Sensory neurons: An integrated component of innate immunity.

The sensory nervous system possesses the ability to integrate exogenous threats and endogenous signals to mediate downstream effector functions. Sensory neurons have been shown to activate or suppress host defense and immunity against pathogens, depending on the tissue and disease state. Through this lens, pro- and anti-inflammatory neuroimmune effector functions can be interpreted as evolutionary adaptations by host or pathogen. Here, we discuss recent and impactful examples of neuroimmune circuitry that regulate tissue homeostasis, autoinflammation, and host defense. Apparently paradoxical or conflicting reports in the literature also highlight the complexity of neuroimmune interactions that may depend on tissue- and microbe-specific cues. These findings expand our understanding of the nuanced mechanisms and the greater context of sensory neurons in innate immunity.

Basophils are important for development of allergic skin inflammation.

BACKGROUND: Atopic dermatitis skin lesions exhibit increased infiltration by basophils. Basophils produce IL-4, which plays an important role in the pathogenesis of atopic dermatitis. OBJECTIVE: We sought to determine the role of basophils in a mouse model of antigen-driven allergic skin inflammation. METHODS: Wild-type mice, mice with selective and inducible depletion of basophils, and mice expressing Il4-driven enhanced green fluorescent protein were subjected to epicutaneous sensitization with ovalbumin or saline. Sensitized skin was examined by histology for epidermal thickening. Cells were analyzed for surface markers and intracellular expression of enhanced green fluorescent protein by flow cytometry. Gene expression was evaluated by real-time reverse transcription-quantitative PCR. RESULTS: Basophils were important for epidermal hyperplasia, dermal infiltration by CD4+ T cells, mast cells, and eosinophils in ovalbumin-sensitized mouse skin and for the local and systemic TH2 response to epicutaneous sensitization. Moreover, basophils were the major source of IL-4 in epicutaneous-sensitized mouse skin and promote the ability of dendritic cells to drive TH2 polarization of naive T cells. CONCLUSION: Basophils play an important role in the development of allergic skin inflammation induced by cutaneous exposure to antigen in mice.

S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis.

Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown. Here, we show that Staphylococcus aureus, a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch. Epicutaneous S. aureus exposure causes robust itch and scratch-induced damage. By testing multiple isogenic bacterial mutants for virulence factors, we identify the S. aureus serine protease V8 as a critical mediator in evoking spontaneous itch and alloknesis. V8 cleaves proteinase-activated receptor 1 (PAR1) on mouse and human sensory neurons. Targeting PAR1 through genetic deficiency, small interfering RNA (siRNA) knockdown, or pharmacological blockade decreases itch and skin damage caused by V8 and S. aureus exposure. Thus, we identify a mechanism of action for a pruritogenic bacterial factor and demonstrate the potential of inhibiting V8-PAR1 signaling to treat itch.

Six-Year Change in Cataract Surgical Coverage and Postoperative Visual Outcomes in Rural Southern China: The Yangxi Eye Study.

PURPOSE: The purpose of this study was to investigate a 6-year change in cataract surgical coverage (CSC), effective cataract surgical coverage (eCSC), and visual outcomes in an elderly population in rural southern China. DESIGN: This is a prospective population-based study with a 6-year follow-up. METHODS: The study included rural residents aged 50 years and above in southern China with comprehensive eye examinations at baseline and follow-up in 2014 and 2020, respectively. RESULTS: Five thousand six hundred thirty-eight participants underwent baseline examinations (mean age 66.1±10.2 y, 50.8% women); and 3141 (64.9%) of 4841 eligible survivors attended the 6-year follow-up. Cataract surgical coverage was 41.7% and 40.6% at baseline and follow-up, respectively, while eCSC were 32.6% and 26.6%. In multivariate models, the 6-year likelihood of cataract surgery decreased with older age [odds ratio (OR)=0.97 per year, 95% confidence interval (CI): 0.94, 0.99, P =0.012] and worse baseline presenting uncorrected visual acuity (PVA) in the worse-seeing eye (OR=0.35 per unit logarithm of the minimum angle of resolution (logMAR), 95% CI: 0.25, 0.48, P <0.001), and increased with prior cataract surgical history at baseline (OR=3.88, 95% CI: 1.91, 7.09, P <0.001). The likelihood of receiving effective cataract surgery decreased with worse baseline PVA in the worse eye (OR=0.49 per unit logMAR, 95% CI: 0.24, 0.97, P =0.042) and better-seeing eye (OR=0.68 per unit logMAR, 95% CI: 0.48, 0.95, P =0.026). Posterior capsular opacification was the main reason for PVA <6/18, reporting it in logMAR (0.5) in operated eyes (38.4% at baseline; 28.1% at follow-up). CONCLUSIONS: World Health Organization has established a global target of increasing eCSC by 30% before 2030, but no increase was found in rural southern China between 2014 and 2020, let alone reaching the World Health Organization target of 56.3%. Strategies to improve surgery incidence should focus on older persons and those with worse preoperative PVA.

Uniformity improvement of a mini-LED backlight by a quantum-dot color conversion film with nonuniform thickness.

Mini-LED backlights energized by quantum-dot color conversion (QDCC) hold great potential for technological breakthroughs of liquid crystal displays. However, luminance uniformity issues should still be urgently solved owing to the large interval of direct-lit mini-LEDs, especially when covering with a QDCC film (QDCCF) with uniform thickness. Herein, we propose a uniformity improvement approach of mini-LED backlights by employing a QDCCF with nonuniform thickness based on the Lambertian distribution of mini-LEDs, which is demonstrated by screen-printing preparation and ray-tracing simulation. Experimental results show that the luminance uniformity of the nonuniform QDCCF can reach 89.91%, which is 24.92% higher than the uniform one. Ray-tracing simulation further elaborates the mechanism of this significant improvement. Finally, by employing this nonuniform QDCCF, a mini-LED backlight prototype is assembled and achieves high uniformity of 92.15%, good white balance with color coordinates of (0.3482, 0.3137), and high color gamut of 109% NTSC. This work should shed some new light on mini-LED-based display technology.

A collaboration between immune cells and the choroid plexus epithelium in brain inflammation.

The choroid plexus (ChP) is a vital brain barrier and source of cerebrospinal fluid (CSF). Here, we use chronic two-photon imaging in awake mice and single-cell transcriptomics to demonstrate that in addition to these roles, the ChP is a complex immune organ that regulates brain inflammation. In a mouse meningitis model, neutrophils and monocytes accumulated in ChP stroma and surged across the epithelial barrier into the CSF. Bi-directional recruitment of monocytes from the periphery and, unexpectedly, macrophages from the CSF to the ChP helped eliminate neutrophils and repair the barrier. Transcriptomic analyses detailed the molecular steps accompanying this process, including the discovery of epithelial cells that transiently specialized to nurture immune cells, coordinate their recruitment, survival, and differentiation, and ultimately, control the opening/closing of the ChP brain barrier. Collectively, we provide a new conceptual understanding and comprehensive roadmap of neuroinflammation at the ChP brain barrier.

On-person adaptive evolution of Staphylococcus aureus during treatment for atopic dermatitis.

The opportunistic pathogen Staphylococcus aureus frequently colonizes the inflamed skin of people with atopic dermatitis (AD) and worsens disease severity by promoting skin damage. Here, we show, by longitudinally tracking 23 children treated for AD, that S. aureus adapts via de novo mutations during colonization. Each patient's S. aureus population is dominated by a single lineage, with infrequent invasion by distant lineages. Mutations emerge within each lineage at rates similar to those of S. aureus in other contexts. Some variants spread across the body within months, with signatures of adaptive evolution. Most strikingly, mutations in capsule synthesis gene capD underwent parallel evolution in one patient and across-body sweeps in two patients. We confirm that capD negativity is more common in AD than in other contexts, via reanalysis of S. aureus genomes from 276 people. Together, these findings highlight the importance of the mutation level when dissecting the role of microbes in complex disease.

Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion.

The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache1,2. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system, affecting more than 2.5 million people a year3-5. How pain and neuroimmune interactions impact meningeal antibacterial host defences are unclear. Here we show that Nav1.8+ nociceptors signal to immune cells in the meninges through the neuropeptide calcitonin gene-related peptide (CGRP) during infection. This neuroimmune axis inhibits host defences and exacerbates bacterial meningitis. Nociceptor neuron ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors through its pore-forming toxin pneumolysin to release CGRP from nerve terminals. CGRP acted through receptor activity modifying protein 1 (RAMP1) on meningeal macrophages to polarize their transcriptional responses, suppressing macrophage chemokine expression, neutrophil recruitment and dural antimicrobial defences. Macrophage-specific RAMP1 deficiency or pharmacological blockade of RAMP1 enhanced immune responses and bacterial clearance in the meninges and brain. Therefore, bacteria hijack CGRP-RAMP1 signalling in meningeal macrophages to facilitate brain invasion. Targeting this neuroimmune axis in the meninges can enhance host defences and potentially produce treatments for bacterial meningitis.

Estimation of effects of extreme temperature on the risk of hospitalisation in Taiwan.

BACKGROUND: Extreme temperatures are triggering and exacerbating hospital admissions and health burdens; however, it is still understudied. Therefore, we evaluated the effects of the average temperature on overall hospitalisation and the average length of hospital stay. METHODS: Daily area-specific age-sex stratified hospitalisation records from 2006 to 2020 were collected from the National Health Research Institutes of Taiwan. The distributed lag non-linear model was used to estimate the area-specific relative risk (RR) and 95% CI associated with daily average temperature. Overall cumulative RR was pooled from area-specific RRs using random effects meta-analysis. Temperature effects of extreme high and low thresholds were also evaluated based on the 99th (32°C) and 5th (14°C) percentiles, respectively. RESULTS: Our findings suggested that the elderly (age ≥65 years) are vulnerable to temperature effects, while differential gender effects are not explicit in Taiwan. A higher risk of in-patient visits was seen among the elderly during extreme low temperatures (RR 1.08; 95% CI 1.04 to 1.11) compared with extreme high temperatures (RR 1.07; 95% CI 1.05 to 1.10). Overall, high-temperature extremes increased the risk of hospitalisation with an RR of 1.05 (95% CI 1.03 to 1.07) among the all-age-sex population in Taiwan. Additionally, lag-specific analysis of the study revealed that high-temperature effects on in-patient visits are effective on the same day of exposure, while cold effects occurred after 0-2 days of exposure. The average length of hospital stays can also increase with high-temperature extremes among age group 41-64 years and the elderly. CONCLUSION: Public health preparedness should consider the increased load on health facilities and health expenditures during extreme temperatures.

Quantifying the effects of anomalies of temperature, precipitation, and surface water storage on diarrhea risk in Taiwan.

OBJECTIVES: Diarrheal disease continues to be a significant cause of morbidity and mortality. We investigated how anomalies in monthly average temperature, precipitation, and surface water storage (SWS) impacted bacterial, and viral diarrhea morbidity in Taiwan between 2004 and 2015. METHODS: A multivariate analysis using negative binomial generalized estimating equations was employed to quantify age-specific and cause-specific cases of diarrhea associated with anomalies in temperature, precipitation, and SWS. RESULTS: Temperature anomalies were associated with an elevated rate of all-cause infectious diarrhea at a lag of 2 months, with the highest risk observed in the under-5 age group (incidence rate ratio [IRR], 1.03, 95% confidence interval [CI], 1.01 to 1.07). Anomalies in SWS were associated with increased viral diarrhea rates, with the highest risk observed in the under-5 age group at a 2-month lag (IRR, 1.27; 95% CI, 1.14 to 1.42) and a lesser effect at a 1-month lag (IRR, 1.18; 95% CI, 1.06 to 1.31). Furthermore, cause-specific diarrheal diseases were significantly affected by extreme weather events in Taiwan. Both extremely cold and hot conditions were associated with an increased risk of all-cause infectious diarrhea regardless of age, with IRRs ranging from 1.03 (95% CI, 1.02 to 1.12) to 1.18 (95% CI, 1.16 to 1.40). CONCLUSIONS: The risk of all-cause infectious diarrhea was significantly associated with average temperature anomalies in the population aged under 5 years. Viral diarrhea was significantly associated with anomalies in SWS. Therefore, we recommend strategic planning and early warning systems as major solutions to improve resilience against climate change.

Immunity to the microbiota promotes sensory neuron regeneration.

Tissue immunity and responses to injury depend on the coordinated action and communication among physiological systems. Here, we show that, upon injury, adaptive responses to the microbiota directly promote sensory neuron regeneration. At homeostasis, tissue-resident commensal-specific T cells colocalize with sensory nerve fibers within the dermis, express a transcriptional program associated with neuronal interaction and repair, and promote axon growth and local nerve regeneration following injury. Mechanistically, our data reveal that the cytokine interleukin-17A (IL-17A) released by commensal-specific Th17 cells upon injury directly signals to sensory neurons via IL-17 receptor A, the transcription of which is specifically upregulated in injured neurons. Collectively, our work reveals that in the context of tissue damage, preemptive immunity to the microbiota can rapidly bridge biological systems by directly promoting neuronal repair, while also identifying IL-17A as a major determinant of this fundamental process.

The impact of temperature and precipitation on all-infectious-, bacterial-, and viral-diarrheal disease in Taiwan.

BACKGROUND: The ongoing climate change will elevate the incidence of diarrheal in 2030-2050 in Asia, including Taiwan. This study investigated associations between meteorological factors (temperature, precipitation) and burden of age-cause-specific diarrheal diseases in six regions of Taiwan using 13 years of (2004-2016) population-based data. METHODS: Weekly cause-specific diarrheal and meteorological data were obtained from 2004 to 2016. We used distributed lag non-linear model to assess age (under five, all age) and cause-specific (viral, bacterial) diarrheal disease burden associated with extreme high (99th percentile) and low (5th percentile) of climate variables up to lag 8 weeks in six regions of Taiwan. Random-effects meta-analysis was used to pool these region-specific estimates. RESULTS: Extreme low temperature (15.30 °C) was associated with risks of all-infectious and viral diarrhea, with the highest risk for all-infectious diarrheal found at lag 8 weeks among all age [Relative Risk (RR): 1.44; 95 % Confidence Interval (95 % CI): 1.24-1.67]. The highest risk of viral diarrheal infection was observed at lag 2 weeks regardless the age. Extreme high temperature (30.18 °C) was associated with risk of bacterial diarrheal among all age (RR: 1.07; 95 % CI: 1.02-1.13) at lag 8 weeks. Likewise, extreme high precipitation (290 mm) was associated with all infectious diarrheal, with the highest risk observed for bacterial diarrheal among population under five years (RR: 2.77; 95 % CI: 1.60-4.79) at lag 8 weeks. Extreme low precipitation (0 mm) was associated with viral diarrheal in all age at lag 1 week (RR: 1.08; 95 % CI: 1.01-1.15)]. CONCLUSION: In Taiwan, extreme low temperature is associated with an increased burden of viral diarrheal, while extreme high temperature and precipitation elevated burden of bacterial diarrheal. This distinction in cause-specific and climate-hazard specific diarrheal disease burden underscore the importance of incorporating differences in public health preparedness measures designed to enhance community resilience against climate change.

A broad-spectrum antibacterial and tough hydrogel dressing accelerates healing of infected wound in vivo.

Infection can disturb the wound healing process and lead to poor skin regeneration, chronic wound, septicemia and even death. To combat the multi-drug resistance bacteria or fungi, it is urgent and necessary to develop advanced antimicrobial wound dressings. In this study, a composite hydrogel dressing composed of polyvinyl alcohol (PVA), agarose, glycerol and antibacterial hyperbranched polylysine (HBPL) was prepared by a freeze-thawing method. The hydrogel showed robust mechanical properties, and the HBPL in the hydrogel displayed effective and broad-spectrum antimicrobial properties to bacteria and fungi as well as biofilms. The composite hydrogel exhibited good biocompatibility with respect to the levels of cells, blood, tissue and main organs. In an animal experiment of an infected wound model, the hydrogel significantly eliminated the infection and accelerated the wound regeneration with better tissue morphology and angiogenesis. The hydrogel also successfully achieved scalable production of over 600 g with a yield over 90 %, suggesting the great potential for the application in practice.

Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection.

Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.8+CGRP+ nociceptor neurons are juxtaposed with and signal to intestinal goblet cells to drive mucus secretion and gut protection. Nociceptor ablation led to decreased mucus thickness and dysbiosis, while chemogenetic nociceptor activation or capsaicin treatment induced mucus growth. Mouse and human goblet cells expressed Ramp1, receptor for the neuropeptide CGRP. Nociceptors signal via the CGRP-Ramp1 pathway to induce rapid goblet cell emptying and mucus secretion. Notably, commensal microbes activated nociceptors to control homeostatic CGRP release. In the absence of nociceptors or epithelial Ramp1, mice showed increased epithelial stress and susceptibility to colitis. Conversely, CGRP administration protected nociceptor-ablated mice against colitis. Our findings demonstrate a neuron-goblet cell axis that orchestrates gut mucosal barrier protection.

Promoting the healing of infected diabetic wound by an anti-bacterial and nano-enzyme-containing hydrogel with inflammation-suppressing, ROS-scavenging, oxygen and nitric oxide-generating properties.

The diabetic wound is easily to develop into a chronic wound because of the extremely serious and complex inflammatory microenvironment including biofilm formation, over-expressed reactive oxygen species (ROS), hypoxia and insufficiency of nitric oxide (NO) synthesis. In this work, a multifunctional hydrogel was designed and prepared by crosslinking hydrophilic poly(PEGMA-co-GMA-co-AAm) (PPGA) polymers with hyperbranched poly-L-lysine (HBPL)-modified manganese dioxide (MnO2) nanozymes. Pravastatin sodium, which is supposed to participate in the synthesis of NO, was further loaded to obtain the HMP hydrogel. The capabilities of this hydrogel in scavenging different types of ROS, generating O2, killing broad spectrum bacteria, and protecting cells against oxidative stress were confirmed in vitro. The transcriptome analysis revealed that HBPL inhibited bacterial quorum sensing (QS) system, downregulated virulent genes, and interfered bacterial metabolism. The HBPL-crosslinked hydrogels killed up to 94.1%-99.5% of methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli (E. coli) and Pseudomonas aeruginosa even at 109 CFU/mL. HBPL modification greatly increased the stability of MnO2 nanosheets in physiological environment. The MRSA-caused infection was effectively treated by the HBPL-crosslinked HMP hydrogel in vivo, and thereby the wound closure at inflammatory phase was promoted significantly. The treatment of HMP hydrogel reduced the ROS degree and relieved the inflammatory level significantly, accompanied by the decreased neutrophil infiltration and enhanced M2-type macrophage polarization in vivo. Significantly lower levels of inflammatory factors such as interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α) and chemokines-1 (CXCL-1), and higher levels of anti-inflammatory cytokines such as IL-4 and IL-10 were also confirmed. Moreover, the HMP hydrogel could promote the secretion of transforming growth factor-ß (TGF-ß) and stimulate neovascularization, and deposition of collagen with a thicker skin and epithelium structure.

A tough synthetic hydrogel with excellent post-loading of drugs for promoting the healing of infected wounds in vivo.

Bacterial infection is a major obstacle to the wound healing process. The hydrogel dressings with a simpler structure and good antibacterial and wound healing performance are appealing for clinical application. Herein, a robust hydrogel was synthesized from acrylamide (AM), acrylic acid (AA) and N,N'-methylene diacrylamide (MBA) via a redox initiating polymerization. The polymerization conditions were optimized to obtain the hydrogel with minimum unreacted monomers, which were 0.25% and 0.12% for AM and AA, respectively. The hydrogel had good mechanical strength, and could effectively resist damage by external forces and maintain a good macroscopic shape. It showed large water uptake capacity, and could post load a wide range of molecules via hydrogen bonding and electrostatic interaction. Loading of antibiotic doxycycline (DOX) enabled the hydrogel with good antibacterial activity against both Gram-positive bacteria and Gram-negative bacteria in vitro and in vivo. In a rat model of methicillin-resistant Staphylococcus aureus (MRSA)-infected full-thickness skin defect wound, the DOX-loaded hydrogel showed good therapeutic effect. It could significantly promote the wound closure, increased the collagen coverage area, down-regulate the expressions of pro-inflammatory TNF-α and IL-1ß factors, and up-regulate the expressions of anti-inflammatory IL-4 factor and CD31 neovascularization factor.

A neuropeptide regulates immunity across species.

Communication between the nervous system and immune system is important for regulating immunity in health and disease. Yu et al. (2022) show that neuropeptide Y and its homolog NPF serve as a "language" to facilitate crosstalk between these two systems across species, enabling neurons to downregulate harmful immune responses.

Cordycepin augments the chemosensitivity of osteosarcoma to cisplatin by activating AMPK and suppressing the AKT signaling pathway.

BACKGROUND: Osteosarcoma is the most common primary bone tumor in children and adolescents. However, some patients with osteosarcoma develop resistance to chemotherapy, leading to a poor clinical prognosis. Hence, effective therapeutic agents that can improve the response to chemotherapy drugs to improve the prognosis of patients with osteosarcoma are urgently needed. Cordycepin has recently emerged as a promising antitumor drug candidate. This study aims to explore the effect of cordycepin in suppressing osteosarcoma in vivo and in vitro and the synergistic effect of cordycepin combined with cisplatin and to demonstrate the underlying molecular mechanism. METHODS: CCK-8 assay was performed to investigate the inhibition effect of cordycepin combined with cisplatin in osteosarcoma cell lines. The colony formation and invasion abilities were measured by colony formation assay and Transwell assay. Osteosarcoma cells apoptosis was detected by flow cytometry. Western blot analysis were used to detect the expression of cell apoptosis-related proteins and AMPK and AKT/mTOR signaling pathway-related proteins. Finally, we performed the in vivo animal model to further explore whether cordycepin and cisplatin exert synergistic antitumor effects. RESULTS: Notably, we found that treatment with cordycepin inhibited cell proliferation, invasion, and induced apoptosis in osteosarcoma cells in vitro and in vivo. Moreover, the combination of cordycepin and cisplatin led to marked inhibition of osteosarcoma cell proliferation and invasion and promoted osteosarcoma cell apoptosis in vitro and in vivo. Mechanistically, we demonstrated that cordycepin enhanced the sensitivity of osteosarcoma cells to cisplatin by activating AMPK and inhibiting the AKT/mTOR signaling pathway. CONCLUSIONS: In brief, this study provides comprehensive evidence that cordycepin inhibits osteosarcoma cell growth and invasion and induces osteosarcoma cell apoptosis by activating AMPK and inhibiting the AKT/mTOR signaling pathway and enhances the sensitivity of osteosarcoma cells to cisplatin, suggesting that cordycepin is a promising treatment for osteosarcoma.

Nociceptive Sensory Neurons Mediate Inflammation Induced by Bacillus Anthracis Edema Toxin.

Bacterial products are able to act on nociceptive neurons during pathogenic infection. Neurogenic inflammation is an active part of pain signaling and has recently been shown to impact host-pathogen defense. Bacillus anthracis Edema Toxin (ET) produces striking edema in peripheral tissues, but the cellular mechanisms involved in tissue swelling are not completely understood. Here, we find that nociceptive neurons play a role in ET-induced edema and inflammation in mice. Subcutaneous footpad infection of B. anthracis Sterne caused ET-dependent local mechanical allodynia, paw swelling and body weight gain. Subcutaneous administration of ET induced paw swelling and vascular leakage, the early phases of which were attenuated in the absence of Trpv1+ or Nav1.8+ nociceptive neurons. Nociceptive neurons express the anthrax toxin receptor ANTXR2, but this did not mediate ET-induced edema. ET induced local cytokine expression and neutrophil recruitment, which were dependent in part on Trpv1+ nociceptive neurons. Ablation of Trpv1+ or Nav1.8+ nociceptive neurons also attenuated early increases in paw swelling and body weight gain during live B. anthracis infection. Our findings indicate that nociceptive neurons play an active role in inflammation caused by B. anthracis and Edema Toxin to potentially influence bacterial pathogenesis.