Cryptococcosis remains a significant cause of morbidity and mortality world-wide, particularly among AIDS patients. Yet, to date, there are no licensed vaccines clinically available to treat or ...prevent cryptococcosis. In this review, we provide a rationale to support continued investment in Cryptococcus vaccine research, potential challenges that must be overcome along the way, and a literature review of the current progress underway towards developing a vaccine to prevent cryptococcosis.
Expansion of Cryptococcus in unique patient populations and environmental niches highlights the need for a prophylactic vaccine to prevent cryptococcosis caused by virulent C. neoformans and C. gattii.
Vaccination with heat-killed Cryptococcus mutants containing cell-wall modifications appears to induce protective immune responses against cryptococcosis in mice.
Experimental studies show potential for eliciting long-lasting protective immunity against cryptococcosis in CD4+ T cell-deficient hosts.
Administration of fungal glycolipids, such as glucosylceramide, demonstrates significant protection against subsequent Cryptococcus infection in mice.
Mice vaccinated with an innovative β-glucan antigen-delivery platform containing immune stimulatory Cryptococcus fractions have protective anticryptococcal immune responses against virulent strains of C. neoformans and C. gattii.
Development of vaccines against opportunistic infections is difficult as patients most at risk of developing disease are deficient in aspects of the adaptive immune system. Here, we utilized an ...experimental immunization strategy to induce innate memory in macrophages in vivo. Unlike current trained immunity models, we present an innate memory-like phenotype in macrophages that is maintained for at least 70 days post-immunization and results in complete protection against secondary challenge in the absence of adaptive immune cells. RNA-seq analysis of in vivo IFN-γ primed macrophages revealed a rapid up-regulation of IFN-γ and STAT1 signaling pathways following secondary challenge. The enhanced cytokine recall responses appeared to be pathogen-specific, dependent on changes in histone methylation and acetylation, and correlated with increased STAT1 binding to promoter regions of genes associated with protective anti-fungal immunity. Thus, we demonstrate an alternative mechanism to induce macrophage innate memory in vivo that facilitates pathogen-specific vaccine-mediated immune responses.
Dimorphic fungal pathogens are a significant cause of human disease worldwide. Notably, the dimorphic fungal pathogens within the order Onygenales are considered primary pathogens, causing disease in ...healthy hosts. Current changes in taxonomy are underway due to advances in molecular phylogenetics, population genetics, and new emerging dimorphic fungal pathogens causing human disease. In this review, we highlight evolutionary relationships of dimorphic fungal pathogens that cause human disease within the order Onygenales and provide rationale to support increased investment in studies understanding the evolutionary relationships of these pathogens to improve rapid diagnostics, help identify mechanisms of antifungal resistance, understand adaptation to human host, and factors associated with virulence.
Coccidioidomycosis (Valley fever) is a fungal disease caused by the inhalation of
or
. This neglected disease occurs in the desert areas of the western United States, most notably in California and ...Arizona, where infections continue to rise. Clinically, coccidioidomycosis ranges from asymptomatic to severe pulmonary disease and can disseminate to the brain, skin, bones, and elsewhere. New estimates suggest as many as 350,000 new cases of coccidioidomycosis occur in the United States each year. Thus, there is an urgent need for the development of a vaccine and new therapeutic drugs against
infection. In this review, we discuss the battle against
including the development of potential vaccines, the quest for new therapeutic drugs, and our current understanding of the protective host immune response to
infection.
Coccidioides immitis and Coccidioides posadasii are soil-dwelling fungi of arid regions in North and South America that are responsible for Valley fever (coccidioidomycosis). Forty percent of ...patients with Valley fever exhibit symptoms ranging from mild, self-limiting respiratory infections to severe, life-threatening pneumonia that requires treatment. Misdiagnosis as bacterial pneumonia commonly occurs in symptomatic Valley fever cases, resulting in inappropriate treatment with antibiotics, increased medical costs, and delay in diagnosis. In this proof-of-concept study, we explored the feasibility of developing breath-based diagnostics for Valley fever using a murine lung infection model. To investigate potential volatile biomarkers of Valley fever that arise from host−pathogen interactions, we infected C57BL/6J mice with C. immitis RS (n = 6), C. posadasii Silveira (n = 6), or phosphate-buffered saline (n = 4) via intranasal inoculation. We measured fungal dissemination and collected bronchoalveolar lavage fluid (BALF) for cytokine profiling and for untargeted volatile metabolomics via solid-phase microextraction (SPME) and two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC×GC-TOFMS). We identified 36 volatile organic compounds (VOCs) that were significantly correlated (p < 0.05) with cytokine abundance. These 36 VOCs clustered mice by their cytokine production and were also able to separate mice with moderate-to-high cytokine production by infection strain. The data presented here show that Coccidioides and/or the host produce volatile metabolites that may yield biomarkers for a Valley fever breath test that can detect coccidioidal infection and provide clinically relevant information on primary pulmonary disease severity.
The rapid evolution of SARS-CoV-2 variants highlights the need for new therapies to prevent disease spread. SARS-CoV-2, like SARS-CoV-1, uses the human cell surface protein angiotensin-converting ...enzyme 2 (ACE2) as its native receptor. Here, we design and characterize a mutant ACE2 that enables rapid affinity purification of a dimeric protein by altering the active site to prevent autoproteolytic digestion of a C-terminal His
epitope tag. In cultured cells, mutant ACE2 competitively inhibits lentiviral vectors pseudotyped with spikes from multiple SARS-CoV-2 variants and infectious SARS-CoV-2. Moreover, the protein can be nebulized and retains virus-binding properties. We developed a system for the delivery of aerosolized ACE2 to K18-hACE2 mice and demonstrated protection by our modified ACE2 when delivered as a prophylactic agent. These results show proof-of-concept for an aerosolized delivery method to evaluate anti-SARS-CoV-2 agents
and suggest a new tool in the ongoing fight against SARS-CoV-2 and other ACE2-dependent viruses.
The rapid evolution of SARS-CoV-2 variants poses a challenge for immune recognition and antibody therapies. However, the virus is constrained by the requirement that it recognizes a human host receptor protein. A recombinant ACE2 could protect against SARS-CoV-2 infection by functioning as a soluble decoy receptor. We designed a mutant version of ACE2 with impaired catalytic activity to enable the purification of the protein using a single affinity purification step. This protein can be nebulized and retains the ability to bind the relevant domains from SARS-CoV-1 and SARS-CoV-2. Moreover, this protein inhibits viral infection against a panel of coronaviruses in cells. Finally, we developed an aerosolized delivery system for animal studies and show the modified ACE2 offers protection in an animal model of COVID-19. These results show proof-of-concept for an aerosolized delivery method to evaluate anti-SARS-CoV-2 agents
and suggest a new tool in the ongoing fight against SARS-CoV-2.
Cryptococcosis is a fungal disease caused by multiple
serotypes; particularly
(serotypes A and D) and
(serotypes B and C). To date, there is no clinically available vaccine to prevent cryptococcosis. ...Mice given an experimental pulmonary vaccination with a
serotype A strain engineered to produce interferon-γ, denoted H99γ, are protected against a subsequent otherwise lethal experimental infection with
serotype A. Thus, we determined the efficacy of immunization with
strain H99γ to elicit broad-spectrum protection in BALB/c mice against multiple disparate
serotypes. We observed significantly increased survival rates and significantly decreased pulmonary fungal burden in H99γ immunized mice challenged with
serotypes A, B, or D compared to heat-killed H99γ (HKH99γ) immunized mice. Results indicated that prolonged protection against
serotypes B or D in H99γ immunized mice was CD4
T cell dependent and associated with the induction of predominantly Th1-type cytokine responses. Interestingly, immunization with H99γ did not elicit greater protection against challenge with the
serotype C tested either due to low overall virulence of this strain or enhanced capacity of this strain to evade host immunity. Altogether, these studies provide "proof-of-concept" for the development of a cryptococcal vaccine that provides cross-protection against multiple disparate serotypes of
.
LY6E is an antiviral restriction factor that inhibits coronavirus spike-mediated fusion, but the cell types in vivo that require LY6E for protection from respiratory coronavirus infection are ...unknown. Here we used a panel of seven conditional Ly6e knockout mice to define which Ly6e-expressing cells confer control of airway infection by murine coronavirus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Loss of Ly6e in Lyz2-expressing cells, radioresistant Vav1-expressing cells and non-haematopoietic cells increased susceptibility to murine coronavirus. Global conditional loss of Ly6e expression resulted in clinical disease and higher viral burden after SARS-CoV-2 infection, but little evidence of immunopathology. We show that Ly6e expression protected secretory club and ciliated cells from SARS-CoV-2 infection and prevented virus-induced loss of an epithelial cell transcriptomic signature in the lung. Our study demonstrates that lineage confined rather than broad expression of Ly6e sufficiently confers resistance to disease caused by murine and human coronaviruses.
Purpose of Review
Coccidioidomycosis is an infectious disease that gained clinical significance in the early 20th century. Many of the foundational contributions to coccidioidomycosis research, ...including the discovery of the fungal disease agent, Coccidioides spp., were made by women. We review recent progress in Coccidioides research and big questions remaining in the field, while highlighting some of the contributions from women.
Recent Findings
New molecular-based techniques provide a promising method for detecting Coccidioides, which can help determine the dominate reservoir host and ideal environmental conditions for growth. Genetic and genomic analyses have allowed an understanding of population structure, species level diversity, and evolutionary histories. We present a current, comprehensive genome list, where women contributed many of these entries. Several efforts to develop a coccidioidomycosis vaccine are underway.
Summary
Women continue to pioneer research on Coccidioides, including the relationships between the fungi and the environment, genetics, and clinical observations. Significant questions remain in the field of Coccidioides, including the main host reservoir, the relationships between genotypic and phenotypic variation, and the underlying cause for chronic clinical coccidioidomycosis cases.
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