Scholarly Works, Center for Emerging, Zoonotic, and Arthropod-borne Pathogens (CeZAP)

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Assessing sexual dimorphism in the common vampire bat, Desmodus rotundus
Cifuentes-Rincon, Analorena; Sarmiento-Arias, Karen D.; Soler-Tovar, Diego; Rodríguez-Bolaños, Abelardo; Bravo-Garcia, Carlos; Reyes-Amaya, Nicolas; Ávila-Vargas, Laura; Escobar, Luis E. (Public Library of Science, 2026-01)
Sexual dimorphism in bats is understudied, with conflicting evidence across species and geographic regions. For Desmodus rotundus, the common vampire bat, previous reports on morphological sex differences have been inconsistent. This study aimed to assess sexual dimorphism in D. rotundus using a combination of contemporary field measurements and historical museum specimens. We analyzed six morphometric traits, including body mass, head length, body length, tibia length, ear length, and forearm length. Data were collected from 46 wild-captured individuals from five locations across Colombia in South America. Additionally, forearm length was examined in an expanded dataset of 490 specimens, including additional 444 individuals from museum vouchers collected over the past century. Principal components analysis and hierarchical clustering of the six-trait dataset showed patterns of differentiation between sexes, with partial overlap. Forearm length, analyzed independently in the full 490-specimen dataset, showed strong evidence of sexual dimorphism. Females had significantly longer forearms (mean = 61.8 mm) than males (mean = 58.5 mm), with non-overlapping 95% confidence intervals and a highly significant t-test result (t = -12.68, p < 2 × 10 ⁻ ¹⁶). Sex explained 25.7% of the variation in forearm length (R² = 0.26). Tibia length also differed significantly between sexes of the wild-catch individuals (p = 0.004), with females exhibiting greater values. Comparisons between museum specimens (historical) and wild-caught specimens (contemporary) showed no significant differences across time in either sex. Among females, the difference was not significant (t = -0.93, df = 208, p = 0.355), and the same was true for males (t = -0.01, df = 278, p = 0.992). A follow-up MANOVA on the six morphometric traits indicated a significant effect of sex (Pillai's trace = 0.389, approx. F(6,39)=4.14, p < 2.2 × 10 ⁻ ¹⁶). After correcting for multiple comparisons, significant sexual dimorphism remained for forearm and tibia lengths, with forearm showing the strongest signal. These findings provide robust support for modest but consistent female-biased dimorphism in D. rotundus. The use of both multivariate and univariate analysis, combined with long-term historical data, enhanced the reliability of signals detected regarding morphological differences. Desmodus rotundus play a role as a primary reservoir for zoonotic viruses, has potential relevance in biomedical research, and provides ecosystem services. Understanding sex-based morphological variation is critical to inform public health, ecology, and biological conservation strategies. Females were consistently larger than males, but segregation was not absolute, with some individuals falling outside the expected data range for their sex. This study contributes to a clearer understanding of morphological variation and lays the groundwork for future research into the ecological and evolutionary drivers of dimorphism in bats.
Hotspots of bacterial pathogen abundance and exposure risk in soils of the contiguous United States
Matthews, Emily A.; Goh, Ying-Xian; Hepp, Shannon L.; Liao, Jingqiu; Calder, Ryan S. D. (American Geophysical Union, 2025-12-11)
Soils are reservoirs of pathogenic bacteria that cause human illness, particularly after mobilizing events such as extreme rain. Land-use patterns (e.g., proximity to agriculture) and soil properties (e.g., moisture) are associated with abundance of individual pathogenic bacteria. However, there are major uncertainties in (a) the importance of local/regional land-use decisions relative to overall natural variability of pathogenicity and (b) the correlations among pathogen abundance, climate-linked physical processes increasing pathogen mobility, and the vulnerability of human receptors. This impairs identification of priority areas for outbreak surveillance, which has traditionally focused on food and water distribution networks, and the development of process-based risk screening models. Here, we analyze a novel data set of 622 soil samples covering 42 of the 48 contiguous United States. We describe (a) the relationship between putative pathogenicity and natural and land-use drivers and (b) how hotspots of putative pathogen abundance intersect with climate-linked hazard of mobilization via fire, floods, wind, and fluvial transport, and the social vulnerability of local human populations. Variability in putative pathogenicity can be partially explained by known drivers, with natural variables having greater explanatory power than land-use variables. Relative abundance of putative pathogens is generally higher in forested ecoregions, notably in the eastern and southeastern United States and in proximity to surface waters. Higher relative abundance of putative pathogens, climate risks promoting pathogen mobility, and a relatively vulnerable rural population intersect in the southeastern United States. Integrated sampling and modeling are needed to monitor and forecast health risks from soilborne pathogens.
Isolation and characterization of four novel Vibrio parahaemolyticus bacteriophages from oysters
Aldaroub, Joud; Walsky, Chrissy M.; Elwell, Rylee E.; Aylward, Frank O.; Stevens, Ann M.; Burke, Alison Kernell (2025-12-29)
Vibrio parahaemolyticus (VP) is a bacterial pathogen found in brackish and marine water that infects many marine organisms, such as oysters and shrimp. Consumption of raw or undercooked seafood contaminated with V. parahaemolyticus is a primary cause of seafood-borne gastroenteritis in humans. Due to increasing ocean temperatures, V. parahaemolyticus contamination of oyster beds in the United States has spread up the east and west coasts to the northern-most states. Promising new research is exploring the isolation of bacteriophages against V. parahaemolyticus with a long-term goal to possibly decontaminate oyster beds, thereby expanding the harvest season and allowing for safer consumption of seafood. In this study, storebought oysters harvested from the Chesapeake Bay in Virginia were used to isolate four bacteriophages with activity against a specific V. parahaemolyticus strain. A standard double agar overlay plaque assay was used to identify phage activity. After phage isolation, the genomes were sequenced, and transmission electron microscopy (TEM) was performed to visualize the virions. The genomes and TEM images revealed four distinct phages. Three of the phages are distinct isolates that exhibit podovirus-like morphology with short tails and genome sizes of approximately 43 kbp. One phage has siphovirus-like morphology and is a mid-sized tailed phage with a genome size of 80 kbp. Although spot tests performed with the oyster homogenates on up to 10 different V. parahaemolyticus strains recovered activity across a wide range of hosts, plaque assays with the isolated phages showed limited host range. Future work will be necessary to determine the viability of using the bacteriophages for elimination of V. parahaemolyticus in harvested oysters, treatment of aquaculture seed and spat, and/or the environment.
Contrasting La Crosse Virus Lineage III Vector Competency in Two Geographical Populations of Aedes triseriatus and Aedes albopictus Mosquitoes
Faw, Lindsey R.; Armstrong, Philip M.; Paulson, Sally L.; Eastwood, Gillian (MDPI, 2025-12-11)
La Crosse virus (LACV) is a mosquito-borne virus (family Peribunyaviridae) that can result in severe human infection in children under sixteen. Historically, LACV comprised two lineages, predominantly in the Midwest and Appalachian regions of the US. In 2005, a virus of a third lineage was detected in the Northeast; however, this and subsequently isolated strains of lineage III have not, to date, been implicated in human disease. One hypothesis for this discrepancy is that vector mosquitoes have a reduced vector competency for LACV lineage III, thus preventing horizontal transmission and clinical cases. Here, we utilized two mosquito species, Aedes triseriatus, the native vector, and Aedes albopictus, an invasive potential vector, each from both a historic LACV range (Virginia) and from the region of lineage III (Connecticut). Utilizing oral feeding and intrathoracic inoculation methods of viral exposure, rates of LACV infection, dissemination, and transmission (proxied via salivary secretion) and capability for vertical transmission (proxied via virus-positive ovaries) were determined by harvesting mosquito bodies, legs, saliva, and ovaries, respectively. Overall, we did not detect consistent differences in transmission between any lineage, species, or state of origin, at day 14 post-infection. However, we highlight the transmission potential of LACV lineage III in all mosquito populations tested here, representing the first evidence of lineage III competency in Aedes triseriatus and Aedes albopictus, indicating the potential for human disease. We thus suggest that the absence of human cases of LACV lineage III is not modulated by a lack of vector competency in mosquitoes.
Chromosomal inversions and their impact on insect evolution
Sharakhov, Igor V.; Sharakhova, Maria V. (Elsevier, 2024-12)
Insects can adapt quickly and effectively to rapid environmental change and maintain long-term adaptations, but the genetic mechanisms underlying this response are not fully understood. In this review, we summarize studies on the potential impact of chromosomal inversion polymorphisms on insect evolution at different spatial and temporal scales, ranging from long-term evolutionary stability to rapid emergence in response to emerging biotic and abiotic factors. The study of inversions has recently been advanced by comparative, population, and 3D genomics methods. The impact of inversions on insect genome evolution can be profound, including increased gene order rearrangements on sex chromosomes, accumulation of transposable elements, and facilitation of genome divergence. Understanding these processes provides critical insights into the evolutionary mechanisms shaping insect diversity.
Analysis of somatic piRNAs in the malaria mosquito Anopheles coluzzii reveals atypical classes of genic small RNAs
Funikov, Sergei; Rezvykh, Alexander; Akulenko, Natalia; Liang, Jiangtao; Sharakhov, Igor V.; Kalmykova, Alla (Taylor & Francis, 2025-12-31)
Piwi-interacting small RNAs (piRNA) play a key role in controlling the activity of transposable elements (TEs) in the animal germline. In diverse arthropod species, including the pathogen vectors mosquitoes, the piRNA pathway is also active in nongonadal somatic tissues, where its targets and functions are less clear. Here, we studied the features of small RNA production in head and thorax tissues of an uninfected laboratory strain of Anopheles coluzzii focusing on the 24–32-nt-long RNAs. Small RNAs derived from repetitive elements constitute a minor fraction while most small RNAs process from long noncoding RNAs (lncRNAs) and protein-coding gene mRNAs. The majority of small RNAs derived from repetitive elements and lncRNAs exhibited typical piRNAs features. By contrast, majority of protein-coding gene-derived 24–32 nt small RNAs lack the hallmarks of piRNAs and have signatures of nontemplated 3' end tailing. Most of the atypical small RNAs exhibit female-biased expression and originate from mitochondrial and nuclear genes involved in energy metabolism. We also identified atypical genic small RNAs in Anopheles gambiae somatic tissues, which further validates the noncanonical mechanism of their production. We discuss a novel mechanism of small RNA production in mosquito somatic tissues and the possible functional significance of genic small RNAs.
Obesity fosters severe disease outcomes in a mouse model of coronavirus infection associated with transcriptomic abnormalities
Rai, Pallavi; Marano, Jeffrey M.; Kang, Lin; Coutermarsh-Ott, Sheryl; Daamen, Andrea R.; Lipsky, Peter E.; Weger-Lucarelli, James (Wiley, 2024-04-01)
Obesity has been identified as an independent risk factor for severe outcomes in humans with coronavirus disease 2019 (COVID-19) and other infectious diseases. Here, we established a mouse model of COVID-19 using the murine betacoronavirus, mouse hepatitis virus 1 (MHV-1). C57BL/6 and C3H/HeJ mice exposed to MHV-1 developed mild and severe disease, respectively. Obese C57BL/6 mice developed clinical manifestations similar to those of lean controls. In contrast, all obese C3H/HeJ mice succumbed by 8 days postinfection, compared to a 50% mortality rate in lean controls. Notably, both lean and obese C3H/HeJ mice exposed to MHV-1 developed lung lesions consistent with severe human COVID-19, with marked evidence of diffuse alveolar damage (DAD). To identify early predictive biomarkers of worsened disease outcomes in obese C3H/HeJ mice, we sequenced RNA from whole blood 2 days postinfection and assessed changes in gene and pathway expression. Many pathways uniquely altered in obese C3H/HeJ mice postinfection aligned with those found in humans with severe COVID-19. Furthermore, we observed altered gene expression related to the unfolded protein response and lipid metabolism in infected obese mice compared to their lean counterparts, suggesting a role in the severity of disease outcomes. This study presents a novel model for studying COVID-19 and elucidating the mechanisms underlying severe disease outcomes in obese and other hosts.
Inter-epidemic seroprevalence of Rift Valley fever virus and associated risk factors in humans in Eastern Rwanda
Nsengimana, Isidore; Kelvin, David; Uwibambe, Evodie; Rwagasore, Edson; Muvunyi, Claude M.; Eastwood, Gillian; Chengula, Augustino A.; Kasanga, Christopher J. (Public Library of Science, 2025-08-01)
Background: Rift Valley fever (RVF) is a mosquito-borne zoonosis that causes periodic and explosive epizootics/epidemics in Africa and the Arabian Peninsula. In Rwanda, RVF virus (RVFV) circulation has resulted into two major outbreaks in 2018 and 2022, both of which involving humans. Information on the magnitude of human exposure to RVFV in the country is scarce. This cross-sectional study aimed to investigate the seroprevalence of RVFV and associated risk factors in humans in the Eastern province of Rwanda, 3 years after the end of the 2018 outbreak. Methodology: A total of 552 outpatients at health facilities in five districts of the Eastern province were randomly sampled and interviewed between December 2021 and February 2022. Exposure to RVFV was examined by detection of anti-RVFV IgG/IgM antibodies in serum samples using a competitive enzyme linked immunosorbent assay (c-ELISA). Bivariate and multivariate logistic regressions were used to assess the association between risk factors and RVFV seropositivity. Results: The findings revealed an overall seroprevalence of 9.6%. The highest seropositivity, but without significant difference, was observed in Bugesera district (12.9%), followed by Kayonza, (10.8%), Kirehe (8.6%), Rwamagana (7.0%) and Ngoma (6.8%). Odds of seropositivity were significantly higher in people with a history of slaughtering animals (OR 2.26, 95% CI 1.04-4.91, p=0.03), and milking (OR 2.60, 95% CI 1.23-5.49, p=0.012). Sex and age-related differences were not significant. Conclusion: This study is a first serological survey of RVFV spillover to humans in the country and shows that rural communities in Rwanda have been exposed to RVFV. These findings suggest the Eastern province of Rwanda as a potential hotspot for RVFV circulation, and emphasize the need for a countrywide One Health-based surveillance, prevention, and control strategy to minimize the effects of RVFV in the country.
Noninvasive Analysis of Peptidoglycan from Living Animals
Ocius, Karl L.; Kolli, Sree H.; Ahmad, Saadman S.; Dressler, Jules M.; Chordia, Mahendra D.; Jutras, Brandon L.; Rutkowski, Melanie R.; Pires, Marcos M. (American Chemical Society, 2024-04-09)
The role of the intestinal microbiota in host health is increasingly revealed in its contributions to disease states. The host-microbiome interaction is multifactorial and dynamic. One of the factors that has recently been strongly associated with host physiological responses is peptidoglycan from bacterial cell walls. Peptidoglycan from gut commensal bacteria activates peptidoglycan sensors in human cells, including the nucleotide-binding oligomerization domain-containing protein 2. When present in the gastrointestinal tract, both the polymeric form (sacculi) and depolymerized fragments can modulate host physiology, including checkpoint anticancer therapy efficacy, body temperature and appetite, and postnatal growth. To utilize this growing area of biology toward therapeutic prescriptions, it will be critical to directly analyze a key feature of the host-microbiome interaction from living hosts in a reproducible and noninvasive way. Here we show that metabolically labeled peptidoglycan/sacculi can be readily isolated from fecal samples collected from both mice and humans. Analysis of fecal samples provided a noninvasive route to probe the gut commensal community including the metabolic synchronicity with the host circadian clock. Together, these results pave the way for noninvasive diagnostic tools to interrogate the causal nature of peptidoglycan in host health and disease.
Once bitten, twice shy: A modeling framework for incorporating heterogeneous mosquito biting into transmission models
Dahlin, Kyle J. M.; Robert, Michael A.; Childs, Lauren M. (Springer, 2025-11-01)
The risk and intensity of mosquito-borne disease outbreaks are tightly linked to the frequency at which mosquitoes feed on blood, also known as the biting rate. However, standard models of mosquito-borne disease transmission inherently assume that mosquitoes bite only once per reproductive cycle—an assumption commonly violated in nature. Drivers of multiple biting, such as host defensive behaviors or climate factors, also affect the mosquito gonotrophic cycle duration (GCD), a quantity customarily used to estimate the biting rate. Here, we present a novel framework for incorporating more complex mosquito biting behaviors into transmission models. This framework can account for heterogeneity in and linkages between mosquito biting rates and multiple biting. We provide general formulas for the basic offspring number, N0, and basic reproduction number, R0, threshold measures for mosquito population and pathogen transmission persistence, respectively. To exhibit its flexibility, we expand on specific models derived from the framework that arise from empirical, phenomenological, or mechanistic modeling perspectives. Using the gonotrophic cycle duration as a standard quantity to make comparisons among the models, we show that assumptions about the biting process strongly affect the relationship between GCD and R0. While under the standard assumption of one bite per reproductive cycle, R0 is an increasing linear function of the inverse of the GCD, alternative models of the biting process can exhibit saturating or concave relationships. Critically, from a mechanistic perspective, decreases in the GCD can lead to substantial decreases in R0. Through sensitivity analysis of the mechanistic model, we determine that parameters related to probing and ingesting success are the most important targets for disease control. This work highlights the importance of incorporating the behavioral dynamics of mosquitoes into transmission models and provides a method for evaluating how individual-level interventions against mosquito biting scale up to determine population-level mosquito-borne disease risk.
Regioselective Annulation of 6-Carboxy-Substituted Pyrones as a Two-Carbon Unit in Formal [4+2] Cycloaddition Reactions
Kohanov, Zachary A.; Shuvo, Suzzudul Islam; Lowell, Andrew N. (American Chemical Society, 2024-06-13)
Heterocycles serve as a critical motif in chemistry, but despite being present in more than 85% of pharmaceuticals, there are limited methods for their construction. Here, we describe the incorporation of intact pyrone (2H-pyran-2-one) into larger ring systems via annulation. In a formal [4 + 2] cycloaddition, the pyrone regioselectively accepts a benzylic anion as a nucleophile in a conjugate addition fashion, with the subsequent pyrone-derived enolate attaching to a pendant ester on the initial nucleophile. Subsequent base-driven enolate formation and elimination establish aromaticity of the newly formed ring. After optimization of this process using an NMR-based assessment to overcome solubility and separation challenges, the reaction was successfully applied to a library of 6-ester and -amide-substituted pyrones and using a phenyl ester and other substituted sulfoxides. This technology enables the incorporation of intact pyrone rings into more complex systems, such as for the total synthesis of the natural product thermorubin.
Competitive Binding of Viral Nuclear Localization Signal Peptide and Inhibitor Ligands to Importin-α Nuclear Transport Protein
Delfing, Bryan M.; Laracuente, Xavier E.; Jeffries, William; Luo, Xingyu; Olson, Audrey; Foreman, Kenneth W.; Petruncio, Greg; Lee, Kyung Hyeon; Paige, Mikell; Kehn-Hall, Kylene; Lockhart, Christopher; Klimov, Dmitri K. (American Chemical Society, 2024-06-13)
Venezuelan equine encephalitis virus (VEEV) is a highly virulent pathogen whose nuclear localization signal (NLS) sequence from capsid protein binds to the host importin-alpha transport protein and blocks nuclear import. We studied the molecular mechanisms by which two small ligands, termed I1 and I2, interfere with the binding of VEEV's NLS peptide to importin-alpha protein. To this end, we performed all-atom replica exchange molecular dynamics simulations probing the competitive binding of the VEEV coreNLS peptide and I1 or I2 ligand to the importin-alpha major NLS binding site. As a reference, we used our previous simulations, which examined noncompetitive binding of the coreNLS peptide or the inhibitors to importin-alpha. We found that both inhibitors completely abrogate the native binding of the coreNLS peptide, forcing it to adopt a manifold of nonnative loosely bound poses within the importin-alpha major NLS binding site. Both inhibitors primarily destabilize the native coreNLS binding by masking its amino acids rather than competing with it for binding to importin-alpha. Because I2, in contrast to I1, binds off-site localizing on the edge of the major NLS binding site, it inhibits fewer coreNLS native binding interactions than I1. Structural analysis is supported by computations of the free energies of the coreNLS peptide binding to importin-alpha with or without competition from the inhibitors. Specifically, both inhibitors reduce the free energy gain from coreNLS binding, with I1 causing significantly larger loss than I2. To test our simulations, we performed AlphaScreen experiments measuring IC50 values for both inhibitors. Consistent with in silico results, the IC50 value for I1 was found to be lower than that for I2. We hypothesize that the inhibitory action of I1 and I2 ligands might be specific to the NLS from VEEV's capsid protein.
The PTP4A3 inhibitor KVX-053 reduces Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virulence, inflammation, and development of acute lung injury in K18-hACE2 mice
Colunga-Biancatelli, Ruben M. L.; Solopov, Pavel A.; Woodson, Caitlin M.; Allen, Irving C.; Akhrymuk, Ivan; Akhrymuk, Maryna; Heath, Brittany N.; Ivester, Hannah M.; Day, Tierney; Austin, Dan E.; Kehn-Hall, Kylene; Lazo, John S.; Sharlow, Elizabeth R.; Catravas, John D. (2025-10-28)
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused a global health crisis, marked by high transmissibility and virulence. Despite widespread vaccination efforts, effective treatments for COVID-19, particularly for severe cases leading to Acute Respiratory Distress Syndrome (ARDS), remain limited. This study investigates the efficacy of KVX-053, a protein tyrosine phosphatase type IVA (PTP4A3) small molecule inhibitor, in modulating SARS-CoV-2-induced inflammation and lung injury using in vitro cell models and in vivo K18-hACE2 transgenic mice. KVX-053 reduced in vitro pro-inflammatory cytokine expression, including TNFα, CXCL10, and CXCL11, without impacting viral replication or cell viability. K18-hACE2 mice treated with KVX-053 demonstrated marked improvement in clinical scores and reduced histological evidence of lung injury compared to untreated SARS-CoV-2-infected controls. KVX-053 mitigated the activation of key inflammatory mediators in the lung, including NLRP3 inflammasomes, IL-6, and phosphorylated STAT3, effectively curbing the “cytokine storm” associated with severe COVID-19. Importantly, treatment preserved lung parenchymal integrity, reduced edema, and minimized macrophage infiltration. Our findings highlight PTP4A3 as a potential critical regulator of the inflammatory response during SARS-CoV-2 infection. KVX-053, a potent and selective PTP4A3 inhibitor, emerges as a promising host-directed therapeutic strategy for mitigating ARDS and inflammation-driven lung injury in SARS-CoV-2 and potentially other respiratory viral infections. Future studies are required to optimize dosing strategies, elucidate precise molecular mechanisms, and validate these findings in clinical settings.
Immune Evasion by the NSs Protein of Rift Valley Fever Virus: A Viral Houdini Act
Petraccione, Kaylee; Omichinski, James G.; Kehn-Hall, Kylene (MDPI, 2025-10-21)
Rift Valley fever virus (RVFV) is a negative-sense arbovirus that causes several severe diseases, including hemorrhagic fever in ruminants and humans. There are currently no FDA-approved vaccines or therapeutics for RVFV. The viral nonstructural protein NSs acts like a molecular Harry Houdini, the world-famous escape artist, to help the virus evade the host’s innate immune response and serves as the main virulence factor of RVFV. In this review, we discuss the molecular mechanisms by which NSs interacts with multiple factors to modulate host processes, evade the host immune response, and facilitate viral replication. The impact of NSs mutations that cause viral attenuation is also discussed. Understanding the molecular mechanisms by which NSs evades the host innate immune response is crucial for developing novel therapeutics and vaccines targeting RVFV.
Obesity's Unexpected Influence: Reduced Alphavirus Transmission and Altered Immune Activation in the Vector
Rai, Pallavi; Webb, Emily M.; Paulson, Sally L.; Kang, Lin; Weger-Lucarelli, James (Wiley, 2024-11-01)
Chikungunya virus (CHIKV) and Mayaro virus (MAYV) are emerging/re-emerging alphaviruses transmitted by Aedes spp. mosquitoes and responsible for recent disease outbreaks in the Americas. The capacity of these viruses to cause epidemics is frequently associated with increased mosquito transmission, which in turn is governed by virus-host-vector interactions. Although many studies have explored virus-vector interactions, significant gaps remain in understanding how vertebrate host factors influence alphavirus transmission by mosquitoes. We previously showed that obesity, a ubiquitous vertebrate host biological factor, reduces alphavirus transmission potential in mosquitoes. We hypothesized that alphavirus-infected obese bloodmeals altered immune genes and/or pathways in mosquitoes, thereby inhibiting virus transmission. To test this, we conducted RNA sequencing (RNA-seq) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) on midgut RNA from mosquitoes fed on alphavirus-infected lean and obese mice. This approach aimed to identify potential antiviral or proviral genes and pathways altered in mosquitoes after consuming infected obese bloodmeals. We found upregulation of the Toll pathway and downregulation of several metabolic and other genes in mosquitoes fed on alphavirus-infected obese bloodmeals. Through gene knockdown studies, we demonstrated the antiviral role of Toll pathway and proviral roles of AAEL009965 and fatty acid synthase (FASN) in the transmission of alphaviruses by mosquitoes. Therefore, this study utilized obesity to identify factors influencing alphavirus transmission by mosquitoes and this research approach may pave the way for designing broadly effective antiviral measures to combat mosquito-borne viruses, such as releasing transgenic mosquitoes deficient in the identified genes.
Highly Active Oligoethylene Glycol Pleuromutilins via Systematic Linker Synthesis/One-Pot Attachment and a Microscale Solubility Method
Breiner, Logan M.; Slowinski, Roman P.; Lowell, Andrew N. (American Chemical Society, 2024-12-18)
The semisynthetic derivatization of natural products is crucial for their continued development as antibiotics. While commercial pleuromutilin derivatives depend on amines for solubility, we demonstrate the high activity and solubility of oligoethylene glycol-substituted pleuromutilins achieved via a one-pot deprotection/attachment approach using thiolates protected as thioesters. The bifunctional linker synthesis is versatile and can be broadly applied to other chemistries. Antibacterial assays revealed this simple glycolate modification enhanced inhibition 4-8-fold relative to that of pleuromutilin. A new microscale solubility method is also introduced.
Larval environment reshapes mosquito disease risk via phenotypic and molecular plasticity
Chandrasegaran, Karthikeyan; Walker, Melody; Marano, Jeffrey M.; Rami, Spruha; Bisese, Adaline; Weger-Lucarelli, James; Lahondère, Chloé; Robert, Michael A.; Childs, Lauren M.; Vinauger, Clément (2025-06-21)
Early-life environmental conditions can exert profound, lasting effects on adult phenotypes, with major consequences for fitness and disease transmission, especially in holometabolous insects like mosquitoes, which are a key vector species. Yet, the molecular mechanisms through which juvenile environments shape adult physiology and behavior via transstadial effects remain largely unresolved. Here, we demonstrate that larval competition, a key ecological stressor, profoundly alters adult body size, survival, reproductive output, host-seeking behavior, olfactory neurophysiology, and vector competence in the mosquito Aedes aegypti. Crucially, using transcriptomic profiling and integrative network analyses, we identify seven regulatory hub genes whose expression is strongly associated with size-dependent variation in olfactory behavior, reproductive investment, and Zika virus transmission potential. These hub genes belong to gene modules enriched for functions in chemosensory processing, metabolic regulation, and signal transduction, revealing a molecular framework mediating environmentally induced plasticity across metamorphosis. Integrating these empirical findings into a transmission model, we show that incomplete larval control can inadvertently increase outbreak risk by producing larger, longer-lived, and more competent vectors. Our results uncover molecular mechanisms underpinning phenotypic plasticity in disease vectors and highlight the critical need to account for transstadial effects in models of vector-borne disease transmission.
Guinea Pigs Are Not a Suitable Model to Study Neurological Impacts of Ancestral SARS-CoV-2 Intranasal Infection
Joyce, Jonathan D.; Moore, Greyson A.; Thompson, Christopher K.; Bertke, Andrea S. (MDPI, 2025-05-15)
Neurological symptoms involving the central nervous system (CNS) and peripheral nervous system (PNS) are common complications of acute COVID-19 as well as post-COVID conditions. Most research into these neurological sequalae focuses on the CNS, disregarding the PNS. Guinea pigs were previously shown to be useful models of disease during the SARS-CoV-1 epidemic. However, their suitability for studying SARS-CoV-2 has not been experimentally demonstrated. To assess the suitability of guinea pigs as models for SARS-CoV-2 infection and the impact of SARS-CoV-2 infection on the PNS, and to determine routes of CNS invasion through the PNS, we intranasally infected wild-type Dunkin-Hartley guinea pigs with ancestral SARS-CoV-2 USA-WA1/2020. We assessed PNS sensory neurons (trigeminal ganglia, dorsal root ganglia), autonomic neurons (superior cervical ganglia), brain regions (olfactory bulb, brainstem, cerebellum, cortex, hippocampus), lungs, and blood for viral RNA (RT-qPCR), protein (immunostaining), and infectious virus (plaque assay) at three- and six-days post infection. We show that guinea pigs, which have previously been used as a model of SARS-CoV-1 pulmonary disease, are not susceptible to intranasal infection with ancestral SARS-CoV-2, and are not useful models in assessing neurological impacts of infection with SARS-CoV-2 isolates from the early pandemic.
Neurological manifestations of encephalitic alphaviruses, traumatic brain injuries, and organophosphorus nerve agent exposure
VanderGiessen, Morgen; de Jager, Caroline; Leighton, Julia; Xie, Hehuang; Theus, Michelle H.; Johnson, Erik; Kehn-Hall, Kylene (Frontiers, 2024-12-13)
Encephalitic alphaviruses (EEVs), Traumatic Brain Injuries (TBI), and organophosphorus nerve agents (NAs) are three diverse biological, physical, and chemical injuries that can lead to long-term neurological deficits in humans. EEVs include Venezuelan, eastern, and western equine encephalitis viruses. This review describes the current understanding of neurological pathology during these three conditions, provides a comparative review of case studies vs. animal models, and summarizes current therapeutics. While epidemiological data on clinical and pathological manifestations of these conditions are known in humans, much of our current mechanistic understanding relies upon animal models. Here we review the animal models findings for EEVs, TBIs, and NAs and compare these with what is known from human case studies. Additionally, research on NAs and EEVs is limited due to their classification as high-risk pathogens (BSL-3) and/or select agents; therefore, we leverage commonalities with TBI to develop a further understanding of the mechanisms of neurological damage. Furthermore, we discuss overlapping neurological damage mechanisms between TBI, NAs, and EEVs that highlight novel medical countermeasure opportunities. We describe current treatment methods for reducing neurological damage induced by individual conditions and general neuroprotective treatment options. Finally, we discuss perspectives on the future of neuroprotective drug development against long-term neurological sequelae of EEVs, TBIs, and NAs.
Hantavirus in rodents in the United States: Temporal and spatial trends and report of new hosts
Astorga, Francisca; Alkishe, Abdelghafar; Paansri, Paanwaris; Mantilla, Gabriel; Escobar, Luis E. (Wiley, 2025-03-16)
In North America, the rodent-borne hantavirus pulmonary syndrome ispredominantly caused by the Sin Nombre virus, typically associated with the deer mouse Peromyscus maniculatus. Utilizing data from the National Ecological Observatory Network (NEON) hantavirus program, we assessed factors that may influence the spatial and temporal distribution of hantavirus inrodent populations across the United States. Between 2014 and 2019, the NEON hantavirus program conducted 104,379 small mammal captures and collected 14,004 blood samples from 49 species at 45 field sites. Our study identified 296 seropositive samples across 15 rodent species, including 8 Peromyscusspecies. We describe six new species with hantavirus seropositive samples not previously reported as hantavirus hosts. The highest number of seropositivesamples was obtained from Pe. maniculatus (n = 116; 2.9% seroprevalence),followed by Peromyscus leucopus (n = 96; 2.8%) and Microtus pennsylvanicus(n = 33; 4.2%). Hantavirus seroprevalence showed an uneven spatial distribution, with the highest seroprevalence found in Virginia (7.8%, 99 seropositivesamples), Colorado (5.7%, n = 37), and Texas (4.8%, n = 19). Hantavirus sero-positive samples were obtained from 32 sites, 10 of which presented seropositive samples in species other than Pe. maniculatus or Pe. leucopus. Seroprevalence was inconsistent across years but showed intra-annual bimodal trends, and in Pe. maniculatus and Pe. leucopus, the number of captures correlated with sero-prevalence in the following months. Seroprevalence was higher in adult males, with only one seropositive sample obtained from a juvenile Peromyscus truei. Higher body mass, presence of scrotal testes, and nonpregnant status were associated with higher seropositivity. The NEON dataset, derived from a multiyear and structured surveillance system, revealed the extensive distribution of hantavirus across broad taxonomic and environmental ranges. Future research should consider winter season surveillance and continued analyses of stored samples for a comprehensive spatiotemporal study of hantavirus circulation in wildlife. Global changes are expected to affect the dynamics of rodent populations by affecting their availability of resources and demography and, consequently, may modify transmission rates of rodent-borne zoonotic pathogens such as hantavi-rus. This study can be considered a baseline to assess hantavirus patterns across host taxa, geographies, and seasons in the United States.

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