Breaking down barriers to COPD management in primary care: applying the updated 2023 Canadian Thoracic Society guideline for pharmacotherapy.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent yet under-recognized and sub-optimally managed disease that is associated with substantial morbidity and mortality. Primary care providers (PCPs) are at the frontlines of COPD management, and they play a critical role across the full spectrum of the COPD patient journey from initial recognition and diagnosis to treatment optimization and referral to specialty care. The Canadian Thoracic Society (CTS) recently updated their guideline on pharmacotherapy in patients with stable COPD, and there are several key changes that have a direct impact on COPD management in the primary care setting.

Immunological correlates of protection mediated by a whole organism, , vaccine deficient in chitosan.

Unlabelled: The global burden of infections due to the pathogenic fungus is substantial in persons with low CD4 T-cell counts. Previously, we deleted three chitin deacetylase genes from to create a chitosan-deficient, avirulent strain, designated as , which, when used as a vaccine, protected mice from challenge with virulent strain KN99. Here, we explored the immunological basis for protection.

Protection against experimental cryptococcosis elicited by Cationic Adjuvant Formulation 01-adjuvanted subunit vaccines.

The fungal infection, cryptococcosis, is responsible for >100,000 deaths annually. No licensed vaccines are available. We explored the efficacy and immune responses of subunit cryptococcal vaccines adjuvanted with Cationic Adjuvant Formulation 01 (CAF01).

Immunological correlates of protection mediated by a whole organism vaccine deficient in chitosan.

Unlabelled: The global burden of infections due to the pathogenic fungus is substantial in persons with low CD4 T cell counts. Previously, we deleted three chitin deacetylase genes from to create a chitosan-deficient, avirulent strain, designated which, when used as a vaccine, protected mice from challenge with virulent strain KN99. Here, we explored the immunological basis for protection.

Chitosan-Deficient Cryptococcus as Whole-Cell Vaccines.

Creating a safe and effective vaccine against infection by the fungal pathogen Cryptococcus neoformans is an appealing option that complements the discovery of new small molecule antifungals. Recent animal studies have yielded promising results for a variety of vaccines that include live-attenuated and heat-killed whole-cell vaccines, as well as subunit vaccines formulated around recombinant proteins. Some of the recombinantly engineered cryptococcal mutants in the chitosan biosynthesis pathway are avirulent and very effective at conferring protective immunity.

A glucan-particle based tularemia subunit vaccine induces T-cell immunity and affords partial protection in an inhalation rat infection model.

Tularemia is a zoonotic disease caused by the facultative intracellular gram-negative bacterium Francisella tularensis. F. tularensis has a very low infection dose by the aerosol route which can result in an acute, and potentially lethal, infection in humans.

Protection against experimental cryptococcosis elicited by Cationic Adjuvant Formulation 01-adjuvanted subunit vaccines.

The fungal infection, cryptococcosis, is responsible for >100,000 deaths annually. No licensed vaccines are available. We explored the efficacy and immune responses of subunit cryptococcal vaccines adjuvanted with Cationic Adjuvant Formulation 01 (CAF01).

Immune evasion by in vaccinated mice coinfected with .

and , the etiologic agents of cryptococcosis, cause over 100,000 deaths worldwide every year, yet no cryptococcal vaccine has progressed to clinical trials. In preclinical studies, mice vaccinated with an attenuated strain of deleted of three cryptococcal chitin deacetylases (-ΔΔΔ) were protected against a lethal challenge with strain KN99. While ΔΔΔ extended the survival of mice infected with strain R265 compared to unvaccinated groups, we were unable to demonstrate fungal clearance as robust as that seen following KN99 challenge.

Dysregulated pulmonary inflammatory responses exacerbate the outcome of secondary aspergillosis following influenza.

Severe influenza is a risk factor for fatal invasive pulmonary aspergillosis; however, the mechanistic basis for the lethality is unclear. Utilizing an influenza-associated pulmonary aspergillosis (IAPA) model, we found that mice infected with influenza A virus followed by had 100% mortality when superinfected during the early stages of influenza but survived at later stages. While superinfected mice had dysregulated pulmonary inflammatory responses compared to controls, they had neither increased inflammation nor extensive fungal growth.

Dysregulated Pulmonary Inflammatory Responses Exacerbate the Outcome of Secondary Aspergillosis Following Influenza.

Unlabelled: Inhalation of airborne conidia of the ubiquitous fungus commonly occurs but invasive aspergillosis is rare except in profoundly immunocompromised persons. Severe influenza predisposes patients to invasive pulmonary aspergillosis by mechanisms that are poorly defined. Using a post-influenza aspergillosis model, we found that superinfected mice had 100% mortality when challenged with conidia on days 2 and 5 (early stages) of influenza A virus infection but 100% survival when challenged on days 8 and 14 (late stages).

One Step Purification-Vaccine Delivery System.

Glucan particles (GPs) are hollow, porous 3-5 µm microspheres derived from the cell walls of Baker's yeast (). Their 1,3-β-glucan outer shell allows for receptor-mediated uptake by macrophages and other phagocytic innate immune cells expressing β-glucan receptors. GPs have been used for the targeted delivery of a wide range of payloads, including vaccines and nanoparticles, encapsulated inside the hollow cavity of GPs.

An efficient (nano) silica - In glucan particles protein encapsulation approach for improved thermal stability.

Glucan particles (GPs) are hollow, porous microspheres derived from Saccharomyces cerevisiae (Baker's yeast). The hollow cavity of GPs allows for efficient encapsulation of different types of macromolecules and small molecules. The β-1,3-D-glucan outer shell provides for receptor-mediated uptake by phagocytic cells expressing β-glucan receptors and uptake of particles containing encapsulated proteins elicit protective innate and acquired immune responses against a wide range of pathogens.

Immunological correlates of protection following vaccination with glucan particles containing Cryptococcus neoformans chitin deacetylases.

Vaccination with glucan particles (GP) containing the Cryptococcus neoformans chitin deacetylases Cda1 and Cda2 protect mice against experimental cryptococcosis. Here, immunological correlates of vaccine-mediated protection were explored. Studies comparing knockout and wild-type mice demonstrated CD4 T cells are crucial, while B cells and CD8 T cells are dispensable.

Similar evolutionary trajectories in an environmental isolate after human and murine infection.

A pet cockatoo was the suspected source of recovered from an immunocompromised patient with cryptococcosis based on molecular analyses available in 2000. Here, we report whole genome sequence analysis of the clinical and cockatoo strains. Both are closely related MATα strains belonging to the VNII lineage, confirming that the human infection likely originated from pet bird exposure.

They shall not grow mold: Soldiers of innate and adaptive immunity to fungi.

Fungi are ubiquitous commensals, seasoned predators, and important agents of emerging infectious diseases [1]. The immune system assumes the essential responsibility for responding intelligently to the presence of known and novel fungi to maintain host health. In this Review, we describe the immune responses to pathogenic fungi and the varied array of fungal agents confronting the vertebrate host within the broader context of fungal and animal evolution.

Cross-reactivity between vaccine antigens from the chitin deacetylase protein family improves survival in a mouse model of cryptococcosis.

Meningitis due to the fungal pathogen is estimated to cause nearly 200,000 deaths annually, mostly in resource-limited regions. We previously identified cryptococcal protein antigens which, when delivered in glucan particles, afford vaccine-mediated protection against an otherwise lethal infection. Many of these proteins exhibit significant homology to other similar cryptococcal proteins leading us to hypothesize that protection may be augmented by immunologic cross-reactivity to multiple members of a protein family.

Expanded Access Use of Rezafungin for Salvage Therapy of Invasive Infection: A Case Report.

Rezafungin is a semisynthetic, long-acting echinocandin with broad-spectrum activity against many species and species, including a subset of drug-resistant strains. It is currently in phase III trials and was found to be safe and effective for the treatment of candidemia and/or invasive infections in a phase II trial. However, there are no long-term safety or efficacy data.

Protection of Mice against Experimental Cryptococcosis by Synthesized Peptides Delivered in Glucan Particles.

The high global burden of cryptococcosis has made development of a protective vaccine a public health priority. We previously demonstrated that a vaccine composed of recombinant Cryptococcus neoformans chitin deacetylase 2 (Cda2) delivered in glucan particles (GPs) protects BALB/c and C57BL/6 mice from an otherwise lethal challenge with a highly virulent C. neoformans strain.

Cda1 and Cda2 coordinate deacetylation of chitin during infection to control fungal virulence.

Chitosan, a deacetylated form of chitin, is required for the virulence of . There are three chitin deacetylase genes (CDA) that are essential for chitosan production, and deletion of all three genes results in the absence of chitosan, loss of virulence, and induction of a protective host response when used as a vaccine. Cda1 plays a major role in deacetylating chitin during pulmonary infection of CBA/J mice.

Lung eosinophils elicited during allergic and acute aspergillosis express RORγt and IL-23R but do not require IL-23 for IL-17 production.

Exposure to the mold, Aspergillus, is ubiquitous and generally has no adverse consequences in immunocompetent persons. However, invasive and allergic aspergillosis can develop in immunocompromised and atopic individuals, respectively. Previously, we demonstrated that mouse lung eosinophils produce IL-17 in response to stimulation by live conidia and antigens of A.

The "Black Fungus" in India: The Emerging Syndemic of COVID-19-Associated Mucormycosis.

A surge in cases of mucormycosis is occurring during India's catastrophic “second wave” of the COVID- 19 pandemic. Multiple actions are urgently needed to prevent and treat this life-threatening disease.

Structural basis of Blastomyces Endoglucanase-2 adjuvancy in anti-fungal and -viral immunity.

The development of safe subunit vaccines requires adjuvants that augment immunogenicity of non-replicating protein-based antigens. Current vaccines against infectious diseases preferentially induce protective antibodies driven by adjuvants such as alum. However, the contribution of antibody to host defense is limited for certain classes of infectious diseases such as fungi, whereas animal studies and clinical observations implicate cellular immunity as an essential component of the resolution of fungal pathogens.

Vaccines for human fungal diseases: close but still a long way to go.

Despite the substantial global burden of human fungal infections, there are no approved fungal vaccines to protect at risk individuals. Here, we review the progress that has been made and the challenges that lie ahead in the quest towards efficacious fungal vaccines. In mouse studies, protection has been achieved with vaccines directed against fungal pathogens, including species of Candida, Cryptococcus, and Aspergillus, that most commonly cause life-threatening human disease.

All You Need to Know and More about the Diagnosis and Management of Rare Mold Infections.

Invasive mold infections caused by molds other than spp. or Mucorales are emerging. The reported prevalences of infection due to these rare fungal pathogens vary among geographic regions, driven by differences in climatic conditions, susceptible hosts, and diagnostic capabilities.