Miscellaneous Research Thread
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Chandelier
Senior Member (Voting Rights)
Longitudinal characterization of mixed-genotype SARS-CoV-2 infections in a military cohort reveals compartmentalized viral populations, 2026, Long et al.
To better understand intra-host viral dynamics, we analyzed specimens from 24 participants from the U.S. Military Health System’s Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential COVID-19 cohort with suspected mixed-genotype SARS-CoV-2 infections.
From an initial 24 suspected cases, we confirmed 17 as genuine coinfections and graded them by evidence: 7 were “strong”; 4 were “moderate”; 6 were “weak”; and 7 were deemed unlikely to be true mixed-genotype infections.
Access to swabs from multiple body sites across the course of infection allowed us to observe compartmentalization and shifts in variant dominance that would have been missed by a single-timepoint analysis, as well as one recombinant Omicron BA.1/BA.2 genome.
By using an evidence-based bioinformatic framework to assess sequencing data from well-characterized clinical cases, we distinguished genuine coinfections from bioinformatic artifacts.
Our findings emphasize the importance of both extensive specimen collection and careful bioinformatic approaches in ascertaining dual genotype infections.
We analyzed a longitudinal data set with specimens from multiple body sites, providing an opportunity to assess intra-host dynamics.
To distinguish true coinfection from bioinformatic artifacts with confidence, we applied a framework that grades evidence for mixed genotypes by incorporating lineage and clade with manually validated variant calls.
This allowed investigation beyond abundance levels of mixed genotypes within a single specimen, including observations of compartmentalization and a recombinant virus.
This work enables further study of evolutionary, immunological, and clinical implications of mixed SARS-CoV-2 genotypes.
Detecting dual-genotype infections and discriminating between true dual-genotype infection vs potential bioinformatics-based artifacts support public health and military readiness.
These efforts provide evidence to bolster decision-making in molecular epidemiological studies to track transmission and for the choice of effective countermeasures.
Web | DOI | PDF | Microbiology Spectrum | Open Access
Long, Kyle A.; Paskey, Adrian C.; Adhikari, Bishwo N.; Fries, Anthony C.; Mende, Katrin; Richard, Stephanie A.; Malagon, Francisco; Cer, Regina Z.; Miller, Robin H.; Chitty, J. Alexander; Voegtly, Logan J.; Miner, Haven; Lanteri, Charlotte; Tribble, David R.; Agan, Brian K.; Simons, Mark P.; Burgess, Timothy H.; Pollett, Simon D.; Bishop-Lilly, Kimberly A.
ABSTRACT
Mixed-genotype severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are a concern due to the potential generation of novel recombinants that give rise to new variants.To better understand intra-host viral dynamics, we analyzed specimens from 24 participants from the U.S. Military Health System’s Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential COVID-19 cohort with suspected mixed-genotype SARS-CoV-2 infections.
From an initial 24 suspected cases, we confirmed 17 as genuine coinfections and graded them by evidence: 7 were “strong”; 4 were “moderate”; 6 were “weak”; and 7 were deemed unlikely to be true mixed-genotype infections.
Access to swabs from multiple body sites across the course of infection allowed us to observe compartmentalization and shifts in variant dominance that would have been missed by a single-timepoint analysis, as well as one recombinant Omicron BA.1/BA.2 genome.
By using an evidence-based bioinformatic framework to assess sequencing data from well-characterized clinical cases, we distinguished genuine coinfections from bioinformatic artifacts.
Our findings emphasize the importance of both extensive specimen collection and careful bioinformatic approaches in ascertaining dual genotype infections.
IMPORTANCE
Novel recombinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) arise from coinfections with different lineages, but mixed infections are not screened for despite risk to public health, and most surveillance relies on single swabs.We analyzed a longitudinal data set with specimens from multiple body sites, providing an opportunity to assess intra-host dynamics.
To distinguish true coinfection from bioinformatic artifacts with confidence, we applied a framework that grades evidence for mixed genotypes by incorporating lineage and clade with manually validated variant calls.
This allowed investigation beyond abundance levels of mixed genotypes within a single specimen, including observations of compartmentalization and a recombinant virus.
This work enables further study of evolutionary, immunological, and clinical implications of mixed SARS-CoV-2 genotypes.
Detecting dual-genotype infections and discriminating between true dual-genotype infection vs potential bioinformatics-based artifacts support public health and military readiness.
These efforts provide evidence to bolster decision-making in molecular epidemiological studies to track transmission and for the choice of effective countermeasures.
Chandelier
Senior Member (Voting Rights)
‘Stomach bugs’ send protective immune cells rushing from gut to brain
Voyaging gut-derived immune cells ‘remember’ past stomach infections in mice.
www.nature.com
‘Stomach bugs’ send protective immune cells rushing from gut to brain
Voyaging gut-derived immune cells ‘remember’ past stomach infections in mice.By Gemma Conroy
…
The study is “outstanding” and could help researchers to learn more about how the gut interacts with the central nervous system, says Francisco Quintana, a neuroimmunologist at Harvard University in Cambridge, Massachusetts.
“It opens up several possibilities,” he says, such as exploring how gut infections might affect neurological disorders, and developing therapies that harness that relationship.
Intestinal infections establish antigen-specific, long-lived memory CD4+ T cells in the brain and meninges, 2026, Fleming et al
Intestinal infections establish antigen-specific, long-lived memory CD4+ T cells in the brain and meninges
Abstract
Abstract The meninges form the border between the brain and periphery and house a rich network of immune cells. Here we show that gastrointestinal challenges (intracellular or extracellular bacteria and parasites) reshape the nature of CD4 + T cells in the dura mater, the outer meningeal layer, changing the dominant polarization states to T helper (T H ) 1, T H 17 and T H 2 cells, respectively, with differing cytokine profiles. This occurs via CXCR6–CXCL16-dependent migration of gut-activated CD4 + T cells to the central nervous system, where they establish long-lived memory populations around the dural venous sinuses, within dural lymphoid aggregates and in the brain. Functionally, these orally primed dural CD4 + T were capable of rapid, antigen-specific recall responses, proliferating and producing cytokines upon intravenous rechallenge. Our findings reveal a direct link between intestinal and dural immunity, enabling the central nervous system borders to acquire immunological memory of gut microorganisms, a major source of bloodborne pathogens capable of reaching the brain via fenestrated dural vasculature.
Web | DOI | PDF | Nature Neuroscience
Fleming, Aaron; Neish, Karen; Di Marco-Barros, Rafael; Posner, David A.; Lee, Colin Y. C.; Stewart, Andrew; Tuong, Zewen Kelvin; Bremridge, Miles; Peñalver, Ana; Cabantous, Mia; Richoz, Nathan; Portet, Anais; Harcourt, Katherine; Gillman, Eleanor; Sow, Tammie Tao Min; Hasegawa, Tetsuo; Ruano-Gallego, David; Frankel, Gad; Withers, David; Clare, Simon; Clatworthy, Menna R.
Abstract
Abstract The meninges form the border between the brain and periphery and house a rich network of immune cells. Here we show that gastrointestinal challenges (intracellular or extracellular bacteria and parasites) reshape the nature of CD4 + T cells in the dura mater, the outer meningeal layer, changing the dominant polarization states to T helper (T H ) 1, T H 17 and T H 2 cells, respectively, with differing cytokine profiles. This occurs via CXCR6–CXCL16-dependent migration of gut-activated CD4 + T cells to the central nervous system, where they establish long-lived memory populations around the dural venous sinuses, within dural lymphoid aggregates and in the brain. Functionally, these orally primed dural CD4 + T were capable of rapid, antigen-specific recall responses, proliferating and producing cytokines upon intravenous rechallenge. Our findings reveal a direct link between intestinal and dural immunity, enabling the central nervous system borders to acquire immunological memory of gut microorganisms, a major source of bloodborne pathogens capable of reaching the brain via fenestrated dural vasculature.
Web | DOI | PDF | Nature Neuroscience
Chandelier
Senior Member (Voting Rights)
Will there be a warning for the next pandemic?, 2026, Lessler et al
Web | DOI | PMC | PDF | Science Advances | Open Access
Lessler, Justin; Metcalf, C. Jessica E.
Abstract
How to best allocate resources to combat the threat of pathogen emergence remains an important open question. Using archetypes that characterize the link from genotype to fitness in both zoonotic reservoirs and humans, we show that, across a range of plausible conditions, emergences of pathogens with pandemic potential in humans are unlikely to be preceded by detectable, failed, attempts.
Yet, the number of “failed” emergence events contains information about the emergence potential of zoonotic pathogens, and should modify our beliefs about the underlying fitness landscape. Our work suggests that the most important, modifiable, risk factors for emergence may be phenomena that alter fitness landscapes, such as viral ecology in bridge species and human immunological landscapes.
Abstract
How to best allocate resources to combat the threat of pathogen emergence remains an important open question. Using archetypes that characterize the link from genotype to fitness in both zoonotic reservoirs and humans, we show that, across a range of plausible conditions, emergences of pathogens with pandemic potential in humans are unlikely to be preceded by detectable, failed, attempts.
Yet, the number of “failed” emergence events contains information about the emergence potential of zoonotic pathogens, and should modify our beliefs about the underlying fitness landscape. Our work suggests that the most important, modifiable, risk factors for emergence may be phenomena that alter fitness landscapes, such as viral ecology in bridge species and human immunological landscapes.
Web | DOI | PMC | PDF | Science Advances | Open Access
Chandelier
Senior Member (Voting Rights)
Airport air sampling captures COVID, influenza viruses
Researchers say air monitoring complements wastewater testing in detecting respiratory pathogens from diverse populations, including asymptomatic or pre-symptomatic people.
Airport air sampling captures COVID, influenza viruses
News brief
September 17, 2026
Paper the article is based on:
Multimodal genomic surveillance for respiratory pathogens at four U.S. international airports: A comparison of air, wastewater, clinical, and national surveillance data, 2026, Gratalo et al
Gratalo, Dawn; Friedman, Cindy R.; Morley, Valerie J.; Qiu, Xueting; Ruskey, Ian; Rothstein, Andrew P.; Tiburcio, Patrick B.; Philipson, Casandra W.; Aichele, Thomas W. S.; Bart, Stephen M.; Jaynes, Dustin; Simen, Birgitte B.; O’Connor, Shelby L.; O’Connor, David H.
Abstract
Early detection of outbreaks and emerging pathogens is critical for public health and global biosecurity. Airports, as major international travel hubs with dense, enclosed populations, are high-risk settings for disease transmission and potential pathogen introduction. The U.S. Centers for Disease Control and Prevention, in collaboration with Ginkgo Biosecurity and the University of Wisconsin–Madison, implemented air monitoring for pathogen surveillance in congregate areas at four U.S. international airports. From October 2023 to August 2024, SARS-CoV-2 was detected by PCR in 98.3% of air samples and influenza A in 17.2%. Influenza A positivity in air samples correlated with aviation wastewater (r = 0.48), traveler nasal swab positivity (r = 0.73), and national clinical surveillance (r = 0.86), whereas SARS-CoV-2 measurements did not correlate significantly across these modalities. Targeted amplicon sequencing of SARS-CoV-2 from air samples identified contemporaneous lineages also detected in wastewater collected from the same airports. Targeted enrichment sequencing detected 30 viral species and recovered high-quality genomes for SARS-CoV-2, influenza, bocavirus, and seasonal coronaviruses. Together, these findings demonstrate that air sampling can complement aviation wastewater surveillance at ports of entry, although performance and concordance vary by pathogen and sample type.
Web | DOI | PMC | PDF | PLOS Global Public Health | Open Access
Chandelier
Senior Member (Voting Rights)
Gp120-Activated Allogeneic Regulatory T cells for Prevention of Graft-versus-Host-Disease: A First-in-Human Trial, 2026, Tuettenberg et al
Abstract
Acute graft-versus-host disease (aGvHD) remains a major complication after allogeneic hematopoietic cell transplantation (alloHCT). Adoptive regulatory T-cell (Treg) therapy may suppress alloreactive T-cell responses, but clinical implementation has been limited by donor-specific manufacturing, prolonged ex vivo expansion, and logistical complexity. We developed ATreg, a cell therapy product consisting of gp120-activated, polyclonal Tregs derived from HLA-unmatched third-party donors.
The primary objective was to assess the safety, tolerability and toxicity of ATreg, hypothesizing that this would be feasable and safe for aGvHD prevention early after alloHCT in patients with hematologic malignancies. ATreg-001 is a first-in-human, prospective, open-label, single-arm, multi-center phase 1/2 trial (EU CT number 2024-516599-14-00) conducted at 4 German centers (Mainz, Dresden, Münster, and Dortmund). ATreg was generated from standard non-mobilized apheresis products by Treg isolation followed by 16 hours of gp120-mediated activation in the presence of IL-2, without ex vivo expansion, thereby enhancing suppressive function and (potentially) enabling a therapeutic effect at substantially lower Treg doses. Ten patients received ATreg at 0.1 to 1.0 × 10⁶ cells/kg body weight on day +10 ± 5 after alloHCT, in addition to standard GvHD prophylaxis, in a dose-escalation design across 3 cohorts.
ATreg was administered within 24 hours after manufacturing. The primary endpoint was the type, incidence, and severity of ATreg-related serious adverse events within 14 days after administration. Secondary endpoints included manufacturing feasibility, aGvHD incidence/severity within 100 days, engraftment, and infections. ATreg administration was well tolerated, with no infusion-related toxicities or other safety signals attributable to ATreg. All treated patients achieved hematopoietic engraftment and full donor chimerism. Within 100 days after alloHCT, no grade 3 to 4 aGvHD occurred, the cumulative incidence of grade 2 to 4 aGvHD was 10%, and no nonrelapse mortality was observed.
These first clinical data support the feasibility and favorable safety profile of ATreg, a third-party, gp120-activated Treg product requiring no ex vivo expansion, and warrant further evaluation in larger prospective clinical trials. (1) HLfv and (2) ATreg therapy showed early clinical signals for GvHD prevention, with no cases of grade 3 to 4 aGvHD observed.
Web | DOI | Transplantation and Cellular Therapy | Open Acess
Tuettenberg, Andrea; Ruhnke, Leo; Schlöder, Janine; Zimmer, Niklas; Rücker, Christoph; Wehler, Daniela; Epp, Katharina; Janson, Dietlinde; Wetzko, Katrin; Reicherts, Christian; Bornhäuser, Martin; Zeiser, Robert; Stelljes, Matthias; Meyer, Ralf Georg; Wermke, Martin; Wagner-Drouet, Eva Maria; Jonuleit, Helmut
Abstract
Acute graft-versus-host disease (aGvHD) remains a major complication after allogeneic hematopoietic cell transplantation (alloHCT). Adoptive regulatory T-cell (Treg) therapy may suppress alloreactive T-cell responses, but clinical implementation has been limited by donor-specific manufacturing, prolonged ex vivo expansion, and logistical complexity. We developed ATreg, a cell therapy product consisting of gp120-activated, polyclonal Tregs derived from HLA-unmatched third-party donors.
The primary objective was to assess the safety, tolerability and toxicity of ATreg, hypothesizing that this would be feasable and safe for aGvHD prevention early after alloHCT in patients with hematologic malignancies. ATreg-001 is a first-in-human, prospective, open-label, single-arm, multi-center phase 1/2 trial (EU CT number 2024-516599-14-00) conducted at 4 German centers (Mainz, Dresden, Münster, and Dortmund). ATreg was generated from standard non-mobilized apheresis products by Treg isolation followed by 16 hours of gp120-mediated activation in the presence of IL-2, without ex vivo expansion, thereby enhancing suppressive function and (potentially) enabling a therapeutic effect at substantially lower Treg doses. Ten patients received ATreg at 0.1 to 1.0 × 10⁶ cells/kg body weight on day +10 ± 5 after alloHCT, in addition to standard GvHD prophylaxis, in a dose-escalation design across 3 cohorts.
ATreg was administered within 24 hours after manufacturing. The primary endpoint was the type, incidence, and severity of ATreg-related serious adverse events within 14 days after administration. Secondary endpoints included manufacturing feasibility, aGvHD incidence/severity within 100 days, engraftment, and infections. ATreg administration was well tolerated, with no infusion-related toxicities or other safety signals attributable to ATreg. All treated patients achieved hematopoietic engraftment and full donor chimerism. Within 100 days after alloHCT, no grade 3 to 4 aGvHD occurred, the cumulative incidence of grade 2 to 4 aGvHD was 10%, and no nonrelapse mortality was observed.
These first clinical data support the feasibility and favorable safety profile of ATreg, a third-party, gp120-activated Treg product requiring no ex vivo expansion, and warrant further evaluation in larger prospective clinical trials. (1) HLfv and (2) ATreg therapy showed early clinical signals for GvHD prevention, with no cases of grade 3 to 4 aGvHD observed.
GRAPHICAL ABSTRACT
Web | DOI | Transplantation and Cellular Therapy | Open Acess
Two parallel lineage-committed progenitors contribute to the developing brain
Carolyn E. Dundes, Rayyan T. Jokhai et al
Abstract
The hindbrain is a life-sustaining brain region. In one model, a common neural progenitor
generates all brain regions. Here our studies of mouse embryos and human pluripotent stem
cells (hPSCs) support a different model: two parallel brain progenitors emerge simultaneously
during gastrulation, anterior neural ectoderm (forebrain/midbrain progenitor) and posterior
neural ectoderm (hindbrain progenitor). Not only are they lineage-committed to respectively
form forebrain/midbrain vs. hindbrain in vitro, but they also have diverging chromatin
landscapes foreshadowing future forebrain/midbrain vs. hindbrain identities. Leveraging these
differences, we differentiated hPSCs into hindbrain rhombomere 5/6-specific motor neurons,
hitherto difficult to generate in vitro. We postulate the brain is a composite organ emanating
from two lineage-restricted progenitors; these dual progenitors may be evolutionarily conserved
across 550 million years from hemichordates to mammals.
neurosciencenews.com
Carolyn E. Dundes, Rayyan T. Jokhai et al
Abstract
The hindbrain is a life-sustaining brain region. In one model, a common neural progenitor
generates all brain regions. Here our studies of mouse embryos and human pluripotent stem
cells (hPSCs) support a different model: two parallel brain progenitors emerge simultaneously
during gastrulation, anterior neural ectoderm (forebrain/midbrain progenitor) and posterior
neural ectoderm (hindbrain progenitor). Not only are they lineage-committed to respectively
form forebrain/midbrain vs. hindbrain in vitro, but they also have diverging chromatin
landscapes foreshadowing future forebrain/midbrain vs. hindbrain identities. Leveraging these
differences, we differentiated hPSCs into hindbrain rhombomere 5/6-specific motor neurons,
hitherto difficult to generate in vitro. We postulate the brain is a composite organ emanating
from two lineage-restricted progenitors; these dual progenitors may be evolutionarily conserved
across 550 million years from hemichordates to mammals.
The Brain Is Two Separate Organs Joined by Evolution - Neuroscience News
A new study reveals the human brain is composed of two independently evolved organs, enabling the first lab-grown human hindbrain neurons.
neurosciencenews.com