PLoS Pathog
· 2026 Apr · PMID 42030347
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Bordetella pertussis causes whooping cough (pertussis), a respiratory infectious disease that is resurgent despite high vaccine coverage. Research on the mechanisms of immunity to B. pertussis have demonstrated protectiv...Bordetella pertussis causes whooping cough (pertussis), a respiratory infectious disease that is resurgent despite high vaccine coverage. Research on the mechanisms of immunity to B. pertussis have demonstrated protective roles for innate immune cells, antibodies and T cells in immunity induced by natural infection. Studies in animal models have demonstrated that IL-17-secreting respiratory tissue-resident memory CD4+ T (TRM) cells and associated recruitment of neutrophils play a critical role in clearance of bacteria from nasal mucosa. However, current acellular pertussis (aP) vaccines, while inducing potent serum antibody responses and protecting against pertussis disease, fail to induce local immune responses in the respiratory tract, thus allowing transmission of the bacteria from vaccinated individuals. Motivated by the resurgence of pertussis and the limitations of the current aP vaccines, several research groups involved in the design of more effective third generation pertussis vaccines are focusing on nasal-delivery approaches that induce respiratory TRM cells and mucosal IgA, as well as circulating antibodies.
Shang H, Yang S, Sun M
… +11 more, Zhao Y, Guo R, Wang W, Qian B, Li Y, Hu M, Bian X, Cao Q, Li C, Fan B, Li B
PLoS Pathog
· 2026 Apr · PMID 42030333
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Porcine epidemic diarrhea virus (PEDV) poses a significant threat to the global swine industry; however, the host factors that support its replication remain poorly understood. Our previous study showed that myeloid cell...Porcine epidemic diarrhea virus (PEDV) poses a significant threat to the global swine industry; however, the host factors that support its replication remain poorly understood. Our previous study showed that myeloid cell leukemia 1 (MCL1) is a pro-PEDV replication cellular factor through genome-scale CRISPR-Cas9-knockout (KO) screening. Nevertheless, the molecular mechanism whereby MCL1 promotes PEDV replication is unclear. In this study, we first demonstrated that MCL1 promotes PEDV replication through its BCL-2 homology (BH) domain. Deletion of MCL1 prevented arachidonic acid (AA) from undergoing β-oxidation which led to the increase of free AA and activation of its secondary metabolic pathways resulting in significant inhibition of PEDV replication. Complementation of MCL1-KO cells with a BH domain fragment of MCL1 restored β-oxidation capacity and rescued PEDV replication. In addition, we identified acyl-CoA synthetase bubblegum family member 1 (ACSBG1) as a novel metabolic regulator that binds to the N-terminus of MCL1, rather than its BH domain, and cooperates with MCL1 to facilitate AA β-oxidation. We further demonstrated that ACSBG1 and MCL1 act together as proviral factors specifically during the replication stage of PEDV infection. In summary, this work reveals a unique and concerted interaction between MCL1 and ACSBG1 that function together to promote PEDV replication by regulating the AA metabolic pathway.
Korber B, Seaman MS, Mkhize NN
… +13 more, Greene K, Gao H, Shen X, Domin E, Tang H, Theiler J, Wagh K, Moore PL, Williamson C, Mullins JI, Doria-Rose NA, Montefiori D, Giorgi EE
PLoS Pathog
· 2026 Apr · PMID 42024654
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Although a protective HIV-1 vaccine has not yet been realized, significant progress has been made in vaccine designs that trigger B cell lineages with potential to produce broadly neutralizing antibodies (bnAbs). Advanci...Although a protective HIV-1 vaccine has not yet been realized, significant progress has been made in vaccine designs that trigger B cell lineages with potential to produce broadly neutralizing antibodies (bnAbs). Advancing these strategies by optimizing vaccine boosting regimens requires early detection of maturing antibodies with neutralizing activity against native envelope glycoprotein (Env) trimers and streamlined strategies to identify antibodies as they begin to manifest desired levels of breadth and potency. Thus, we designed three types of pseudovirus screening panels based on Envs of contemporary HIV-1 isolates to facilitate detection of bnAb lineages that are on favorable trajectories during a vaccination course. The panels were selected from Tier 2 Transmitted Founder Lineage (TFL) HIV-1 Envs from placebo participants in the Antibody Mediated Prevention (AMP) efficacy trials. Using 15 bnAbs to evaluate the neutralization sensitivity of the viruses, we selected 8-member bnAb class-specific panels most sensitive to bnAbs representing their class: V2-apex, V3-glycan, CD4-receptor binding site (CD4bs), Membrane-Proximal External Region (MPER), or fusion peptide (FP). Next, we combined the most sensitive viruses among the class-specific panels to create a 12-virus panel to enable optimal detection of low-titer bnAb activity across epitope specificities. Finally, as HIV-1 continues to evolve greater levels of antigenic diversity and as current global pseudoviruses bnAb panels rely on viruses collected more than twenty years ago, we showed the importance of using contemporary viral panels to assess bnAb breadth and potency and designed a 12-virus panel representative of the spectrum neutralization profiles among AMP placebo viruses. We characterized pseudoviruses bearing each selected Env using standardized human sera to confirm their Tier 2 status and biological relevance. These updated panels enable sensitive screening of neutralization activity in vaccine studies and can also provide a realistic assessment of the expected breadth and potency of maturing responses against contemporary HIV-1 Envs.
Matczak S, Sadi M, Leroux P
… +12 more, Labé P, Bouchez V, Schmutz S, Libri V, Seffer V, Novault S, Volant S, Brisse S, Hasan M, Duffy D, Tonnerre P, Toubiana J
PLoS Pathog
· 2026 Apr · PMID 42018590
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Pertussis is typically more severe in neonates and young infants, with fulminant forms possibly linked to age-specific systemic immune responses. However, the early events that shape the development of the immune respons...Pertussis is typically more severe in neonates and young infants, with fulminant forms possibly linked to age-specific systemic immune responses. However, the early events that shape the development of the immune response in neonates are poorly understood, mainly due to limited sample access and the absence of human ex vivo infection models. Here, multi-omic profiling of an ex vivo whole-blood infection model was used to investigate systemic immune responses to Bordetella pertussis. We observed a stronger pro-inflammatory immune response in cord blood (CB) compared to adult blood (AB), marked by a hyperinflammatory cytokine signature and an early loss of myeloid-derived suppressor cells. B cell remodeling was observed in both blood types, characterized by an increased fraction of CD25 + B lymphocytes exhibiting an activated transitional phenotype, with upregulated expression of activation markers, chemokines and immunosuppressors. Transcriptomic analysis of whole blood revealed a skewed immune response favoring innate immune cell activation in CB. Our findings shed light on early immune responses to B. pertussis, paving the way for further exploration of immune pathways in the pathogenesis of this major public health threat.
Russ A, Viherlehto V, Brey S
… +11 more, Wittmann S, Irrgang P, Leicht N, Cordsmeier A, Ensser A, Rieker RJ, Geppert C, Sticht H, Tenbusch M, Winkler TH, Gramberg T
PLoS Pathog
· 2026 Apr · PMID 42018583
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Advanced age is one of the greatest risk factors for a severe outcome of COVID-19. Although mRNA vaccines were highly successful in protecting the elderly, the strongest increase in morbidity and mortality upon infection...Advanced age is one of the greatest risk factors for a severe outcome of COVID-19. Although mRNA vaccines were highly successful in protecting the elderly, the strongest increase in morbidity and mortality upon infection with emerging SARS-CoV-2 variants was among the elderly. To better understand SARS-CoV-2 pathogenicity and to thoroughly evaluate novel vaccination strategies, better models reliably reproducing human SARS-CoV-2 pathogenicity are needed. Here, we generated mice expressing a human-mouse chimera of ACE2 (chACE2) by CRISPR/Cas9-mediated gene editing in C57BL/6 mouse zygotes. ChACE2 mice express the chimeric viral receptor at physiological levels, enabling efficient SARS-CoV-2 infection without the heightened mortality seen in K18-hACE2 mice due to neuroinvasion. We used the chACE2 model to analyze SARS-CoV-2 infection as well as antiviral immune responses in vitro and in vivo. Similar to SARS-CoV-2 in elderly humans, aged chACE2 mice suffered from a highly aggravated disease. In addition, we found that a live attenuated vaccine candidate, LAVNsp16, induces robust mucosal and systemic immune responses in these mice despite being highly attenuated. The immunization with LAVNsp16 protected aged chACE2 mice from otherwise severe pathogenicity of SARS-CoV-2 by blocking viral replication of homologous and heterologous SARS-CoV-2 variants. The newly developed chACE2 model allows for longer observation periods of SARS-CoV-2 infection in mice, which is essential for assessing the immunogenicity of novel vaccine designs or monitoring viral pathogenicity over time. Immunization with LAVNsp16 induced robust and protective immune responses in young and aged mice, making viruses lacking 2'-O-methyltrasferse activity promising candidates for future live attenuated vaccine development.
Hendrix J, Al Mubarak R, Reichlen MJ
… +12 more, Tabor ST, Bateman A, Massoudi LM, Rossmassler K, Kaya F, Zimmerman MD, Nielsen H, Wynn EA, Voskuil MI, Robertson GT, Moore CM, Walter ND
PLoS Pathog
· 2026 Apr · PMID 42018569
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Post-antibiotic effect (PAE) describes the delay in bacterial growth that continues after antibiotics are cleared. The physiologic basis of PAE in Mycobacterium tuberculosis (Mtb) remains poorly understood. Here, we eval...Post-antibiotic effect (PAE) describes the delay in bacterial growth that continues after antibiotics are cleared. The physiologic basis of PAE in Mycobacterium tuberculosis (Mtb) remains poorly understood. Here, we evaluated the long-standing hypothesis that PAE reflects the time required for bacteria to recover from drug-induced physiologic damage by comparing Mtb after varying durations of treatment with the four-drug isoniazid, rifampin, pyrazinamide, ethambutol combination in vitro and in BALB/c mice using two novel molecular readouts of bacterial health. In aerobic axenic culture and in the high-dose aerosol mouse model, quantification of Mtb rRNA synthesis via the RS ratio and Mtb transcriptional profiling via SEARCH-TB revealed that longer drug exposure was associated with greater injury and adaptation during treatment, as well as slower recovery after treatment, i.e., longer PAE. Recovery followed a conserved sequence, from resumption of rRNA synthesis, to broad transcriptional reprogramming, to eventual CFU change. In mice, however, physiologic recovery was markedly slower and less complete than in vitro, indicating longer PAE in the context of immunity. Our observation that PAE in Mtb depends on the duration of drug exposure and correlates with the degree of bacterial injury support the hypothesis that nonlethal physiologic damage contributes to PAE. Our observation that PAE of the standard TB regimen is longer in mice than in vitro indicates that immunity augments PAE for Mtb. Molecular evaluation of bacterial physiology provides a new basis for probing recovery from drug exposure and understanding PAE.
Toesca J, Castell M, Jacquemin C
… +10 more, Lalande A, Ogire E, Burlaud-Gaillard J, Roingeard P, Ramière C, Mathieu C, Perrin-Cocon L, Lotteau V, Vidalain PO, Diaz O
PLoS Pathog
· 2026 Apr · PMID 42018568
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BACKGROUND & AIMS: Hepatitis C virus (HCV) has the unique characteristic of forming lipo-viro-particles (LVPs), which are lipid-rich virions containing both the viral components and host apolipoproteins such as ApoB and...BACKGROUND & AIMS: Hepatitis C virus (HCV) has the unique characteristic of forming lipo-viro-particles (LVPs), which are lipid-rich virions containing both the viral components and host apolipoproteins such as ApoB and E. This unique composition gives to LVPs a low buoyant density, facilitates their entry into the hepatocyte, and is a hallmark of highly-infectious HCV particles. Although recent studies have shown that inhibiting NAD biosynthesis can both disrupt central carbon metabolism and thereby interfere with the replication of hepatotropic viruses such as dengue virus (DENV) and hepatitis B virus (HBV), the impact of nicotinamide biosynthesis inhibition on HCV replication and LVP formation has not yet been explored. METHODS: We therefore investigated the dependance of HCV on NAD(H) biosynthesis in Huh7 cells by using the antimetabolite 6-Aminonicotinamide (6-AN) or by specifically inhibiting NAMPT, a key enzyme in the nicotinamide salvage pathway. The impact on cellular metabolism was assessed by LC-MS/MS to quantify metabolites, by confocal microscopy to analyze lipid droplets and by ELISA for ApoB/E secretion. Glycolytic activity and mitochondrial respiration were evaluated by real-time measurement of extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), respectively. Consequences on viral replication were analyzed using both a subgenomic replicon (strain JFH1) and the full-length infectious virus (strain Jc1). The effect of 6-AN on the formation of double-membrane vesicles (DMVs) where the virus replicates was determined by transmission electron microscopy. Finally, the secretion and specific infectivity of virions were analyzed by RT-qPCR and titration technics, either before or after separation by density-gradient centrifugation to focus on LVPs. RESULTS: Pharmacological inhibition of NAD(H) biosynthesis in Huh7 cells impaired HCV replication, the formation of DMVs and the production of infectious LVPs. Mechanistically, 6-AN drastically inhibited glycolysis but increased oxidative phosphorylation as compensatory mechanism. This metabolic reprogramming was associated with decreased intracellular levels of triglycerides, smaller lipid droplets and reduced secretion of Apo B and E, which altogether could explain the impact of 6-AN on HCV replication and the production of LVPs. CONCLUSIONS: Inhibiting NAD(H) biosynthesis disrupts central carbon metabolism, reduces intracellular triglycerides and blocks ApoB⁺-lipoprotein secretion-a pathway essential for HCV replication and LVP production. These results reveal, for the first time, that HCV life cycle is critically dependent on NAD(H) metabolism, reinforcing the interest of this pathway as a potential therapeutic target against hepatotropic viruses.
Saha A, Michalets SE, Uddbäck I
… +4 more, Ahmed H, Kohlmeier JE, Antia R, Koelle K
PLoS Pathog
· 2026 Apr · PMID 42013175
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Viral transmission from infected donors to uninfected recipients is the key event underlying the spread of viral pathogens at the level of a host population. Successful viral transmission from a donor to a recipient depe...Viral transmission from infected donors to uninfected recipients is the key event underlying the spread of viral pathogens at the level of a host population. Successful viral transmission from a donor to a recipient depends on several factors including the infectiousness of the donor. Donor infectiousness in turn can depend on the viral kinetics and viral load of the donor, donor behavior and symptoms, and donor immunity. Here, we use a mouse model of murine respirovirus (otherwise known as Sendai virus SeV) infection to quantitatively explore donor determinants of respiratory virus transmission. The experimental transmission studies we analyze are specifically designed to address the effect that pre-existing donor immunity may have on transmission potential by studying SeV transmission from both immunized and control (placebo-immunized) donors to naïve recipients. We specifically focus on the impact of tissue resident memory (TRM) CD8 T cells on donor transmission potential by considering immunization strategies that primarily generate CD8 T cell immunity. Through quantitative analyses of these experiments, we find that pre-existing CD8 TRMs act to reduce donor transmission potential. This finding is in agreement with previous findings and can be in part explained by a reduction in total infection load in immunized donors. However, even once differences in infection load between immunized and control donors are accounted for, immunized donors still have reduced infectiousness relative to control donors. We explore possible reasons for this unexpected pattern using a mathematical model that integrates within-host viral dynamics and between-host transmission occurrences. Analysis of model simulations, along with observations from knock-out experiments, suggests that interferon gamma (IFN-[Formula: see text]) may be partly responsible for the observed differences in infectiousness between control and immune donors. Future experimental transmission studies should consider measuring IFN-[Formula: see text] levels and its effects when interpreting transmission outcomes in the context of host immunity.
PLoS Pathog
· 2026 Apr · PMID 42013167
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Lyme disease, caused by the spirochete, Borrelia burgdorferi sensu latu (Bbsl), is a tickborne infection of increasing incidence in North America, Europe and Asia. While vaccines based on Outer surface protein A (OspA) h...Lyme disease, caused by the spirochete, Borrelia burgdorferi sensu latu (Bbsl), is a tickborne infection of increasing incidence in North America, Europe and Asia. While vaccines based on Outer surface protein A (OspA) have proven highly efficacious at blocking Bbsl tick-to-human transmission, the high degree of antigenic variability among the major OspA serotypes (ST) has made the development of a broadly cross protective vaccine difficult. Recent profiling of protective human monoclonal antibodies (mAbs) has suggested the existence of conserved epitopes situated within OspA's central β-sheet (CBS), although direct comparisons of cross-serotype functionality has been hindered by biological differences among the major Bbsl genospecies. To address these issues, we developed a panel of isogenic B. burgdorferi reporter strains expressing the seven major OspA serotypes (ST1-7) and probed them with CBS-targeting mAbs to evaluate their complement-dependent borreliacidal activity. The mAbs segregated into three distinct classes: class 1 mAbs exhibited potent killing against all seven OspA serotypes, while classes 2 and 3 had restricted or no activity against two of the seven serotypes. Structural analysis of Fabs derived from each class of mAbs in complex with OspA ST1 showed that they target overlapping epitopes spanning β-strands 6-10 and involve contact with largely invariant residues. Further analysis of B. burgdorferi reporter strains expressing OspA variants from 17 additional Bbsl genospecies identified Lys-107 as a determinant of susceptibility for nearly all CBS mAbs. Taken together, these findings raise the prospect of structure-based design of a broadly protective monovalent Lyme disease vaccine.
Maseeme M, Tezera LB, Noursadeghi M
… +2 more, Leslie A, Pollara G
PLoS Pathog
· 2026 Apr · PMID 42013127
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The number 17 is considered unlucky by some Italians as its Roman numerals - XVII - can be rearranged as Vixi, a Latin expression that can be interpreted as "my life is over". In other contexts, the number 17 is associat...The number 17 is considered unlucky by some Italians as its Roman numerals - XVII - can be rearranged as Vixi, a Latin expression that can be interpreted as "my life is over". In other contexts, the number 17 is associated with wisdom and success. This paradox holds true when it comes to the role of interleukin 17 (IL-17) in tuberculosis (TB). On one hand, immune correlates of protection studies have consistently identified IL-17 responses as key players in natural and vaccine induced protection against infection and disease. On the other, IL-17 has been proposed as a main driver of the immunopathology that underlies TB morbidity and mortality. Thus, while some researchers seek to develop novel TB vaccine approaches that promote IL-17 responses, others hunt for host-directed therapeutic approaches that block its activity. In this article, we attempt to address this conundrum and synthesise the main arguments supporting a role for IL-17 in the protection and pathogenesis of this deadly human infectious disease. Ultimately, as with superstition, whether the 17th interleukin is friend or foe in human TB is likely to depend on the context.
PLoS Pathog
· 2026 Apr · PMID 42008600
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Domestic animals play a central role in pathogen transmission at the human-wildlife interface. Domestic cats, in particular, are uniquely consequential in disease spillover dynamics due to their global distribution, larg...Domestic animals play a central role in pathogen transmission at the human-wildlife interface. Domestic cats, in particular, are uniquely consequential in disease spillover dynamics due to their global distribution, large, human-subsidized free-roaming populations, and high contact rate with humans, domestic animals, and wildlife. However, the extent to which human ownership and management mitigate this spillover risk remains a key knowledge gap. To address this gap, we conducted a global systematic review and quantitative synthesis of the prevalence and diversity of zoonotic pathogens in indoor-only, outdoor-owned (roaming unsupervised), and unowned (feral or stray) cats. Our dataset comprised 174,064 individuals from 88 countries, representing 124 pathogen species, 97 of which are zoonotic. Using generalized linear models within a Bayesian framework and rarefaction analyses, we show that ownership provides limited protection against zoonoses when owned cats have unsupervised outdoor access. Outdoor-owned cats were 3-5 times more likely to carry zoonotic pathogens than indoor-only cats, and, notably, had infection odds statistically equivalent to those of feral cats, despite receiving presumed veterinary care and feeding. Feral cats carried the highest pathogen diversity, however, outdoor-owned cats still harbour 1.5 times the helminth richness of indoor cats, highlighting their potential as effective bridges for pathogen spillover. With approximately 62% of owned cats roaming freely worldwide, and rates exceeding 90% in some regions, these findings reveal a major yet overlooked route of zoonotic risk. Public health and One Health frameworks have traditionally focused on feral cats; however, our results highlight the need to explicitly incorporate owned outdoor cats into zoonotic disease prevention strategies by restricting unsupervised roaming and promoting responsible ownership practices. Without such integration, current frameworks risk overlooking a pervasive and preventable pathway for pathogen transmission at the human-wildlife-domestic animal interface.
Liu K, Xie X, Li Y
… +4 more, Zhang S, Zang W, Li Q, Pan Y
PLoS Pathog
· 2026 Apr · PMID 42008577
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Fusobacterium nucleatum, a periodontal pathogen, has been increasingly implicated in pulmonary diseases including chronic obstructive pulmonary disease (COPD). This study demonstrates that F. nucleatum adheres to and inv...Fusobacterium nucleatum, a periodontal pathogen, has been increasingly implicated in pulmonary diseases including chronic obstructive pulmonary disease (COPD). This study demonstrates that F. nucleatum adheres to and invades pulmonary epithelial cells in a dose-dependent manner, primarily mediated by its adhesin FadA. We identify cadherin-11 (CDH11), which is upregulated in COPD lungs and in pulmonary epithelial cells treated with F. nucleatum or FadAc protein, as the key host receptor for FadA. This FadA-CDH11 interaction not only mediates bacterial adhesion and invasion, but also activates the MAPK13/JUN pathway, leading to significant upregulation of pro-inflammatory cytokines including CSF3, TNF-α, CCL20, and TGF-β. Genetic knockdown of CDH11 abolishes MAPK13/JUN activation and cytokine induction but does not affect FadA-mediated p53 suppression, indicating a separate pathway for this oncogenic event. Our findings establish the FadA-CDH11-MAPK13/JUN axis as a central mechanism driving F. nucleatum-exacerbated pulmonary inflammation and tissue damage, highlighting its potential as a therapeutic target for mitigating COPD progression.
Gracias S, Le Seac'h E, Donaire-Carpio S
… +21 more, Vuillier F, Vendramini L, Moundib A, Temmam S, Rutkowska M, Donati F, Cupic A, Juste J, Martinez-Romero C, Morel N, Schwartz O, Krogan NJ, Miorin L, Müller MA, Demeret C, Munier S, Roingeard P, Batra J, Garcia-Sastre A, Caval V, Jouvenet N
PLoS Pathog
· 2026 Apr · PMID 42008572
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Asian Rhinolophus bats are considered the natural reservoirs of an ancestral SARS-CoV-2. However, the biology of SARS-CoV-2-related viruses in bat cells is not well understood. Here, we investigated the replication of an...Asian Rhinolophus bats are considered the natural reservoirs of an ancestral SARS-CoV-2. However, the biology of SARS-CoV-2-related viruses in bat cells is not well understood. Here, we investigated the replication of an isolate of BANAL-236, the only bat-derived SARS-CoV-2 relative isolated to date, in Rhinolophus ferrumequinum lungs (Rfe) cells. BANAL-236 did not replicate in wild-type Rhinolophus cell lines. Entry assays using pseudoviruses expressing the spike proteins (S) of SARS-CoV-2, BANAL-236, and BANAL-52 revealed that efficient S-mediated entry depends on the expression of human ACE2 (hACE2) and human TMPRSS2 (hTMPRSS2) in human and Rhinolophus cells. Through biochemical, virological, and electron microscopy analyses, we showed that BANAL-236 and SARS-CoV-2 completed their replication cycles in RFe cells engineered to express high levels of hACE2 and hTMPRSS2. Despite efficient viral replication in modified Rhinolophus and human cells, no induction of interferon (IFN)-stimulated genes was detected. Using a screening approach, we identified several BANAL-236 proteins that antagonize IFN production and signalling in human cells. Our findings thus show that BANAL-236 possesses critical features that enabled zoonotic spillover: hACE2 usage and potent evasion of human IFN responses. The Rhinolophus cellular model we established offers a platform for further investigating the interactions between bat sarbecoviruses and their reservoir hosts.
Sotiropoulos AG, Müller MC, Kunz L
… +6 more, Graf JP, Kiss L, Hückelhoven R, Schlagenhauf E, Keller B, Wicker T
PLoS Pathog
· 2026 Apr · PMID 42008569
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Grass powdery mildews (Blumeria spp.) include economically important fungal crop pathogens with complex and highly repetitive genomes. To investigate the diversity and genome evolution in Blumeria graminis, we combined p...Grass powdery mildews (Blumeria spp.) include economically important fungal crop pathogens with complex and highly repetitive genomes. To investigate the diversity and genome evolution in Blumeria graminis, we combined population genetic and pangenomic analyses using a worldwide sample of 399 wheat powdery mildew isolates. Additionally, we produced high-quality genome assemblies for seven isolates from wheat and one from rye powdery mildew. Using these, we compiled the first grass powdery mildew pangenome comprising 11 Blumeria graminis isolates. We found multiple chromosomal rearrangements between the isolates that grow on wheat, rye and/or triticale hosts. Interestingly, chr-11 showed some characteristics, comparable to accessory chromosomes such as presence/absence of large chromosomal segments and higher sequence diversity. Additionally, we identified nearly 67,000 cases of copy number variations (CNVs), which were highly enriched within effector gene families. Furthermore, we found evidence for recent and high transposable element (TE) activity, such as high numbers of TE insertion polymorphisms. Analyses of TE families showed enrichment 1 kb to 2 kb up- and downstream of effector genes, and we also found high levels of TE insertion polymorphisms between populations. Our results demonstrate that chromosomal variations, gene family expansions and contractions, and TE activity are important sources of genome diversification and diversity in grass powdery mildews. Our findings indicate that a combination of pangenomic and population genetics analyses is needed to understand drivers of evolution in plant pathogenic fungi in a comprehensive way.
Brito LF, Ostermann E, Tödter S
… +7 more, Virdi S, Indenbirken D, Brixel R, Arens R, Grundhoff A, Brune W, Stahl FR
PLoS Pathog
· 2026 Apr · PMID 42008567
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Differential antiviral T cell immunity in early life impacts the clinical outcome of Cytomegalovirus (CMV) infection, but the underlying mechanisms are not well understood. T cells are known to be involved in protection...Differential antiviral T cell immunity in early life impacts the clinical outcome of Cytomegalovirus (CMV) infection, but the underlying mechanisms are not well understood. T cells are known to be involved in protection from CMV disease. To further elucidate these mechanisms, we used a model of respiratory murine CMV (MCMV) infection and adoptive T cell transfers to characterize MCMV-specific T cell responses in early life. We analyzed the effector T cell differentiation using single-cell RNA sequencing and assessed the local pulmonary cytokine milieu. We found delayed enrichment of early-life murine MCMV-specific CD8 T cells due to a general deficiency of αβ T cells. Adoptive transfer of naïve adult T cells into neonates did not protect from lung MCMV infection due to generation of non-cytotoxic CD8 effector T cells. Furthermore, key cytokines required for effective CD8 T cell priming were absent in early life. Supplementation with these cytokines enhanced infection control by transferred adult T cells. The effector function of adult-primed T cells was not disrupted in neonates. Together, this study suggests defective CD8 T cell priming in neonates as a factor explaining the higher risk for MCMV lung disease in the early-life phase.
Sellitto S, Caredio D, Bimbati M
… +13 more, Mariutti G, Cerisoli M, Frick L, Bouris V, Morales COO, Vena DL, Neupane S, Baroni F, Ging K, Yin JA, De Cecco E, Armani A, Aguzzi A
PLoS Pathog
· 2026 Apr · PMID 42008486
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Heterogeneous Nuclear Ribonucleoprotein K (hnRNP K) is a limiting factor for prion propagation. However, little is known about the function of hnRNP K except that it is essential to cell survival. Here, we performed a sy...Heterogeneous Nuclear Ribonucleoprotein K (hnRNP K) is a limiting factor for prion propagation. However, little is known about the function of hnRNP K except that it is essential to cell survival. Here, we performed a synthetic-viability CRISPR ablation screen to identify epistatic interactors of HNRNPK. We found that deletion of Transcription Factor AP-2γ (TFAP2C) suppressed the death of hnRNP K-depleted LN-229 and U-251 MG cells, whereas its overexpression hypersensitized cells to hnRNP K loss. HNRNPK ablation decreased cellular ATP, downregulated genes related to lipid and glucose metabolism, and enhanced autophagy. Co-occurrent deletion of TFAP2C reversed these effects, restoring transcriptional balance and alleviating energy deficiency. We linked HNRNPK and TFAP2C functional and genetic interaction to mTOR signaling, observing that hnRNP K depletion inhibited mTORC1 activity through downregulation of mTOR and Rptor, while TFAP2C overexpression enhanced mTORC1 downstream functions. In prion-infected cells, TFAP2C activation reduced prion levels and countered the increased prion propagation caused by HNRNPK suppression. Short-term inhibition of mTORC1 also elevated prion levels and partially mimicked the effects of HNRNPK silencing. Our study identifies TFAP2C as a genetic interactor of HNRNPK, implicates their roles in mTOR metabolic regulation, and establishes a causative link between these activities and prion propagation.
den Boon JA, Jaramillo-Mesa H, Horswill M
… +4 more, Jochem A, Bracken M, Zhan H, Ahlquist P
PLoS Pathog
· 2026 Apr · PMID 42008461
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Positive-strand RNA viruses replicate their RNA genomes in virus-induced, membrane-bounded organelles. As first found for nodaviruses, the necked cytosolic portals of these organelles bear ringed "crown" complexes of vir...Positive-strand RNA viruses replicate their RNA genomes in virus-induced, membrane-bounded organelles. As first found for nodaviruses, the necked cytosolic portals of these organelles bear ringed "crown" complexes of viral RNA replication proteins that drive synthesis, capping and release of new RNA genomes. Nodavirus crowns contain two 12-mer rings of viral protein A with C-proximal polymerase domains stacked. In the basal ring, protein A's N-proximal RNA capping domains form a central, toroidal floor, while in the apical ring these domains extend radially outward. A third protein A conformation provides a putative central Pol domain interacting with the viral dsRNA replication intermediate in a vesicle beneath the crown. Protein A's multiple conformations likely differentially contribute to crown assembly, RNA template recruitment, (-) and (+) strand synthesis, RNA capping, and progeny RNA release. Protein A's high copy numbers may provide robustness to these processes. To test such concepts, we combined mutational, complementation and functional analyses. Strong complementation between null mutants in protein A's polymerase and RNA capping active sites showed that they operate in independent protein A copies, likely at distinct sites. Thus, neither function is required in all protein A copies, nor are both required in any single copy. Lack of complementation between mutants in distinct RNA capping steps implied that major RNA capping steps must be performed in the same protein. Although RNA polymerase and capping activity were not required in all protein A subunits, none of a series of deletions across these domains were complementable, showing the importance of structural and other requirements for crown assembly, etc.. Surprisingly, RNA replication was more sensitive to depleting the fraction of subunits retaining protein A's C-terminal intrinsically disordered region than polymerase or capping activity. These and other results reveal and illuminate the cooperative, interdependent nature of protein A's diverse functions.
PLoS Pathog
· 2026 Apr · PMID 42008454
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The diversity of forest communities is intricately shaped by the mycorrhizal associations that trees form with soil fungi. Mycorrhizae, which are mutualistic relationships between fungi and plants, play pivotal roles in...The diversity of forest communities is intricately shaped by the mycorrhizal associations that trees form with soil fungi. Mycorrhizae, which are mutualistic relationships between fungi and plants, play pivotal roles in nutrient exchange and tree survival. This review explores how the type of mycorrhizal association-arbuscular mycorrhizal (AM) or ectomycorrhizal (ECM)-impacts forest tree diversity across various scales. AM fungi dominate tropical forests, potentially contributing to high species richness, while ECM fungi are more prevalent in temperate regions, where they often correlate with lower diversity. We discuss how these associations influence soil properties, plant-soil feedback, and seedling establishment, ultimately shaping forest structure. We also examine the complexity of the relationship between mycorrhizal type and tree species richness, noting the differences in patterns observed across different spatial scales. As research continues, it will be crucial to examine local dynamics in underrepresented regions and explore how mycorrhizal interactions change over time to understand their role in maintaining forest biodiversity. By considering these dynamics, we can better predict how forests will respond to environmental changes and develop strategies for preserving and restoring forest ecosystems.