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Competing Interests: AC is a member of the Scientific Advisory Board of Sab Therapeutics; has stock options in Sab Therapeutics; and is a member of the COVID-19 Convalescent Plasma Project. DF declares no competing interests.

Competing Interests: Potential conflicts of interest. A. C. serves on the scientific advisory board of SAB Therapeutics. D. F. reports no potential conflicts. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Gene knockout strain collections are important tools for discovery in microbiology. Cryptococcus neoformans is the only human pathogenic fungus with an available genome-wide deletion collection, and this resource is widely used by the research community. We uncovered mix-ups in the assembly of the commercially available C. neoformans deletion collection of ∼6,000 unique strains acquired by our lab. While pursuing the characterization of a gene-of-interest, the corresponding deletion strain from the C. neoformans KO collection displayed several interesting phenotypes associated with virulence. However, RNAseq analysis identified transcripts for the putative knockout gene, and the absence of transcripts for a different knockout strain found in the same plate position in an earlier partial knockout collection, raising the possibility that plates from one collection were substituted for the other. This was supported by determining the size of the nourseothricin (NAT)-resistance cassette used to generate the two separate knockout libraries and was confirmed by RNAseq and genome sequencing. Here we report that our KN99 collection is comprised of mixed plates from two independent KO libraries and present a simple authentication method that other investigators can use to distinguish the identities of these KO collections., Importance: Gene knockout strain collections are important tools for discovery in microbiology. Cryptococcus neoformans is the only human pathogenic fungus with an available genome-wide deletion collection, and this resource is widely used by the research community. Here we report that our KN99 collection is comprised of mixed plates from two independent KO libraries and present a simple authentication method that other investigators can use to distinguish the identities of these KO collections. Above all, this article serves as a reminder to 2015 library collection strains before undertaking large phenotyping experiments.

Invasive mold-associated cutaneous disease is a rare but potentially catastrophic consequence of trauma. However, invertebrate bites are not well recognized as a mechanism for the inoculation of fungi into subcutaneous tissue that can also result in severe infections. Invertebrates often carry fungi with human pathogenic potential as part of their microbiome, and bites break the skin, providing a conduit for them to penetrate subcutaneous tissues where the establishment of infection can produce serious skin and soft tissue fungal diseases. In this essay, we review the existing data for invertebrate bite-associated cutaneous invasive fungal infections (IBA-cIFIs) and consider the potential consequences of global warming on their epidemiology. Climate changes will be associated with changes in the range of invertebrates and adaptation of their associated microbes to warmer temperatures. Fungal adaptation to higher temperatures can defeat the mammalian protective barrier and be associated with both more and different IBA-cIFIs.

Over the past billion years, the fungal kingdom has diversified to more than two million species, with over 95% still undescribed. Beyond the well-known macroscopic mushrooms and microscopic yeast, fungi are heterotrophs that feed on almost any organic carbon, recycling nutrients through the decay of dead plants and animals and sequestering carbon into Earth's ecosystems. Human-directed applications of fungi extend from leavened bread, alcoholic beverages and biofuels to pharmaceuticals, including antibiotics and psychoactive compounds. Conversely, fungal infections pose risks to ecosystems ranging from crops to wildlife to humans; these risks are driven, in part, by human and animal movement, and might be accelerating with climate change. Genomic surveys are expanding our knowledge of the true biodiversity of the fungal kingdom, and genome-editing tools make it possible to imagine harnessing these organisms to fuel the bioeconomy. Here, we examine the fungal threats facing civilization and investigate opportunities to use fungi to combat these threats., Competing Interests: Competing interests: D.W.D. and family hold founder shares in F2G, a University of Manchester spin-out antifungal discovery company, and share options in TFF Pharma. D.W.D. acts or has recently acted as a consultant to Pulmatrix, Pulmocide, Biosergen, TFF Pharmaceuticals, Pfizer, Omega, Novacyt, Rostra Therapeutics, MucPharm, Mundipharma, Lifemine and Cipla; chairs a Data Review Committee for Pulmocide; and acts as a Phase 1 Medical Monitor for Biosergen. In the past three years, D.W.D. has been paid for talks on behalf of BioRad, Basilea and Pfizer. J.E.S. is a paid consultant for Zymergen, Sincarne and Michroma. L.E.C. is a co-founder of and shareholder in Bright Angel Therapeutics, a platform company for the development of novel antifungal therapeutics, and a Science Advisor for Kapoose Creek, a company that harnesses the therapeutic potential of fungi., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

To combat antimicrobial resistance (AMR), advocates have called for passage of the Pioneering Antimicrobial Subscriptions To End Upsurging Resistance (PASTEUR) Act in the United States, which would appropriate $6 billion in new taxpayer-funded subsidies for antibiotic development. However, the number of antibiotics in clinical development, and US Food and Drug Administration approvals of new antibiotics, have already markedly increased in the last 15 years. Thus, instead of focusing on more economic subsidies, we recommend reducing selective pressure driving AMR by (1) establishing pay-for-performance mechanisms that disincentivize overprescribing of antibiotics, (2) focusing existing research and development funding on strategies that decrease reliance on antibiotics, and (3) changing regulation or law to require specialized training in antibiotic stewardship for a clinician to be able to prescribe new antibiotics that target unmet AMR need. To stabilize the antibiotic market, we recommend (1) establishment of an advisory board of clinical practitioners to more accurately target existing antibiotic incentives and (2) endowment of nonprofit companies that sustainably self-fund antibiotic discovery, creating a bench of molecules that can be partnered with industry at later stages of development., Competing Interests: Conflicts of interest: Please see ICMJE form(s) for author conflicts of interest. These have been provided as supplementary materials., (© The Author(s) 2025. Published by Oxford University Press on behalf of Project HOPE - The People-To-People Health Foundation, Inc.)

Background: The Association for the Advancement of Blood and Biotherapies guidelines recommend the use of high-titer COVID-19 convalescent plasma (CCP) for patients with SARS-CoV-2 at high risk of disease progression, including those who are immunocompromised. We hypothesized that conventional plasma units have comparable neutralizing antibody levels to CCP., Study Design and Methods: Conventional plasma and CCP units were obtained from blood suppliers. Quantitatively measured antibodies to SARS-CoV-2 were assessed using the MesoScale Discovery multiplex electrochemiluminescence immunoassay. Binding antibody distributions were compared with Wilcoxon rank-sum tests. SARS-CoV-2 neutralizing antibodies were analyzed using the GeneScript ELISA-based neutralization assay. The proportion of conventional and CCP units with a percent signal inhibition of ≥80% (as defined by the United States Food and Drug Administration for CCP in 2021) and exact binomial confidence intervals (CIs) were calculated., Results: Among 218 conventional plasma units and 74 CCP units collected between September 2023 and July 2024, the distribution of total antibody binding levels largely overlapped between conventional plasma and CCP, though statistically significant differences in median nucleocapsid and spike Omicron variant concentrations were observed. Median percent signal neutralization was 97.5% (range 3.4%-98.6%) among conventional plasma units and 97.7% (range 95.4%-98.6%) among CCP units. For conventional plasma, 95.0% (95% CI = 91.2%-97.5%) met the neutralization antibody threshold for high-titer CCP. For CCP, 100% (95% CI = 95.1%-100.0%) met the neutralization threshold for high-titer CCP., Conclusion: Conventional plasma units demonstrate similar median antibody concentration to CCP units. In countries or regions where licensed CCP is unavailable and titers are unknown, transfusion of multiple conventional plasma units may be of clinical utility., (© 2025 AABB.)

Lomentospora prolificans is a fungal pathogen responsible for serious, often fatal, illness in patients with compromised immune systems. Treatment is rarely successful because L. prolificans is inherently resistant to all major classes of antifungal drugs. In this study we publish three chromosome-level de novo genome assemblies, including the first complete-level assembly of L. prolificans , along with genome annotations. The L. prolificans genome is packaged in 11 nuclear chromosomes and one mitochondrial chromosome, has 36.7-37.1 Mb, and encodes for a putative 7357-7640 genes. The length and composition of contigs in one stain varied from those of the other two strains, supporting the hypothesis that a chromosomal translocation took place. These assemblies were confirmed with pulsed-field gel electrophoresis. The availability of more complete genomes will hopefully help the search for new antifungal drugs and provides insights into the evolutionary history of this pathogenic fungus.

Respiratory syncytial virus (RSV) was discovered in 1956 by the laboratory of Robert Chanock after its isolation from children with upper respiratory infections. Here, we review the events leading to its discovery including its prior isolation as chimpanzee coryza virus and its subsequent association with human disease.

Monoclonal antibodies (mAbs) targeting the SARS-CoV-2 Spike protein were deployed during the COVID-19 pandemic. While all of the clinically authorized mAbs were eventually defeated by SARS-CoV-2 variants, they were highly effective in preventing disease progression when given early in the course of the disease. The experience with mAbs to SARS-CoV-2 offers important lessons for the use of mAbs in future infectious disease emergencies, such as choosing mAbs that target conserved epitopes and designing cocktails to reduce the emergence of escape variants. Planning for future use must include the creation of infusion centers and the development of strategies to minimize the emergence of escape variants.

Diseases caused by the encapsulated fungus Cryptococcus neoformans are major causes of mortality and morbidity in immunocompromised patients. Two important cryptococcal virulence factors are the polysaccharide capsule (CPS) and the secreted exopolysaccharides (EPS), both of which contain predominantly glucuronoxylomannan (GXM) polymers. Here, we evaluated the efficacy of an experimental glycoconjugate vaccine generated by linking minimally processed cryptococcal EPS with the protein carrier CRM 197 . Two different adjuvants (aluminum hydroxide and Freund's adjuvant) were utilized to increase the immunogenicity and to evaluate the efficiency of vaccine protection in a mouse model of cryptococcosis. After a three-dose vaccination schedule, titers of GXM-specific antibodies and survival following lethal challenge were assessed. The protective efficacy of antibodies from sera of vaccinated mice was also evaluated in vitro, through the characterization of their enhancement of macrophage engulfment and opsonization patterns on cryptococcal cells. Antibodies elicited by the EPS-CRM 197 vaccine formulated with Freund's adjuvant showed the best opsonic capabilities as shown by the macrophage engulfment analysis and cryptococcal capsule binding patterns, which was mirrored by longer survival of this vaccine group in our challenge studies. This study confirms that an EPS-protein conjugate vaccine can elicit a protective immune response in mice and provides encouragement for the development of polysaccharide-protein conjugates for the prevention of cryptococcosis., Competing Interests: Declaration of competing interest The authors state that there is no conflict of interest related to research presented in this publication., (Copyright © 2025 British Mycological Society. Published by Elsevier Ltd. All rights reserved.)

The twenty-first century has witnessed seven human viral pandemics. Approximately once every three to four years over the past quarter-century, the world has experienced a new viral epidemic that expanded well beyond its original national borders to become a pandemic. The probability that another pandemic caused by a previously unknown agent will occur in the near future is thus very high and public health agencies must prioritize mechanisms for detecting their first signals. At the onset of these recent pandemics, no specific therapeutic agent was available for any of the newly emergent pathogens. However, convalescent plasma therapy can be available as soon as there are survivors and is likely to be effective if used early and in sufficient strength. But for the three forms of passive antibody-convalescent plasma, monoclonal antibodies, and hyperimmune globulins-to be available and effective in a pandemic situation, careful strategic planning will be necessary. In the pre-pandemic period, we must reinforce the capacities of blood banks and plasma fractionating companies in the production and storage of their products; ensure that outpatient settings can provide intravenous products; educate providers in the proper use of plasma; and create a research infrastructure to examine the effectiveness of passive antibody products. Once a pandemic is underway, regulatory bodies should simplify the approval of research and emergency use protocols and develop treatment registries. Incentives for the rapid production of monoclonal antibodies and hyperimmune globulins will likely be required. A national resource to link providers with passive antibody products and national databases to monitor pandemic progress and pandemic treatment will permit the most effective allocation of pandemic-fighting resources. We cannot afford to wait until the next pandemic is upon us to respond. The time to strengthen clinical, research, and manufacturing infrastructure to permit us to be ready to confront the next new virulent pathogen is now., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Cryptococcus is a genus of saprophytic fungi with global distribution. Two species complexes, Cryptococcus neoformans and Cryptococcus gattii , pose health risks to humans and animals. Cryptococcal infections result from inhalation of aerosolized spores and/or desiccated yeasts from terrestrial reservoirs such as soil and trees. More recently, C. gattii has been implicated in infections in marine mammals, suggesting that inhalation of cells from the air-water interface is also an important, yet understudied, mode of respiratory exposure. Based on historical records and epidemiological factors, water transport has been hypothesized to play a role in the spread of C. gattii from tropical to temperate environments. However, the dynamics of fungal persistence and transport in water have not been fully studied. The size of the cryptococcal capsule was previously shown to reduce cell density and increase buoyancy. Here, we demonstrate that cell buoyancy is also impacted by the salinity of the solution in which cells are suspended, with the formation of a halocline significantly slowing the rate of settling and resulting in persistence of C. neoformans within 1 cm of the water surface for over 60 min and C. gattii for 4-6 h. During the culture of three strains of C. gattii in yeast peptone dextrose media, we also identified aggregates of extracellular polysaccharide with complex structures, which we hypothesize from rafts that entrap cells and augment buoyancy. These findings illustrate new mechanisms by which cryptococcal cells may persist in aquatic environments, with important implications for aqueous transport and pathogen exposure., Importance: Cryptococcosis is a major fungal disease leading to morbidity and mortality worldwide. Cryptococcus neoformans is a major fungal species of public health concern, causing opportunistic systemic infections in immunocompromised patients. Cryptococcus gattii was traditionally a pathogenic fungus confined primarily to tropical regions, but in the 1990s, it emerged in the temperate climates of British Columbia, Canada and the Pacific Northwest of the United States. Outbreaks in these areas also led to the first host record of cryptococcosis in free-ranging cetaceans. C. gattii is particularly concerning as an emerging fungal pathogen due to its capacity to cause clinical disease in immunocompetent patients, its recent spread to a new ecological niche, and its higher resistance to antifungal therapies. Our research defines fungal characteristics that influence the transport of cryptococci through water and persistence of fungal cells near the water surface, improving our understanding of potential mechanisms for cryptococcal environmental transport., Competing Interests: The authors declare no conflict of interest.

The COVID-19 pandemic witnessed the greatest deployment of monoclonal antibody (mAb) therapies for an infectious disease, but all were defeated by SARS-CoV-2 evolution. As new mAbs are developed, the infectious disease community needs stewardship practices to reduce emergence of resistance., Competing Interests: Potential conflicts of interest. A. C. serves on the scientific advisory board of Sab Therapeutics. S. S. declares research funding from Ansun, F2G, and Zeteo and payment for consulting/data review activities from Adagio, Adamis, Celltrion, Karius, Pfizer, and Scynexis. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Plasma collected from recovered patients with COVID-19 (COVID-19 convalescent plasma [CCP]) was the first antibody-based therapy employed to fight the COVID-19 pandemic. While the therapeutic effect of early administration of CCP in COVID-19 outpatients has been recognized, conflicting data exist regarding the efficacy of CCP administration in hospitalized patients., Objectives: To examine the effect of CCP compared to placebo or standard treatment, and to evaluate whether time from onset of symptoms to treatment initiation influenced the effect., Data Sources: Electronic databases were searched for studies published from January 2020 to January 2024., Study Eligibility Criteria: Randomized clinical trials (RCTs) investigating the effect of CCP on COVID-19 mortality in hospitalized patients with COVID-19., Participants: Hospitalized patients with COVID-19., Interventions: CCP versus no CCP., Assessment of Risk of Bias: Cochrane risk of bias tool for RCTs., Methods of Data Synthesis: The random-effects model was used to calculate the pooled risk ratio (RR) with 95% CI for the pooled effect estimates of CCP treatment. The Grading of Recommendations Assessment, Development and Evaluation was used to evaluate the certainty of evidence., Results: Twenty-seven RCTs were included, representing 18,877 hospitalized patients with COVID-19. When transfused within 7 days from symptom onset, CCP significantly reduced the risk of death compared to standard therapy or placebo (RR, 0.76; 95% CI, 0.61-0.95), while later CCP administration was not associated with a mortality benefit (RR, 0.98; 95% CI, 0.90-1.06). The certainty of the evidence was graded as moderate. Meta-regression analysis demonstrated increasing mortality effects for longer interval to transfusion or worse initial clinical severity., Conclusions: In-hospital transfusion of CCP within 7 days from symptom onset conferred a mortality benefit., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Introduction: In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety., Methods: A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites., Results: We performed 1,351 transfusions in 16 months. The transparency of the digital inventory at each site was critical to facilitate qualification, randomization, and overnight shipments of blood group-compatible plasma for transfusions into trial participants. While inventory challenges were heightened with COVID-19 convalescent plasma, the cloud-based system, and the flexible approach of the plasma coordination center staff across the blood bank network enabled decentralized procurement and distribution of investigational products to maintain inventory thresholds and overcome local supply chain restraints at the sites., Conclusion: The rapid creation of a plasma coordination center for outpatient transfusions is infrequent in the academic setting. Distributing more than 3,100 plasma units to blood banks charged with managing investigational inventory across the U.S. in a decentralized manner posed operational and regulatory challenges while providing opportunities for the plasma coordination center to contribute to research of global importance. This program can serve as a template in subsequent public health emergencies., Competing Interests: TJG is a paid consultant and employee of Fenwal, a Fresenius Kabi company (2021–2023); Employee of Werfen (2023-present). AC is on a Scientific Advisory Board of Sabtherapeutics (cow-derived human immunoglobulins COVID-19 treatment and other infectious diseases) and Ortho Diagnostics Speakers Bureau. MAH contracts from Gilead Sciences, Insmed, AN2 Therapeutics, AstraZeneca to the University of Cincinnati, outside the submitted work. EB is a member of the FDA Blood Products Advisory Committee. SS reports research grants; F2G, Cidara, Ansun, Zeteo: personal fees as consultant, advisory board, data safety monitoring board member; Celltrion, Adagio, Immunome, Karius, Pfizer, Scynexis, Adamis, Karyopharm, Intermountain Health: Stock options: Immunome. All other authors report no relevant disclosures., (© The Author(s) 2024.)

After centuries of relative stability, the scientific publishing world has undergone tremendous disruption and change during the first decades of the 21st century. The causes for disruption can be traced to the information revolution, which brought such benefits as rapid publication, greater connectivity, and ready access to large databases, along with less desirable practices including image manipulation, plagiarism, and other ethical transgressions. The information revolution has driven the proliferation of journals, expansion of for-profit academic publishing, and empowerment of the open-access movement, each of which has exerted new financial pressures on traditional publishing models. As journals became the focal point for ethical concerns in science, they have adapted by increasing the scope of their duties, which now include archiving of data, enforcement of good practices, establishment of standards for rigor, and training the next generation of reviewers and editors. Here, we consider the seismic changes occurring in scientific publishing and place them into the context of a rapidly changing landscape of scientific and publishing norms., Competing Interests: The authors declare no conflict of interest.

Alternaria infectoria causes opportunistic human infections and is a source of allergens leading to respiratory allergies. In this work, we prepared cell wall nanoparticles (CWNPs) as a novel approach to study macrophage immunomodulation by fungal hyphal cell walls. A. infectoria was grown in the presence of caspofungin, an inhibitor of β(1,3)-glucan synthesis; nikkomycin Z, an inhibitor of chitin synthases; and pyroquilon, an inhibitor of dihydroxynaphthalene (DHN)-melanin synthesis. Distinct CWNPs were obtained from these cultures, referred to as casCWNPs, nkCWNPs, and pyrCWNPs, respectively. CWNPs are round-shaped particles with a diameter of 70-200 nm diameter particles that when added to macrophages are taken up by membrane ruffling. CWNPs with no DHN-melanin and more glucan (pyrCWNPs) caused early macrophage activation and lowest viability, with the cells exhibiting ultrastructural modifications such as higher vacuolization and formation of autophagy-like structures. CasCWNPs promoted the highest tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) increase, also resulting in the release of partially degraded chitin, an aspect never observed in macrophage-like cells and fungi. After 6 h of interaction with CWNPs, only half were viable, except with control CWNPs. Overall, this work indicates that compounds that modify the fungal cell wall led to CWNPs with new properties that may have implications for the effects of drugs during antifungal therapy. CWNPs provide a new tool to study the interaction of hyphal fungal cell wall components with phagocytic cells and enable to show how the modification of cell wall components in A. infectoria can modulate the response by macrophages.IMPORTANCE Alternaria species are ubiquitous environmental fungi to which the human host can continuously be exposed, through the inhalation of fungal spores but also of fragments of hyphae, from desegregated mycelia. These fungi are involved in hypersensitization and severe respiratory allergies, such as asthma, and can cause opportunistic infections in immunodepressed human host leading to severe disease. The first fungal structures to interact with the host cells are the cell wall components, and their modulation leads to differential immune responses. Here, we show that fungal cells grown with cell wall inhibitors led to cell wall nanoparticles with new properties in their interaction with macrophages. With this strategy, we overcame the limitation of in vitro assays interacting with filamentous fungi and showed that the absence of DNH-melanin leads to higher virulence, while caspofungin leads to cells walls that trigger higher hydrolysis of chitin and higher production of cytokines., Competing Interests: The authors declare no conflict of interest.

Lomentospora prolificans is a filamentous fungus with a global distribution, manifesting particularly higher prevalence in human-impacted environments. This organism is associated with a wide spectrum of human infections, especially in immunosuppressed individuals, for whom it causes severe and debilitating illnesses with high morbidity and mortality that are compounded by its pan-resistant profile with respect to antifungal drugs. Melanin is a ubiquitous pigment among fungi with a broad range of actions that include promoting fungal virulence. Although melanin is one of the most studied virulence factors in pathogenic fungi, relatively little is known about the chemistry of this pigment in L. prolificans. In the current study we characterized L. prolificans -associated melanin using chemical, biological, biophysical and structural techniques, also assessing the impact of inhibitors of distinct melanization pathways. Our results reveal that this pathogenic fungus makes multiple types of melanin pigments and suggests the possibility of a new type of melanin, which is synthesized together with a mixture of DHN-, DOPA- and pyomelanin types. These insights enhance our understanding of L. prolificans' virulence mechanisms, paving the way for potential therapeutic interventions., Competing Interests: Conflict of Interest. All authors declare no competing interests.

L-3,4-dihydroxyphenylalanine (L-DOPA), a naturally occurring tyrosine derivative, is prevalent in environments that include mosquito habitats, potentially serving as part of their diet. Given its role as a precursor for melanin synthesis we investigated the effect of dietary L-DOPA on mosquito physiology and immunity to Plasmodium falciparum and Cryptococcus neoformans infection. Dietary L-DOPA was incorporated into mosquito melanin via a non-canonical pathway and had profound transcriptional effects that were associated with enhanced immunity, increased pigmentation, and reduced lifespan. Increased melanization resulted in an enhanced capacity to absorb electromagnetic radiation that affected mosquito temperatures. Bacteria in the mosquito microbiome were sources of dopamine, which is a substrate for melanization. Our results illustrate how an environmentally abundant amino acid analogue can affect mosquito physiology and suggest its potential usefulness as an environmentally friendly vector control agent to reduce malaria transmission, warranting further research and field studies.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a leading cause of death by an infectious disease globally, with no efficacious vaccine. Antibodies are implicated in Mtb control, but the mechanisms of antibody action remain poorly understood. We assembled a library of TB monoclonal antibodies (mAb) and screened for the ability to restrict Mtb in mice, identifying protective antibodies targeting known and novel antigens. To dissect the mechanism of mAb-mediated Mtb restriction, we optimized a protective lipoarabinomannan-specific mAb through Fc-swapping. In vivo analysis of these Fc-variants revealed a critical role for Fc-effector function in Mtb restriction. Restrictive Fc-variants altered distribution of Mtb across innate immune cells. Single-cell transcriptomics highlighted distinctly activated molecular circuitry within innate immune cell subpopulations, highlighting early activation of neutrophils as a key signature of mAb-mediated Mtb restriction. Therefore, improved antibody-mediated restriction of Mtb is associated with reorganization of the tissue-level immune response to infection and depends on the collaboration of antibody Fab and Fc.

In the Spring of 2020, the United States of America (USA) deployed COVID-19 convalescent plasma (CCP) to treat hospitalized patients. Over 500,000 patients were treated with CCP during the first year of the pandemic. In this study, we estimated the number of actual inpatient lives saved by CCP treatment in the United States of America based on CCP weekly use, weekly national mortality data, and CCP mortality reduction data from meta-analyses of randomized controlled trials and real-world data. We also estimate the potential number of lives saved if CCP had been deployed for 100% of hospitalized patients or used in 15 to 75% of outpatients. Depending on the assumptions modeled in stratified analyses, we estimated that CCP saved between 16,476 and 66,296 lives. The CCP ideal use might have saved as many as 234,869 lives and prevented 1,136,133 hospitalizations. CCP deployment was a successful strategy for ameliorating the impact of the COVID-19 pandemic in the USA. This experience has important implications for convalescent plasma use in future infectious disease emergencies., Competing Interests: Competing interests statement:Klassen S.A., Senefeld J.W., Johnson P.W., Carter R.E., Wiggins C.C., Shoham S., Henderson J.P., Pirofski L.A., Wright R.S., Paneth N.S., Casadevall A., and Joyner M.J. and reviewers Musser J. and Hartmann W.R. were co-authors in a review/position paper dealing with the use of CCP published in 2021.

Italy was the first western country to be hit by the COVID-19 pandemic and has suffered nearly 200,000 deaths so far during the four years of the pandemic. In March 2020, Italy first deployed COVID-19 convalescent plasma (CCP) to treat hospitalized patients. Despite this initial effort, the proportion of COVID-19 patients treated with CCP during the first two years of the pandemic (2020-2021) was very low (approximately 2% of individuals hospitalized for COVID-19). In this study, we estimated the number of actual inpatient lives saved by CCP treatment in Italy using national mortality data, and CCP mortality reduction data from meta-analyses of randomized controlled trials and real-world data. We also estimated the potential number of lives saved if CCP had been deployed to 100% of hospitalized patients or used in 15% to 75% of outpatients. According to these models, CCP usage in 2020-2021 saved between 385-1304 lives, but this number would have increased to 17,751-60,079 if 100% of inpatients had been transfused with CCP. Similarly, broader (15-75%) usage in outpatients could have prevented 21,187-190,689 hospitalizations (desaturating hospitals) and 6144-81,926 deaths. These data have important implications for convalescent plasma use in future infectious disease emergencies.

Cryptococcus neoformans has emerged as a frontrunner among deadly fungal pathogens and is particularly life-threatening for many HIV-infected individuals with compromised immunity. Multiple virulence factors contribute to the growth and survival of C. neoformans within the human host, the two most prominent of which are the polysaccharide capsule and melanin. As both of these features are associated with the cell wall, we were interested to explore possible cooperative or competitive interactions between these two virulence factors. Whereas capsule thickness had no effect on the rate at which cells became melanized, build-up of the melanin pigment layer resulted in a concomitant loss of polysaccharide material, leaving melanized cells with significantly thinner capsules than their nonmelanized counterparts. When melanin was provided exogenously to cells in a transwell culture system we observed a similar inhibition of capsule growth and maintenance. Our results show that melanin sequesters calcium thereby limiting its availability to form divalent bridges between polysaccharide subunits required for outer capsule assembly. The decreased ability of melanized cells to incorporate exported polysaccharide into the growing capsule correlated with the amount of shed polysaccharide, which could have profound negative impacts on the host immune response., Competing Interests: Competing interests statement:The authors declare no competing interest.

Science is humanity's best insurance against threats from nature, but it is a fragile enterprise that must be nourished and protected. The preponderance of scientific evidence indicates a natural origin for SARS-CoV-2. Yet, the theory that SARS-CoV-2 was engineered in and escaped from a lab dominates media attention, even in the absence of strong evidence. We discuss how the resulting anti-science movement puts the research community, scientific research, and pandemic preparedness at risk., Competing Interests: T.D. is on the Board of Directors, Burroughs Wellcome Fund, and is an Editor for the Annual Review of Virology. P.D. receives funding from Moderna. K.F. has substantial financial interest in Vir Biotechnology, Inc., and is cofounder of the company and is coinventor of patents licensed to Vir and receives compensation for consulting. The potential conflict of interest has been reviewed and managed by OHSU. S.G. has done legal consulting on the origins of the pandemic. A.L.G. reports central testing contracts from Pfizer, Novavx, Sanofi, Abbott, Hologic, Cephid, and Quidel and has research support from Gilead. A.M. is scientific founder of Thylacine Biotherapeutics. G.A.S. is President of Thyreos, Inc. Most authors receive funding from the National Institutes of Health and other funding agencies.

Mounting evidence indicates that antibodies can contribute towards control of tuberculosis (TB). However, the underlying mechanisms of humoral immune protection and whether antibodies can be exploited in therapeutic strategies to combat TB are relatively understudied. Here we engineered the receptor-binding Fc (fragment crystallizable) region of an antibody recognizing the Mycobacterium tuberculosis (Mtb) capsule, to define antibody Fc-mediated mechanism(s) of Mtb restriction. We generated 52 Fc variants that either promote or inhibit specific antibody effector functions, rationally building antibodies with enhanced capacity to promote Mtb restriction in a human whole-blood model of infection. While there is likely no singular Fc profile that universally drives control of Mtb, here we found that several Fc-engineered antibodies drove Mtb restriction in a neutrophil-dependent manner. Single-cell RNA sequencing analysis showed that a restrictive Fc-engineered antibody promoted neutrophil survival and expression of cell-intrinsic antimicrobial programs. These data show the potential of Fc-engineered antibodies as therapeutics able to harness the protective functions of neutrophils to promote control of TB., (© 2024. The Author(s).)

The use of the serum or plasma of patients or animals who have recovered from an infectious disease, or had been immunized with a relevant antigen, to treat or prevent the same infection in others began in the late 1880s when French and German scientists uncovered, one step at a time, several of the elements of the immune system's response to infection. A key finding was that the damage caused by some bacteria depends upon their secreted toxins which can be neutralized by biologic agents. Antitoxins to diphtheria and tetanus began to be manufactured in large animals in France, Germany, and the US in the 1890s and were soon being used worldwide. The impact of diphtheria antitoxin on childhood mortality was profound. Shortly after the development of antitoxins, convalescent serum began to be used for its anti-bactericidal properties thus addressing serious infections caused by non-toxin-producing organisms. The effectiveness of antitoxins and antisera was demonstrated by examining mortality rates in hospitals before and after the introduction of antitoxins, by comparisons of treated and untreated patients, by comparing early and late treatment and dosage, by examining vital data mortality trends, and by several randomized and alternate assignment trials. Antitoxins continue to have a role in the rare cases of diphtheria and other conditions largely eradicated by immunization, but serum therapy nearly disappeared from the medical armamentarium with the development of antibiotics in the 1940s. Inasmuch as new human pathogens are now emerging with unprecedented regularity as seen in the recent COVID-19 pandemic, and because specific therapies are unlikely to be available for them, plasma-based antibody therapies are likely to again carve out a niche in infectious disease control., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Cryptococcus neoformans is a fungal pathogen that causes cryptococcosis primarily in immunocompromised patients, such as those with HIV/AIDS. One survival mechanism of C. neoformans during infection is melanin production, which catalyzed by laccase and protects fungal cells against immune attack. Hence, the comparative assessment of laccase activity is useful for characterizing cryptococcal strains. We serendipitously observed that culturing C. neoformans with food coloring resulted in degradation of some dyes with phenolic structures. Consequently, we investigated the color changes for the food dyes metabolized by C. neoformans laccase and by using this effect explored the development of a colorimetric assay to measure laccase activity. We developed several versions of a food dye-based colorimetric laccase assay that can be used to compare the relative laccase activities between different C. neoformans strains. We found that phenolic color degradation was glucose-dependent, which may reflect changes in the reduction properties of the media. Our food color-based colorimetric assay has several advantages, including lower cost, irreversibility, and not requiring constant monitoring , over the commonly used 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay for determining laccase activity. This method has potential applications to bioremediation of water pollutants in addition to its use in determining laccase virulence factor expression.IMPORTANCE Cryptococcus neoformans is present in the environment, and while infection is common, disease occurs mostly in immunocompromised individuals. C. neoformans infection in the lungs results in symptoms like pneumonia, and consequently, cryptococcal meningitis occurs if the fungal infection spreads to the brain. The laccase enzyme catalyzes the melanization reaction that serves as a virulence factor for C. neoformans . Developing a simple and less costly assay to determine the laccase activity in C. neoformans strains can be useful for a variety of procedures ranging from studying the relative virulence of cryptococci to environmental pollution studies., Competing Interests: The authors declare no conflict of interest.

The fungal pathogen Cryptococcus neoformans is well adapted to its host environment. It has several defence mechanisms to evade oxidative and nitrosative agents released by phagocytic host cells during infection. Among them, melanin production is linked to both fungal virulence and defence against harmful free radicals that facilitate host innate immunity. How C. neoformans manipulates its redox environment to facilitate melanin formation and virulence is unclear. Here we show that the antioxidant glutathione is inextricably linked to redox-active processes that facilitate melanin and titan cell production, as well as survival in macrophages and virulence in a murine model of cryptococcosis. Comparative metabolomics revealed that disruption of glutathione biosynthesis leads to accumulation of reducing and acidic compounds in the extracellular environment of mutant cells. Overall, these findings highlight the importance of redox homeostasis and metabolic compensation in pathogen adaptation to the host environment and suggest new avenues for antifungal drug development., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Anti-spike monoclonal antibodies represent one of the most tolerable prophylaxis and therapies for COVID-19 in frail and immunocompromised patients. Unfortunately, viral evolution in Omicron has led all of them to failure., Objectives: We review here the current pipeline of anti-spike mAb's, discussing in detail the most promising candidates., Sources: We scanned PubMed, ClinicalTrials.gov and manufacturers' press releases for clinical studies on anti-spike monoclonal antibodies., Content: We present state-of-art data clinical progress for AstraZeneca's AZD3152, Invivyd's VYD222, Regeneron's REGN-17092 and Aerium Therapeutics' AER-800., Implications: The anti-spike monoclonal antibody clinical pipeline is currently limited to few agents (most being single antibodies) with unknown efficacy against the dominant JN.1 sublineage. The field of antibody-based therapies requires boosting by both manufacturers and institutions., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Introduction: Monoclonal antibody (mAb) therapies proved safe and effective in preventing progression of COVID-19 to hospitalization, but most were eventually defeated by continued viral evolution. mAb combinations and those mAbs that were deliberatively selected to target conserved regions of the SARS-CoV-2 spike protein proved more resilient to viral escape variants as evident by longer clinical useful lives., Areas Covered: We searched PubMed for literature covering the need, development, and use of mAb therapies for COVID-19. As much of humanity now has immunity to SARS-CoV-2, the population at most risk is that of immunocompromised individuals. Hence, there continues to be a need for mAb therapies for immunocompromised patients. However, mAb use in this population carries the risk for selecting mAb-resistant variants, which could pose a public health concern if they disseminate to the general population., Expert Opinion: Going forward, structural knowledge of the interactions of Spike with its cellular receptor has identified several regions that may be good targets for future mAb therapeutics. A focus on designing variant-resistant mAbs together with cocktails that target several epitopes and the use of other variant mitigating strategies such as the concomitant use of small molecule antivirals and polyclonal preparations could extend the clinical usefulness of future preparations.

The yeasts Cryptococcus neoformans and Cryptococcus gattii are fungal pathogens that can be isolated from the environment, including the surfaces of many plants. Cryptococcus gattii caused an outbreak on Vancouver Island, British Columbia beginning in 1999 that has since spread to the Pacific Northwest of the United States. Coastal Douglas fir (Pseudotsuga menziesii) is an important lumber species and a major component of the ecosystems in this area. Previous research has explored Cryptococcus survival and mating on Douglas fir plants and plant-derived material, but no studies have been done on the production of cryptococcal virulence factors by cells grown on those media. Here, we investigated the effects of growth on Douglas fir-derived media on the production of the polysaccharide capsule and melanin, two of the most important cryptococcal virulence factors. We found that while the capsule was mostly unchanged by growth in Douglas fir media compared to cells grown in defined minimal media, Cryptococcus spp. can use substrates present in Douglas fir to synthesize functional and protective melanin. These results suggest mechanisms by which Cryptococcus species may survive in the environment and emphasize the need to explore how association with Douglas fir trees could affect its epidemiology for human cryptococcosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)