RESUMEN
Infections of the lung cause observable sickness thought to be secondary to inflammation. Signs of sickness are crucial to alert others via behavioral-immune responses to limit contact with contagious individuals. Gram-negative bacteria produce exopolysaccharide (EPS) that provides microbial protection; however, the impact of EPS on sickness remains uncertain. Using genome-engineered Pseudomonas aeruginosa (P. aeruginosa) strains, we compared EPS-producers versus non-producers and a virulent Escherichia coli (E. coli) lung infection model in male and female mice. EPS-negative P. aeruginosa and virulent E. coli infection caused severe sickness, behavioral alterations, inflammation, and hypothermia mediated by TLR4 detection of the exposed lipopolysaccharide (LPS) in lung TRPV1+ sensory neurons. However, inflammation did not account for sickness. Stimulation of lung nociceptors induced acute stress responses in the paraventricular hypothalamic nuclei by activating corticotropin-releasing hormone neurons responsible for sickness behavior and hypothermia. Thus, EPS-producing biofilm pathogens evade initiating a lung-brain sensory neuronal response that results in sickness.
Asunto(s)
Infecciones por Escherichia coli , Escherichia coli , Pulmón , Polisacáridos Bacterianos , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Animales , Femenino , Masculino , Ratones , Biopelículas , Escherichia coli/fisiología , Hipotermia/metabolismo , Hipotermia/patología , Inflamación/metabolismo , Inflamación/patología , Pulmón/microbiología , Pulmón/patología , Neumonía/microbiología , Neumonía/patología , Pseudomonas aeruginosa/fisiología , Células Receptoras Sensoriales , Polisacáridos Bacterianos/metabolismo , Infecciones por Escherichia coli/metabolismo , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/patología , Infecciones por Pseudomonas/metabolismo , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/patología , Nociceptores/metabolismoRESUMEN
Trypanosome parasites control their virulence and spread by using quorum sensing (QS) to generate transmissible "stumpy forms" in their host bloodstream. However, the QS signal "stumpy induction factor" (SIF) and its reception mechanism are unknown. Although trypanosomes lack G protein-coupled receptor signaling, we have identified a surface GPR89-family protein that regulates stumpy formation. TbGPR89 is expressed on bloodstream "slender form" trypanosomes, which receive the SIF signal, and when ectopically expressed, TbGPR89 drives stumpy formation in a SIF-pathway-dependent process. Structural modeling of TbGPR89 predicts unexpected similarity to oligopeptide transporters (POT), and when expressed in bacteria, TbGPR89 transports oligopeptides. Conversely, expression of an E. coli POT in trypanosomes drives parasite differentiation, and oligopeptides promote stumpy formation in vitro. Furthermore, the expression of secreted trypanosome oligopeptidases generates a paracrine signal that accelerates stumpy formation in vivo. Peptidase-generated oligopeptide QS signals being received through TbGPR89 provides a mechanism for both trypanosome SIF production and reception.
Asunto(s)
Proteínas de Transporte de Membrana/fisiología , Percepción de Quorum/fisiología , Trypanosoma/metabolismo , Diferenciación Celular , Secuencia Conservada/genética , Proteínas de Unión al GTP/metabolismo , Proteínas de Transporte de Membrana/genética , Oligopéptidos/genética , Oligopéptidos/fisiología , Filogenia , Proteínas Protozoarias/metabolismo , Percepción de Quorum/genética , Transducción de Señal , Trypanosoma/fisiología , Trypanosoma brucei brucei/metabolismo , Tripanosomiasis Africana/parasitología , Virulencia/fisiologíaRESUMEN
Sickness-induced anorexia is a conserved behavior induced during infections. Here, we report that an intestinal pathogen, Salmonella Typhimurium, inhibits anorexia by manipulating the gut-brain axis. Inhibition of inflammasome activation by the S. Typhimurium effector, SlrP, prevented anorexia caused by IL-1ß-mediated signaling to the hypothalamus via the vagus nerve. Rather than compromising host defenses, pathogen-mediated inhibition of anorexia increased host survival. SlrP-mediated inhibition of anorexia prevented invasion and systemic infection by wild-type S. Typhimurium, reducing virulence while increasing transmission to new hosts, suggesting that there are trade-offs between transmission and virulence. These results clarify the complex and contextual role of anorexia in host-pathogen interactions and suggest that microbes have evolved mechanisms to modulate sickness-induced behaviors to promote health of their host and their transmission at the expense of virulence.
Asunto(s)
Anorexia/microbiología , Infecciones por Salmonella/microbiología , Infecciones por Salmonella/transmisión , Salmonella typhimurium/patogenicidad , Animales , Proteínas Bacterianas/metabolismo , Interacciones Huésped-Patógeno , Humanos , Inflamasomas/inmunología , Interleucina-1beta/inmunología , Ratones , Ratones Endogámicos C57BL , Vías Nerviosas , Infecciones por Salmonella/inmunología , Salmonella typhimurium/fisiología , Organismos Libres de Patógenos Específicos , VirulenciaRESUMEN
Neurological symptoms in SARS-CoV-2-infected patients have been reported, but their cause remains unclear. In theory, the neurological symptoms observed after SARS-CoV-2 infection could be (1) directly caused by the virus infecting brain cells, (2) indirectly by our body's local or systemic immune response toward the virus, (3) by coincidental phenomena, or (4) a combination of these factors. As indisputable evidence of intact and replicating SARS-CoV-2 particles in the central nervous system (CNS) is currently lacking, we suggest focusing on the host's immune reaction when trying to understand the neurocognitive symptoms associated with SARS-CoV-2 infection. In this perspective, we discuss the possible immune-mediated mechanisms causing functional or structural CNS alterations during acute infection as well as in the post-infectious context. We also review the available literature on CNS affection in the context of COVID-19 infection, as well as observations from animal studies on the molecular pathways involved in sickness behavior.
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COVID-19 , SARS-CoV-2 , Animales , Encéfalo , Sistema Nervioso CentralRESUMEN
Microglia, the resident macrophages of the brain parenchyma, are key players in central nervous system (CNS) development, homeostasis, and disorders. Distinct brain pathologies seem associated with discrete microglia activation modules. How microglia regain quiescence following challenges remains less understood. Here, we explored the role of the interleukin-10 (IL-10) axis in restoring murine microglia homeostasis following a peripheral endotoxin challenge. Specifically, we show that lipopolysaccharide (LPS)-challenged mice harboring IL-10 receptor-deficient microglia displayed neuronal impairment and succumbed to fatal sickness. Addition of a microglial tumor necrosis factor (TNF) deficiency rescued these animals, suggesting a microglia-based circuit driving pathology. Single cell transcriptome analysis revealed various IL-10 producing immune cells in the CNS, including most prominently Ly49D+ NK cells and neutrophils, but not microglia. Collectively, we define kinetics of the microglia response to peripheral endotoxin challenge, including their activation and robust silencing, and highlight the critical role of non-microglial IL-10 in preventing deleterious microglia hyperactivation.
Asunto(s)
Endotoxinas/inmunología , Interleucina-10/metabolismo , Microglía/inmunología , Microglía/metabolismo , Animales , Biomarcadores , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/patología , Células Cultivadas , Inmunofenotipificación , Interleucina-10/genética , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Lipopolisacáridos/inmunología , Activación de Macrófagos , Macrófagos/inmunología , Macrófagos/metabolismo , RatonesRESUMEN
Travel can induce motion sickness (MS) in susceptible individuals. MS is an evolutionary conserved mechanism caused by mismatches between motion-related sensory information and past visual and motion memory, triggering a malaise accompanied by hypolocomotion, hypothermia, hypophagia, and nausea. Vestibular nuclei (VN) are critical for the processing of movement input from the inner ear. Motion-induced activation of VN neurons recapitulates MS-related signs. However, the genetic identity of VN neurons mediating MS-related autonomic and aversive responses remains unknown. Here, we identify a central role of cholecystokinin (CCK)-expressing VN neurons in motion-induced malaise. Moreover, we show that CCK VN inputs onto the parabrachial nucleus activate Calca-expressing neurons and are sufficient to establish avoidance to novel food, which is prevented by CCK-A receptor antagonism. These observations provide greater insight into the neurobiological regulation of MS by identifying the neural substrates of MS and providing potential targets for treatment.
Asunto(s)
Mareo por Movimiento , Vestíbulo del Laberinto , Animales , Ratones , Movimiento , Neuronas/fisiología , Núcleos Vestibulares/fisiología , Vestíbulo del Laberinto/fisiologíaRESUMEN
The functions of human Apolipoproteins L (APOLs) are poorly understood, but involve diverse activities like lysis of bloodstream trypanosomes and intracellular bacteria, modulation of viral infection and induction of apoptosis, autophagy, and chronic kidney disease. Based on recent work, I propose that the basic function of APOLs is the control of membrane dynamics, at least in the Golgi and mitochondrion. Together with neuronal calcium sensor-1 (NCS1) and calneuron-1 (CALN1), APOL3 controls the activity of phosphatidylinositol-4-kinase-IIIB (PI4KB), involved in both Golgi and mitochondrion membrane fission. Whereas secreted APOL1 induces African trypanosome lysis through membrane permeabilization of the parasite mitochondrion, intracellular APOL1 conditions non-muscular myosin-2A (NM2A)-mediated transfer of PI4KB and APOL3 from the Golgi to the mitochondrion under conditions interfering with PI4KB-APOL3 interaction, such as APOL1 C-terminal variant expression or virus-induced inflammatory signalling. APOL3 controls mitophagy through complementary interactions with the membrane fission factor PI4KB and the membrane fusion factor vesicle-associated membrane protein-8 (VAMP8). In mice, the basic APOL1 and APOL3 activities could be exerted by mAPOL9 and mAPOL8, respectively. Perspectives regarding the mechanism and treatment of APOL1-related kidney disease are discussed, as well as speculations on additional APOLs functions, such as APOL6 involvement in adipocyte membrane dynamics through interaction with myosin-10 (MYH10).
Asunto(s)
Apolipoproteína L1 , Insuficiencia Renal Crónica , Humanos , Ratones , Animales , Apolipoproteínas L , Apolipoproteína L1/genética , Apolipoproteínas/genética , Apolipoproteínas/metabolismo , MiosinasRESUMEN
BACKGROUND: Neglected tropical diseases are responsible for considerable morbidity and mortality in low-income populations. International efforts have reduced their global burden, but transmission is persistent and case-finding-based interventions rarely target asymptomatic individuals. METHODS: We develop a generic mathematical modeling framework for analyzing the dynamics of visceral leishmaniasis in the Indian sub-continent (VL), gambiense sleeping sickness (gHAT), and Chagas disease and use it to assess the possible contribution of asymptomatics who later develop disease (pre-symptomatics) and those who do not (non-symptomatics) to the maintenance of infection. Plausible interventions, including active screening, vector control, and reduced time to detection, are simulated for the three diseases. RESULTS: We found that the high asymptomatic contribution to transmission for Chagas and gHAT and the apparently high basic reproductive number of VL may undermine long-term control. However, the ability to treat some asymptomatics for Chagas and gHAT should make them more controllable, albeit over relatively long time periods due to the slow dynamics of these diseases. For VL, the toxicity of available therapeutics means the asymptomatic population cannot currently be treated, but combining treatment of symptomatics and vector control could yield a quick reduction in transmission. CONCLUSIONS: Despite the uncertainty in natural history, it appears there is already a relatively good toolbox of interventions to eliminate gHAT, and it is likely that Chagas will need improvements to diagnostics and their use to better target pre-symptomatics. The situation for VL is less clear, and model predictions could be improved by additional empirical data. However, interventions may have to improve to successfully eliminate this disease.
Asunto(s)
Infecciones Asintomáticas , Enfermedad de Chagas , Leishmaniasis Visceral , Modelos Teóricos , Enfermedades Desatendidas , Humanos , Enfermedades Desatendidas/prevención & control , Enfermedades Desatendidas/epidemiología , Enfermedad de Chagas/transmisión , Enfermedad de Chagas/prevención & control , Enfermedad de Chagas/epidemiología , Enfermedad de Chagas/tratamiento farmacológico , Infecciones Asintomáticas/epidemiología , Leishmaniasis Visceral/prevención & control , Leishmaniasis Visceral/epidemiología , Leishmaniasis Visceral/transmisión , Leishmaniasis Visceral/tratamiento farmacológico , Tripanosomiasis Africana/prevención & control , Tripanosomiasis Africana/epidemiología , Tripanosomiasis Africana/transmisión , Tripanosomiasis Africana/tratamiento farmacológico , India/epidemiología , AnimalesRESUMEN
Intermittent hypoxia training (IHT) is a promising approach that has been used to induce acclimatization to hypoxia and subsequently lower the risk of developing acute mountain sickness (AMS). However, the effects of IHT on cognitive and cerebrovascular function after acute hypoxia exposure have not been characterized. In the present study, we first confirmed that the simplified IHT paradigm was effective at relieving AMS at 4300 m. Second, we found that IHT improved participants' cognitive and neural alterations when they were exposed to hypoxia. Specifically, impaired working memory performance, decreased conflict control function, impaired cognitive control, and aggravated mental fatigue induced by acute hypoxia exposure were significantly alleviated in the IHT group. Furthermore, a reversal of brain swelling induced by acute hypoxia exposure was visualized in the IHT group using magnetic resonance imaging. An increase in cerebral blood flow (CBF) was observed in multiple brain regions of the IHT group after hypoxia exposure as compared with the control group. Based on these findings, the simplified IHT paradigm might facilitate hypoxia acclimatization, alleviate AMS symptoms, and increase CBF in multiple brain regions, thus ameliorating brain swelling and cognitive dysfunction.
Asunto(s)
Mal de Altura , Edema Encefálico , Disfunción Cognitiva , Humanos , Hipoxia/complicaciones , Mal de Altura/prevención & control , Aclimatación/fisiología , Enfermedad Aguda , Disfunción Cognitiva/etiología , Disfunción Cognitiva/prevención & controlRESUMEN
BACKGROUND: Cetaceans, having experienced prolonged adaptation to aquatic environments, have undergone evolutionary changes in their respiratory systems. This process of evolution has resulted in the emergence of distinctive phenotypic traits, notably the abundance of elastic fibers and thickened alveolar walls in their lungs, which may facilitate alveolar collapse during diving. This structure helps selective exchange of oxygen and carbon dioxide, while minimizing nitrogen exchange, thereby reducing the risk of DCS. Nevertheless, the scientific inquiry into the mechanisms through which these unique phenotypic characteristics govern the diving behavior of marine mammals, including cetaceans, remains unresolved. RESULTS: This study entails an evolutionary analysis of 42 genes associated with pulmonary fibrosis across 45 mammalian species. Twenty-one genes in cetaceans exhibited accelerated evolution, featuring specific amino acid substitutions in 14 of them. Primarily linked to the development of the respiratory system and lung morphological construction, these genes play a crucial role. Moreover, among marine mammals, we identified eight genes undergoing positive selection, and the evolutionary rates of three genes significantly correlated with diving depth. Specifically, the SFTPC gene exhibited convergent amino acid substitutions. Through in vitro cellular experiments, we illustrated that convergent amino acid site mutations in SFTPC contribute positively to pulmonary fibrosis in marine mammals, and the presence of this phenotype can induce deep alveolar collapse during diving, thereby reducing the risk of DCS during diving. CONCLUSIONS: The study unveils pivotal genetic signals in cetaceans and other marine mammals, arising through evolution. These genetic signals may influence lung characteristics in marine mammals and have been linked to a reduced risk of developing DCS. Moreover, the research serves as a valuable reference for delving deeper into human diving physiology.
Asunto(s)
Fibrosis Pulmonar , Animales , Humanos , Cetáceos/genética , Cetáceos/metabolismo , Pulmón/metabolismo , Mamíferos/metabolismo , Oxígeno/metabolismoRESUMEN
BACKGROUND: We aimed to determine whether and how the combination of acetazolamide and remote ischemic preconditioning (RIPC) reduced the incidence and severity of acute mountain sickness (AMS). METHODS: This is a prospective, randomized, open-label, blinded endpoint (PROBE) study involving 250 healthy volunteers. Participants were randomized (1:1:1:1:1) to following five groups: Ripc (RIPC twice daily, 6 days), Rapid-Ripc (RIPC four times daily, 3 days), Acetazolamide (twice daily, 2 days), Combined (Acetazolamide plus Rapid-Ripc), and Control group. After interventions, participants entered a normobaric hypoxic chamber (equivalent to 4000 m) and stayed for 6 h. The primary outcomes included the incidence and severity of AMS, and SpO2 after hypoxic exposure. Secondary outcomes included systolic and diastolic blood pressure, and heart rate after hypoxic exposure. The mechanisms of the combined regime were investigated through exploratory outcomes, including analysis of venous blood gas, complete blood count, human cytokine antibody array, ELISA validation for PDGF-AB, and detection of PDGF gene polymorphisms. RESULTS: The combination of acetazolamide and RIPC exhibited powerful efficacy in preventing AMS, reducing the incidence of AMS from 26.0 to 6.0% (Combined vs Control: RR 0.23, 95% CI 0.07-0.70, P = 0.006), without significantly increasing the incidence of adverse reactions. Combined group also showed the lowest AMS score (0.92 ± 1.10). Mechanistically, acetazolamide induced a mild metabolic acidosis (pH 7.30 ~ 7.31; HCO3- 18.1 ~ 20.8 mmol/L) and improved SpO2 (89 ~ 91%) following hypoxic exposure. Additionally, thirty differentially expressed proteins (DEPs) related to immune-inflammatory process were identified after hypoxia, among which PDGF-AB was involved. Further validation of PDGF-AB in all individuals showed that both acetazolamide and RIPC downregulated PDGF-AB before hypoxic exposure, suggesting a possible protective mechanism. Furthermore, genetic analyses demonstrated that individuals carrying the PDGFA rs2070958 C allele, rs9690350 G allele, or rs1800814 G allele did not display a decrease in PDGF-AB levels after interventions, and were associated with a higher risk of AMS. CONCLUSIONS: The combination of acetazolamide and RIPC exerts a powerful anti-hypoxic effect and represents an innovative and promising strategy for rapid ascent to high altitudes. Acetazolamide improves oxygen saturation. RIPC further aids acetazolamide, which synergistically regulates PDGF-AB, potentially involved in the pathogenesis of AMS. TRIAL REGISTRATION: ClinicalTrials.gov NCT05023941.
Asunto(s)
Mal de Altura , Precondicionamiento Isquémico , Humanos , Mal de Altura/prevención & control , Mal de Altura/diagnóstico , Acetazolamida , Estudios Prospectivos , Enfermedad Aguda , Hipoxia/prevención & controlRESUMEN
PURPOSE: To observe the growth and resolution of decompression gas bubbles in the spinal cord of live rats in real time using MRI. METHODS: We constructed an MRI-compatible pressure chamber system to visualize gas bubble dynamics in deep tissues in real time. The system pressurizes and depressurizes rodents inside an MRI scanner and monitors their respiratory rate, heart rate, and body temperature while providing gaseous anesthesia under pressure during the experiments. RESULTS: We observed the formation of decompression gas bubbles in the spinal cord of rats after compression to 7.1 bar absolute and rapid decompression inside the MRI scanner while maintaining continuous gaseous anesthesia and vital monitoring. CONCLUSION: We have shown the direct observation of decompression gas bubble formation in real time by MRI in live, anesthetized rats.
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Imagen por Resonancia Magnética , Animales , Ratas , Imagen por Resonancia Magnética/métodos , Ratas Sprague-Dawley , Gases , Sistemas de Computación , Médula Espinal/diagnóstico por imagen , Compresión de la Médula Espinal/diagnóstico por imagen , Diseño de Equipo , MasculinoRESUMEN
BACKGROUND: Acute mountain sickness (AMS) is the most prevalent condition resulting from hypobaric hypoxia (HH) at high altitudes. Although evidence suggests the involvement of inflammatory cytokines in AMS development, there is currently a lack of reports on variations in cytokine levels between individuals susceptible to AMS and those resistant to AMS prior to ascending to high altitude. Thus our current study aims to assess the predictive capability for AMS occurrence by evaluating differences in cytokine levels at low altitudes. METHODS: The present study recruited 48 participants, who ascended from low altitude to middle high-altitude (3700 m) and further to extreme high-altitude (5000 m). Based on Lake Louise Score (LLS) at the two high altitudes, participants were categorized into severe AMS-susceptible (sAMS), moderate AMS-susceptible (mAMS), and non-AMS groups. The Bio-Plex MAGPIX System was employed to measure plasma levels of 11 inflammatory cytokines. Cytokines at low altitude and middle high-altitude were analyzed through receiver operating characteristic (ROC) analysis to obtain area under the ROC curve (AUROC), sensitivity, and specificity. RESULTS: Based on LLS at 3700 m, we initially categorized the study subjects into the sAMS group (n = 8) and the Non-AMS group (n = 40). Among individuals in the non-AMS group (n = 40) at the altitude of 3700 m, those who developed AMS at the altitude of 5000 m were assigned to the mAMS group (n = 17), whereas those who did not experience AMS were included into the non-AMS group (n = 23). The concentration of TNF-α at low altitude exhibited robust predictive performance for predicting AMS occurrence at the altitude of 3700 m. Among the non-AMS group at the altitude of 3700 m, we identified that the concentration of IL-2 and IL-17A demonstrated high efficacy in predicting the onset of AMS following ascent to 5000 m. In addition, differentially expressed cytokines including IL-17A, TNF-α and IL-2 at low altitude possessed discriminatory potential among the three groups at 5000 m.. CONCLUSION: We posited that the levels of TNF-α, IL-2, IL-17A in serum of low altitude could be considered as potential biomarkers to predict the occurrence of AMS at high altitude. NEW & NOTEWORTHY: Through the two comparisons at different two altitudes (baseline level and 3700 m), we provided a model to progressively screen individuals who are susceptible and resistant to different high altitudes (3700 m and 5000 m). TNF-α could firstly screen out the AMS susceptible individuals at the altitude of 3700 m. And through its combination with IL-2 and IL-17A, we could further screen out AMS susceptible individuals at the altitude of 5000 m.
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Mal de Altura , Altitud , Biomarcadores , Interleucina-17 , Interleucina-2 , Factor de Necrosis Tumoral alfa , Humanos , Mal de Altura/sangre , Masculino , Biomarcadores/sangre , Interleucina-17/sangre , Adulto , Factor de Necrosis Tumoral alfa/sangre , Femenino , Interleucina-2/sangre , Enfermedad Aguda , Curva ROC , Persona de Mediana EdadRESUMEN
Social withdrawal is a well-established part of sickness behavior, but in some contexts sick animals might gain from keeping close instead of keeping away. For instance, sick individuals are more willing to be near known individuals who can provide care and safety (close others) compared to when healthy. Yet, interactions with some strangers might also be beneficial (i.e., healthcare professionals), but it is not known how sickness interplay with social behavior towards such individuals. Here, we assessed if sickness affects perception of caregivers, and developed a new task, the Caregiver Perception Task (CgPT). Twenty-six participants performed the CgPT, once after an injection of lipopolysaccharide (LPS, 0.8 ng/kg body weight, n = 24), and once after an injection of saline (n = 25), one hour and forty-five minutes post-injection. During the task, participants watched short video clips of three types of caregivers: a healthcare professional taking care of a sick individual, a healthcare professional not taking care of a sick individual, and a non-healthcare professional taking care of their sick adult child or partner. After each video clip, the likability, trustworthiness, professionalism, and willingness to interact with and receive care from the caregiver were rated on visual analogue scales. Results showed that participants injected with saline rated healthcare professionals who did not take care of a sick individual less positively on all aspects compared to healthcare professionals who took care of a sick individual. Moreover, compared to saline, LPS increased the participants' willingness to receive care from healthcare professionals and non-healthcare professionals providing care, but not from healthcare professionals not providing care. Thus, our results indicate that sick individuals may approach unknown individuals with potential to provide care and support.
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Cuidadores , Endotoxemia , Conducta de Enfermedad , Lipopolisacáridos , Humanos , Masculino , Cuidadores/psicología , Femenino , Adulto , Endotoxemia/psicología , Adulto Joven , Percepción/fisiología , Conducta SocialRESUMEN
Infections are often accompanied by weight loss caused by alterations in host behavior and metabolism, also known as sickness behaviors. Recent studies have revealed that sickness behaviors can either promote or impede survival during infections depending on factors such as the type of infectious pathogen. Nevertheless, we have an incomplete understanding of the underlying mechanisms of sickness behaviors. Furthermore, although the host immune responses to infections have long been known to contribute to the induction of sickness behaviors, recent studies have identified emerging cytokines that are also key regulators of host metabolism during infection and inflammation, such as growth differentiation factor 15 (GDF-15). GDF-15 is a distant member of the TGF-ß superfamily that causes weight loss by suppressing appetite and food consumption and causing emesis. These effects require activation of neurons that express the only known GDF-15 receptor, the GFRAL receptor. GDF-15 also functions in the periphery including the induction of ketogenesis and immunoregulation. Nevertheless, the functions and regulation of GDF-15 during live infections is not yet known. Murine infection with avirulent Toxoplasma gondii is an established model to understand infection-induced weight loss. Past studies have determined that acute T. gondii infection causes weight loss due to diminished food consumption and increased energy expenditure through unknown mechanisms. Additionally, our lab previously demonstrated that T. gondii causes upregulation in serum GDF-15 in an IFN-γ-dependent manner during the post-acute phase of the infection. In this study, we interrogated the in-vivo functions and immune regulation of GDF-15 during Toxoplasma gondii infection. First, we found that in wild-type mice, acute T. gondii infection caused a significant weight loss that is preceded by elevation of serum levels of IFN-γ and GDF-15. To determine whether IFN-γ regulates GDF-15, we neutralized IFN-γ on days 5 and 6 and measured GDF-15 on day 7 and found that serum but not tissue levels of GDF-15 decreased after IFN-γ neutralization. Additionally, exogenous IFN-γ was sufficient to elevate serum GDF-15 in the absence of infection. Next, we compared the outcomes of T. gondii infection between WT and Gdf15-/- mice. We observed that the weight trajectories were declining in WT mice while they were increasing in Gdf15-/-mice during the acute phase of the infection. This difference in trajectories extended throughout the chronic infection resulting to an overall weight loss relative to initial weights in WT mice but not Gdf15-/-mice. Then, we determined that GDF-15 is not essential for survival and immunoregulation during T. gondii infection. We also demonstrated that GDF-15 is required for the induction of FGF21, stress-induced cytokine with prominent roles in regulating host metabolism. Finally, we discovered a cytokine cascade IFN-γ-GDF-15-FGF21 that is likely involved in the regulation of host metabolism. Overall, our study provides evidence that IFN-γ contributes to the regulation of host metabolism during infection by inducing GDF-15 and FGF21. GDF-15 orchestrates changes in host metabolism that supports the host immune response in clearing the infection. These physiological alterations induce FGF21, which in turn, orchestrates the adaptive responses to the effects of GDF-15, which can be detrimental when protracted.
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Factores de Crecimiento de Fibroblastos , Toxoplasma , Toxoplasmosis , Animales , Ratones , Factor 15 de Diferenciación de Crecimiento/genética , Interferón gamma/metabolismo , CitocinasRESUMEN
Administration of low-dose lipopolysaccharide (LPS) to healthy humans is a translational approach to analyze the effects of acute systemic inflammation and sickness behavior. Although studies documented that LPS-induced inflammation can alter social behavior, its impact on empathy remains poorly understood. In this double-blind, placebo-controlled study, 52 healthy female volunteers received an intravenous injection of either LPS (0.4 ng/kg body weight) or placebo and completed the Social Interaction Empathy Task (SIET) two hours after injection. Physiological responses (blood pressure, heart rate, body temperature, cytokines, cortisol) were analyzed along with sickness symptoms and mood before and after LPS or placebo administration. LPS application led to significant increases in plasma cytokines and sickness symptoms as well as low mood. Moreover, volunteers receiving LPS showed significantly less empathy for other's psychological pain than those who received placebo. Furthermore, LPS-injected volunteers with more severe sickness symptoms displayed higher pain ratings in the first-person perspective. Thus, low-grade inflammation reduces empathy for other's psychological pain which might reflect an adaptive strategy to save energy by not responding empathetically when sick oneself.
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Empatía , Inflamación , Lipopolisacáridos , Dolor , Humanos , Femenino , Empatía/efectos de los fármacos , Empatía/fisiología , Método Doble Ciego , Adulto , Lipopolisacáridos/farmacología , Adulto Joven , Dolor/psicología , Hidrocortisona/metabolismo , Hidrocortisona/sangre , Frecuencia Cardíaca/efectos de los fármacos , Citocinas/sangre , Citocinas/metabolismo , Presión Sanguínea/efectos de los fármacos , Afecto/efectos de los fármacos , Conducta de Enfermedad/fisiología , Conducta de Enfermedad/efectos de los fármacos , Interacción Social , Voluntarios Sanos , Temperatura Corporal/efectos de los fármacosRESUMEN
Chronic mountain sickness is a maladaptive syndrome that affects individuals living permanently at high altitude and is characterized primarily by excessive erythrocytosis (EE). Recent results concerning the impact of EE in Andean highlanders on clotting and the possible promotion of hypercoagulability, which can lead to thrombosis, were contradictory. We assessed the coagulation profiles of Andeans highlanders with and without excessive erythrocytosis (EE+ and EE-). Blood samples were collected from 30 EE+ and 15 EE- in La Rinconada (Peru, 5100-5300 m a.s.l.), with special attention given to the sampling pre-analytical variables. Rotational thromboelastometry tests were performed at both native and normalized (40%) haematocrit using autologous platelet-poor plasma. Thrombin generation, dosages of clotting factors and inhibitors were measured in plasma samples. Data were compared between groups and with measurements performed at native haematocrit in 10 lowlanders (LL) at sea level. At native haematocrit, in all rotational thromboelastometry assays, EE+ exhibited hypocoagulable profiles (prolonged clotting time and weaker clot strength) compared with EE- and LL (all P < 0.01). At normalized haematocrit, clotting times were normalized in most individuals. Conversely, maximal clot firmness was normalized only in FIBTEM and not in EXTEM/INTEM assays, suggesting abnormal platelet activity. Thrombin generation, levels of plasma clotting factors and inhibitors, and standard coagulation assays were mostly normal in all groups. No highlanders reported a history of venous thromboembolism based on the dedicated survey. Collectively, these results indicate that EE+ do not present a hypercoagulable profile potentially favouring thrombosis.
Asunto(s)
Altitud , Coagulación Sanguínea , Policitemia , Tromboelastografía , Trombofilia , Humanos , Policitemia/sangre , Coagulación Sanguínea/fisiología , Adulto , Trombofilia/sangre , Masculino , Tromboelastografía/métodos , Femenino , Hematócrito/métodos , Perú , Persona de Mediana Edad , Mal de Altura/sangre , Mal de Altura/fisiopatología , Trombina/metabolismoRESUMEN
Eccentric upper-body exercise performed 24 h prior to high-altitude decompression has previously been shown to aggravate venous gas emboli (VGE) load. Yet, it is unclear whether increasing the muscle mass recruited (i.e., upper vs. whole-body) during eccentric exercise would exacerbate the decompression strain. Accordingly, this study aimed to investigate whether the total muscle mass recruited during eccentric exercise influences the decompression strain. Eleven male participants were exposed to a simulated altitude of 24,000 ft for 90 min on three separate occasions. Twenty-four hours before each exposure, participants performed one of the following protocols: (i) eccentric whole-body exercise (ECCw; squats and arm-cycling exercise), (ii) eccentric upper-body exercise (ECCu; arm-cycling), or (iii) no exercise (control). Delayed onset muscle soreness (DOMS) and isometric strength were evaluated before and after each exercise intervention. VGE load was evaluated at rest and after knee- and arm-flex provocations using the 6-graded Eftedal-Brubakk scale. Knee extensor (-20 ± 14%, P = 0.001) but not elbow flexor (-12 ± 18%, P = 0.152) isometric strength was reduced 24 h after ECCw. ECCu reduced elbow flexor isometric strength at 24 h post-exercise (-18 ± 10%, P < 0.001). Elbow flexor DOMS was higher in the ECCu (median 6) compared with ECCw (5, P = 0.035). VGE scores were higher following arm-flex provocations in the ECCu (median (range), 3 (0-4)) compared with ECCw (2 (0-3), P = 0.039) and control (0 (0-2), P = 0.011), and in ECCw compared with control (P = 0.023). VGE were detected earlier in ECCu (13 ± 20 min) compared with control (60 ± 38 min, P = 0.021), while no differences were noted between ECCw (18 ± 30 min) and control or ECCu. Eccentric exercise increased the decompression strain compared with control. The VGE load varied depending on the body region but not the total muscle mass recruited. HIGHLIGHTS: What is the central question of this study? Does exercise-induced muscle damage (EIMD) resulting from eccentric exercise influence the presence of venous gas emboli (VGE) during a 90 min continuous exposure at 24,000 ft? What is the main finding and its importance? EIMD led to an earlier manifestation and greater VGE load compared with control. However, the decompression strain was dependent on the body region but not the total muscle mass recruited.
Asunto(s)
Ejercicio Físico , Músculo Esquelético , Humanos , Masculino , Músculo Esquelético/fisiopatología , Ejercicio Físico/fisiología , Adulto , Adulto Joven , Altitud , Mialgia/fisiopatología , Descompresión/métodos , Fuerza Muscular/fisiología , Embolia Aérea/fisiopatología , Enfermedad de Descompresión/fisiopatologíaRESUMEN
High altitude (HA) ascent imposes systemic hypoxia and associated risk of acute mountain sickness. Acute hypoxia elicits a hypoxic ventilatory response (HVR), which is augmented with chronic HA exposure (i.e., ventilatory acclimatization; VA). However, laboratory-based HVR tests lack portability and feasibility in field studies. As an alternative, we aimed to characterize area under the curve (AUC) calculations on Fenn diagrams, modified by plotting portable measurements of end-tidal carbon dioxide ( P ETC O 2 ${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) against peripheral oxygen saturation ( S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) to characterize and quantify VA during incremental ascent to HA (n = 46). Secondarily, these participants were compared with a separate group following the identical ascent profile whilst self-administering a prophylactic oral dose of acetazolamide (Az; 125 mg BID; n = 20) during ascent. First, morning P ETC O 2 ${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ and S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ measurements were collected on 46 acetazolamide-free (NAz) lowland participants during an incremental ascent over 10 days to 5160 m in the Nepal Himalaya. AUC was calculated from individually constructed Fenn diagrams, with a trichotomized split on ranked values characterizing the smallest, medium, and largest magnitudes of AUC, representing high (n = 15), moderate (n = 16), and low (n = 15) degrees of acclimatization. After characterizing the range of response magnitudes, we further demonstrated that AUC magnitudes were significantly smaller in the Az group compared to the NAz group (P = 0.0021), suggesting improved VA. These results suggest that calculating AUC on modified Fenn diagrams has utility in assessing VA in large groups of trekkers during incremental ascent to HA, due to the associated portability and congruency with known physiology, although this novel analytical method requires further validation in controlled experiments. HIGHLIGHTS: What is the central question of this study? What are the characteristics of a novel methodological approach to assess ventilatory acclimatization (VA) with incremental ascent to high altitude (HA)? What is the main finding and its importance? Area under the curve (AUC) magnitudes calculated from modified Fenn diagrams were significantly smaller in trekkers taking an oral prophylactic dose of acetazolamide compared to an acetazolamide-free group, suggesting improved VA. During incremental HA ascent, quantifying AUC using modified Fenn diagrams is feasible to assess VA in large groups of trekkers with ascent, although this novel analytical method requires further validation in controlled experiments.
Asunto(s)
Aclimatación , Acetazolamida , Mal de Altura , Altitud , Hipoxia , Acetazolamida/farmacología , Humanos , Aclimatación/fisiología , Masculino , Adulto , Mal de Altura/fisiopatología , Femenino , Hipoxia/fisiopatología , Inhibidores de Anhidrasa Carbónica/farmacología , Adulto Joven , Dióxido de Carbono/metabolismo , Saturación de Oxígeno/fisiología , Saturación de Oxígeno/efectos de los fármacos , Ventilación Pulmonar/efectos de los fármacos , Ventilación Pulmonar/fisiologíaRESUMEN
INTRODUCTION: Healthcare costs and societal impact of myasthenia gravis (MG), a potentially life-threatening rare, chronic neuromuscular disease, are sparsely studied. We assessed healthcare resource utilization (HCRU) and associated costs among patients with newly diagnosed (ND) and preexisting (PE) MG in Sweden. METHODS: This observational, retrospective cohort study used data from four linkable Swedish nationwide population-based registries. Adult MG patients receiving pharmacological treatment for MG and having ≥24-month follow-up during the period January 1, 2010, to December 31, 2017, were included. RESULTS: A total of 1,275 patients were included in the analysis, of which 554 patients were categorized into the ND MG group and 721 into the PE MG group. Mean (±SD) age was 61.3 (±17.4) years, and 52.3% were female. In the first year post-diagnosis, ND patients had significantly higher utilization of acetylcholinesterase inhibitors (96.0% vs. 83.9%), corticosteroids (59.6% vs. 45.8%), thymectomy (12.1% vs. 0.7%), and plasma exchange (3.8% vs. 0.6%); had higher all-cause (70.9% vs. 35.8%) and MG-related (62.5% vs. 18.4%) hospitalization rates with 11 more hospitalization days (all p < 0.01) and an increased risk of hospitalization (odds ratio [95% CI] = 4.4 [3.43, 5.64]) than PE MG. In year 1 post-diagnosis, ND MG patients incurred EUR 7,302 (p < 0.01) higher total all-cause costs than PE MG, of which 84% were estimated to be MG-related and the majority (86%) were related to inpatient care. These results remained significant also after controlling for baseline demographics and comorbidities (p < 0.01). In year 2 post-diagnosis, the all-cause medical costs decreased by â¼55% for ND MG from year 1 and were comparable with PE MG. CONCLUSION: In this population-based study, MG patients required significantly more healthcare resources in year 1 post-diagnosis than PE MG primarily due to more pharmacological treatments, thymectomies, and associated hospitalizations. These findings highlight the need to better understand potential factors including disease characteristics associated with increased health resource use and costs and need for more efficacious treatments early in the disease course.