccines against fungal infections requires the induction of protective, pathogen-specific cell mediated immune responses. Here, we asked whether combination adjuvants based on delta inulin (Advax) formulated with TLR agonists could improve vaccine protection mediated by a fungal recombinant protein, Bl-Eng2, which itself harbors an immunodominant antigen and Dectin-2 agonist/adjuvant. We found that Bl-Eng2 formulated with Advax3 containing TLR9 agonist or Advax8, containing TLR4 agonist, provided the best protection against pulmonary infection with Blastomyces dermatitidis, being more effective than Freunds complete adjuvant or Adjuplex. Advax3 was most efficient in inducing IFN-{gamma} and IL-17 producing antigen-specific T cells that migrated to the lung upon Blastomyces dermatitidis infection. Mechanistic studies revealed Bl-Eng2/Advax3 protection was tempered by neutralization of IL-17 and particularly IFN-{gamma}. Likewise, greater numbers of lung-resident T cells producing IFN-{gamma}, IL-17, or IFN-{gamma}+ and IL-17+ correlated with fewer fungi recovered from lung. Protection was maintained after depletion of CD4+ T cells, partially reduced by depletion of CD8+ T cells, and completely eliminated after depletion of both CD4+ and CD8+ T cells. We conclude that Bl-Eng2 formulated with Advax3 is promising for eliciting vaccine-induced antifungal immunity, through a previously uncharacterized mechanism involving CD8+ and also CD4+ T cells producing IFN-{gamma} and/or IL-17. Although no licensed vaccine exists as yet against any fungal disease, these findings indicate the importance of adjuvant selection for the development of effective fungal vaccines. IMPORTANCEFungal disease remains a challenging clinical and public health problem. Despite medical advances, invasive fungal infections have skyrocketed over the last decade and pose a mounting health threat in immune-competent and -deficient hosts with worldwide mortality rates ranking 7th, even ahead of tuberculosis. The development of safe, effective vaccines remains a major hurdle for fungi. Critical barriers to progress include the lack of defined fungal antigens and suitable adjuvants. Our research is significant in identifying adjuvant combinations that elicit optimal vaccine-induced protection when formulated with a recombinant protective antigen and uncovering the mechanistic bases of the underlaying vaccine protection, which will foster the strategic development of anti-fungal vaccines.

immunology↗