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1.
Angew Chem Int Ed Engl ; 61(41): e202210783, 2022 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-35971950

RESUMO

Intrinsically low lattice thermal conductivity (κlat ) while maintaining the high carrier mobility (µ) is of the utmost importance for thermoelectrics. Topological insulators (TI) can possess high µ due to the metallic surface states. TIs with heavy constituents and layered structure can give rise to high anharmonicity and are expected to show low κlat . Here, we demonstrate that Bi1.1 Sb0.9 Te2 S (BSTS), which is a 3D bulk TI, exhibits ultra-low κlat of 0.46 Wm-1 K-1 along with high µ of ≈401 cm2  V-1 s-1 . Sound velocity measurements and theoretical calculations suggest that chemical bonding hierarchy and high anharmonicity play a crucial role behind such ultra-low κlat . BSTS possesses low energy optical phonons which strongly couple with the heat carrying acoustic phonons leading to ultra-low κlat . Further, Cl has been doped at the S site of BSTS which increases the electron concentration and reduces the κlat resulting in a promising n-type thermoelectric figure of merit (zT) of ≈0.6 at 573 K.

2.
Respirology ; 24(7): 646-651, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30761687

RESUMO

BACKGROUND AND OBJECTIVE: Chronic lower respiratory diseases (CLRD) increase the risk of type 2 diabetes, which in turn may worsen lung function. Metformin, a common antidiabetic with anti-inflammatory and antioxidant properties, may improve respiratory outcomes. Therefore, we examined the association of metformin use with the risk of mortality from CLRD. METHODS: We analysed data from the National Health and Nutrition Examination Survey during 1988-1994 and 1999-2010 for participants aged 40 years or older who had diabetes and were followed up for mortality through 2011. Information on prescription medicine was collected at baseline and CLRD-related mortality during follow-up was defined using the 10th Revision of the International Classification of Diseases (ICD-10). Cox proportional hazards modelling was used to determine the mortality hazard ratio (HR) associated with metformin use, adjusting for relevant covariates. RESULTS: A total of 5266 participants with a median follow-up of 6.1 years were included. The prevalence of metformin use was 31.9% and 1869 participants died during follow-up, including 72 of CLRD. In the adjusted Cox proportional regression analysis, metformin was associated with a decreased risk of CLRD mortality in the overall population (HR: 0.39, 95% CI: 0.15-0.99) and among participants with baseline CLRD (HR: 0.30, 95% CI: 0.10-0.93), after adjusting for age, gender, race/ethnicity, cigarette smoking, body mass index, current asthma and chronic obstructive pulmonary disease (COPD), insulin and other diabetic medications, and glycohaemoglobin level. We found no association between other antidiabetic medications and CLRD mortality. CONCLUSION: In this sample representative of the U.S. population, metformin was associated with lower CLRD mortality in adults with diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Metformina/uso terapêutico , Inquéritos Nutricionais , Doenças Respiratórias/mortalidade , Adulto , Idoso , Estudos Transversais , Diabetes Mellitus Tipo 2/etiologia , Feminino , Seguimentos , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doenças Respiratórias/complicações , Taxa de Sobrevida/tendências , Fatores de Tempo , Estados Unidos/epidemiologia
3.
Infect Immun ; 86(3)2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29263106

RESUMO

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Mutations in this chloride channel lead to mucus accumulation, subsequent recurrent pulmonary infections, and inflammation, which, in turn, cause chronic lung disease and respiratory failure. Recently, rates of nontuberculous mycobacterial (NTM) infections in CF patients have been increasing. Of particular relevance is infection with Mycobacterium abscessus, which causes a serious, life-threatening disease and constitutes one of the most antibiotic-resistant NTM species. Interestingly, an increased prevalence of NTM infections is associated with worsening lung function in CF patients who are also coinfected with Aspergillus fumigatus We established a new mouse model to investigate the relationship between A. fumigatus and M. abscessus pulmonary infections. In this model, animals exposed to A. fumigatus and coinfected with M. abscessus exhibited increased lung inflammation and decreased mycobacterial burden compared with those of mice infected with M. abscessus alone. This increased control of M. abscessus infection in coinfected mice was mucus independent but dependent on both transcription factors T-box 21 (Tbx21) and retinoic acid receptor (RAR)-related orphan receptor gamma t (RORγ-t), master regulators of type 1 and type 17 immune responses, respectively. These results implicate a role for both type 1 and type 17 responses in M. abscessus control in A. fumigatus-coinfected lungs. Our results demonstrate that A. fumigatus, an organism found commonly in CF patients with NTM infection, can worsen pulmonary inflammation and impact M. abscessus control in a mouse model.


Assuntos
Aspergilose/microbiologia , Aspergillus fumigatus/fisiologia , Pulmão/microbiologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium abscessus/fisiologia , Animais , Aspergilose/imunologia , Coinfecção/imunologia , Coinfecção/microbiologia , Coinfecção/patologia , Fibrose Cística/imunologia , Fibrose Cística/microbiologia , Fibrose Cística/patologia , Feminino , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/patologia
4.
PLoS Pathog ; 10(5): e1004099, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24831696

RESUMO

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), infects one third of the world's population. Among these infections, clinical isolates belonging to the W-Beijing appear to be emerging, representing about 50% of Mtb isolates in East Asia, and about 13% of all Mtb isolates worldwide. In animal models, infection with W-Beijing strain, Mtb HN878, is considered "hypervirulent" as it results in increased mortality and causes exacerbated immunopathology in infected animals. We had previously shown the Interleukin (IL) -17 pathway is dispensable for primary immunity against infection with the lab adapted Mtb H37Rv strain. However, it is not known whether IL-17 has any role to play in protective immunity against infection with clinical Mtb isolates. We report here that lab adapted Mtb strains, such as H37Rv, or less virulent Mtb clinical isolates, such as Mtb CDC1551, do not require IL-17 for protective immunity against infection while infection with Mtb HN878 requires IL-17 for early protective immunity. Unexpectedly, Mtb HN878 induces robust production of IL-1ß through a TLR-2-dependent mechanism, which supports potent IL-17 responses. We also show that the role for IL-17 in mediating protective immunity against Mtb HN878 is through IL-17 Receptor signaling in non-hematopoietic cells, mediating the induction of the chemokine, CXCL-13, which is required for localization of T cells within lung lymphoid follicles. Correct T cell localization within lymphoid follicles in the lung is required for maximal macrophage activation and Mtb control. Since IL-17 has a critical role in vaccine-induced immunity against TB, our results have far reaching implications for the design of vaccines and therapies to prevent and treat emerging Mtb strains. In addition, our data changes the existing paradigm that IL-17 is dispensable for primary immunity against Mtb infection, and instead suggests a differential role for IL-17 in early protective immunity against emerging Mtb strains.


Assuntos
Imunidade Inata/genética , Interleucina-17/fisiologia , Mycobacterium tuberculosis/imunologia , Animais , Células Cultivadas , Doenças Transmissíveis Emergentes/genética , Doenças Transmissíveis Emergentes/imunologia , Citoproteção/genética , Citoproteção/imunologia , Feminino , Interleucina-17/genética , Interleucina-1beta/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/patogenicidade , Receptores Tipo I de Interleucina-1/genética , Receptor 2 Toll-Like/fisiologia , Tuberculose/genética , Tuberculose/imunologia
5.
Am J Pathol ; 184(1): 55-63, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24183780

RESUMO

Mucosal vaccines are thought to confer superior protection against mucosal infectious diseases. In addition, mucosal routes of vaccine delivery preferentially induce the generation of T helper 17 (Th17) cells, which produce the cytokine IL-17. Th17 cells are critical in mediating vaccine-induced immunity against several mucosal infectious diseases. However, IL-17 is also a potent proinflammatory cytokine, and we recently showed that IL-17 mediates immunopathology and lung injury after influenza infection in mice. In the present study, we tested the hypothesis that mucosal pre-exposure to Th17-inducing adjuvants can promote disease exacerbation upon subsequent infection with influenza virus. Mice mucosally pre-exposed to Th17-inducing adjuvants, such as type II heat-labile enterotoxin or cholera toxin, resulted in increased morbidity and exacerbated lung inflammation upon subsequent infection with influenza virus. Furthermore, the increased morbidity was accompanied by increased expression of inflammatory chemokines and increased accumulation of neutrophils. Importantly, blockade of the IL-17 pathway in mice pre-exposed to Th17-inducing adjuvants resulted in attenuation of the inflammatory phenotype seen in influenza-infected mice. Our findings indicate that, before mucosal Th17-inducing adjuvants can be used in vaccine strategies, the short- and long-term detrimental effects of such adjuvants on disease exacerbation and lung injury in response to infections, such as influenza, should be carefully studied.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Infecções por Orthomyxoviridae/imunologia , Células Th17/imunologia , Animais , Feminino , Citometria de Fluxo , Imuno-Histoquímica , Hibridização In Situ , Vírus da Influenza A , Vacinas contra Influenza/imunologia , Interleucina-17/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mucosa/imunologia , Infecções por Orthomyxoviridae/patologia , Reação em Cadeia da Polimerase
6.
Am J Pathol ; 183(5): 1397-1404, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24007881

RESUMO

IL-10 production during intracellular bacterial infections is generally thought to be detrimental because of its role in suppressing protective T-helper cell 1 (Th1) responses. Francisella tularensis is a facultative intracellular bacterium that activates both Th1 and Th17 protective immune responses. Herein, we report that IL-10-deficient mice (Il10(-/-)), despite having increased Th1 and Th17 responses, exhibit increased mortality after pulmonary infection with F. tularensis live vaccine strain. We demonstrate that the increased mortality observed in Il10(-/-)-infected mice is due to exacerbated IL-17 production that causes increased neutrophil recruitment and associated lung pathology. Thus, although IL-17 is required for protective immunity against pulmonary infection with F. tularensis live vaccine strain, its production is tightly regulated by IL-10 to generate efficient induction of protective immunity without mediating pathology. These data suggest a critical role for IL-10 in maintaining the delicate balance between host immunity and pathology during pulmonary infection with F. tularensis live vaccine strain.


Assuntos
Vacinas Bacterianas/imunologia , Francisella tularensis/fisiologia , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Pulmão/imunologia , Pulmão/patologia , Infecções Respiratórias/microbiologia , Animais , Suscetibilidade a Doenças , Inflamação/patologia , Interleucina-10/biossíntese , Interleucina-10/deficiência , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Infecções Respiratórias/imunologia , Infecções Respiratórias/patologia , Infecções Respiratórias/prevenção & controle , Células Th1/imunologia , Células Th17/imunologia , Tularemia/imunologia , Tularemia/microbiologia , Tularemia/patologia , Tularemia/prevenção & controle
7.
Am J Respir Crit Care Med ; 188(9): 1137-46, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24047412

RESUMO

RATIONALE: A hallmark of pulmonary tuberculosis (TB) is the formation of granulomas. However, the immune factors that drive the formation of a protective granuloma during latent TB, and the factors that drive the formation of inflammatory granulomas during active TB, are not well defined. OBJECTIVES: The objective of this study was to identify the underlying immune mechanisms involved in formation of inflammatory granulomas seen during active TB. METHODS: The immune mediators involved in inflammatory granuloma formation during TB were assessed using human samples and experimental models of Mycobacterium tuberculosis infection, using molecular and immunologic techniques. MEASUREMENTS AND MAIN RESULTS: We demonstrate that in human patients with active TB and in nonhuman primate models of M. tuberculosis infection, neutrophils producing S100 proteins are dominant within the inflammatory lung granulomas seen during active TB. Using the mouse model of TB, we demonstrate that the exacerbated lung inflammation seen as a result of neutrophilic accumulation is dependent on S100A8/A9 proteins. S100A8/A9 proteins promote neutrophil accumulation by inducing production of proinflammatory chemokines and cytokines, and influencing leukocyte trafficking. Importantly, serum levels of S100A8/A9 proteins along with neutrophil-associated chemokines, such as keratinocyte chemoattractant, can be used as potential surrogate biomarkers to assess lung inflammation and disease severity in human TB. CONCLUSIONS: Our results thus show a major pathologic role for S100A8/A9 proteins in mediating neutrophil accumulation and inflammation associated with TB. Thus, targeting specific molecules, such as S100A8/A9 proteins, has the potential to decrease lung tissue damage without impacting protective immunity against TB.


Assuntos
Calgranulina A/imunologia , Calgranulina B/imunologia , Granuloma do Sistema Respiratório/imunologia , Mediadores da Inflamação/imunologia , Neutrófilos/imunologia , Tuberculose Pulmonar/imunologia , Animais , Quimiocinas/imunologia , Fatores Quimiotáticos/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Humanos , Macaca mulatta , Camundongos , Camundongos Endogâmicos C57BL
8.
Sci Rep ; 14(1): 11124, 2024 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750107

RESUMO

Influenza is a significant public health and economic threat around the world. Epidemiological studies have demonstrated a close association between influenza pandemics and cardiovascular mortality. Moreover, it has been shown that there is a decrease in cardiovascular mortality in high-risk patients following vaccination with the influenza vaccine. Here, we have investigated the role of anti-viral STAT1 signaling in influenza-induced myocarditis. Wild-type mice (C57BL/6) were infected with either influenza A/PR/8/34 or control, and cellular response and gene expression analysis from the heart samples were assessed 7 days later. The expression of interferon response genes STAT1, STAT2, Mx1, OASL2, ISG15, chemokines CCL2, CCL3, CXCL9 and CXCL10, and the frequency of neutrophils (CD45+CD11b+Ly6G+) and CD4+ T cells (CD45+CD4+) were all significantly increased in influenza-infected mice when compared to vehicle controls. These data suggest that influenza infection induces interferons, inflammatory chemokines, and cellular recruitment during influenza infection. We further investigated the role of STAT1 in influenza-induced myocarditis. The frequency of neutrophils and the levels of lipocalin 2 were significantly increased in STAT1-/- mice when compared to WT controls. Finally, we investigated the role of Lcn2 in viral-induced myocarditis. We found that in the absence of Lcn2, there was preserved cardiac function in Lcn2-/- mice when compared to WT controls. These data suggest that the absence of Lcn2 is cardioprotective during viral-induced myocarditis.


Assuntos
Lipocalina-2 , Camundongos Endogâmicos C57BL , Miocardite , Infecções por Orthomyxoviridae , Fator de Transcrição STAT1 , Animais , Camundongos , Lipocalina-2/metabolismo , Lipocalina-2/genética , Camundongos Knockout , Miocardite/virologia , Miocardite/metabolismo , Miocardite/etiologia , Neutrófilos/metabolismo , Neutrófilos/imunologia , Infecções por Orthomyxoviridae/complicações , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/metabolismo , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/genética
9.
Physiol Rep ; 12(1): e15902, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38163670

RESUMO

Although zinc deficiency (secondary to malnutrition) has long been considered an important contributor to morbidity and mortality of infectious disease (e.g. diarrhea disorders), epidemiologic data (including randomized controlled trials with supplemental zinc) for such a role in lower respiratory tract infection are somewhat ambiguous. In the current study, we provide the first preclinical evidence demonstrating that although diet-induced acute zinc deficiency (Zn-D: ~50% decrease) did not worsen infection induced by either influenza A (H1N1) or methicillin-resistant staph aureus (MRSA), Zn-D mice were sensitive to the injurious effects of superinfection of H1N1 with MRSA. Although the mechanism underlying the sensitivity of ZnD mice to combined H1N1/MRSA infection is unclear, it was noteworthy that this combination exacerbated lung injury as shown by lung epithelial injury markers (increased BAL protein) and decreased genes related to epithelial integrity in Zn-D mice (surfactant protein C and secretoglobins family 1A member 1). As bacterial pneumonia accounts for 25%-50% of morbidity and mortality from influenza A infection, zinc deficiency may be an important pathology component of respiratory tract infections.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Desnutrição , Staphylococcus aureus Resistente à Meticilina , Pneumonia Bacteriana , Animais , Camundongos , Pneumonia Bacteriana/complicações , Staphylococcus aureus , Zinco
10.
Eur J Immunol ; 42(2): 364-73, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22101830

RESUMO

The generation of effective type 1 T helper (Th1)-cell responses is required for immunity against intracellular bacteria. However, some intracellular bacteria require interleukin (IL)-17 to drive Th1-cell immunity and subsequent protective host immunity. Here, in a model of Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccination in mice, we demonstrate that the dependence on IL-17 to drive Th1-cell responses is a host mechanism to overcome bacteria-induced IL-10 inhibitory effects. We show that BCG-induced prostaglandin-E2 (PGE2) promotes the production of IL-10 which limits Th1-cell responses, while simultaneously inducing IL-23 and Th17-cell differentiation. The ability of IL-17 to downregulate IL-10 and induce IL-12 production allows the generation of subsequent Th1-cell responses. Accordingly, BCG-induced Th17-cell responses precede the generation of Th1-cell responses in vivo, whereas the absence of the IL-23 pathway decreases BCG vaccine-induced Th17 and Th1-cell immunity and subsequent vaccine-induced protection upon M. tuberculosis challenge. Importantly, in the absence of IL-10, BCG-induced Th1-cell responses occur in an IL-17-independent manner. These novel data demonstrate a role for the IL-23/IL-17 pathway in driving Th1-cell responses, specifically to overcome IL-10-mediated inhibition and, furthermore, show that in the absence of IL-10, the generation of BCG-induced Th1-cell immunity is IL-17 independent.


Assuntos
Interferon gama/metabolismo , Interleucina-17/metabolismo , Mycobacterium bovis/imunologia , Células Th1/metabolismo , Tuberculose/imunologia , Animais , Carga Bacteriana/genética , Dinoprostona/imunologia , Dinoprostona/metabolismo , Modelos Animais de Doenças , Humanos , Imunomodulação , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-23/imunologia , Interleucina-23/metabolismo , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mycobacterium bovis/crescimento & desenvolvimento , Mycobacterium bovis/patogenicidade , Comunicação Parácrina/genética , Células Th1/imunologia , Células Th1/patologia , Vacinação
11.
J Transl Med ; 11: 220, 2013 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-24053111

RESUMO

BACKGROUND: The control of Mycobacterium tuberculosis (Mtb) infection begins with the recognition of mycobacterial structural components by toll like receptors (TLRs) and other pattern recognition receptors. Our objective was to determine the influence of TLRs polymorphisms in the susceptibility to develop tuberculosis (TB) in Amerindian individuals from a rural area of Oaxaca, Mexico with high TB incidence. METHODS: We carried out a case-control association community based study, genotyping 12 polymorphisms of TLR2, TLR4, TLR6 and TLR9 genes in 90 patients with confirmed pulmonary TB and 90 unrelated exposed but asymptomatic household contacts. RESULTS: We found a significant increase in the frequency of the allele A of the TLR9 gene polymorphism rs352139 (A>G) in the group of TB patients (g.f. = 0.522) when compared with controls (g.f. = 0.383), (Pcorr = 0.01, OR = 1.75). Under the recessive model (A/G + A/A vs G/G) this polymorphism was also significantly associated with TB (Pcorr = 0.01, OR= 2.37). The association of the SNP rs352139 was statistically significant after adjustment by age, gender and comorbidities by regression logistic analysis (Dominant model: p value = 0.016, OR = 2.31; Additive model: p value = 0.023, OR = 1.68). The haplotype GAA of TLR9 SNPs was also associated with TB susceptibility (Pcorr = 0.02). Differences in the genotype or allele frequencies of TLR2, TLR4 and TLR6 polymorphisms between TB patients and healthy contacts were not detected. CONCLUSIONS: Our study suggests that the allele A of the intronic polymorphism rs352139 on TLR9 gene might contribute to the risk of developing TB in Mexican Amerindians.


Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Receptor Toll-Like 9/genética , Tuberculose/genética , Adulto , Estudos de Casos e Controles , Demografia , Feminino , Estudos de Associação Genética , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Modelos Logísticos , Masculino , México , Pessoa de Meia-Idade , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Receptor 6 Toll-Like/genética
12.
J Immunol ; 187(10): 5402-7, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-22003199

RESUMO

IL-23 is required for the IL-17 response to infection with Mycobacterium tuberculosis, but is not required for the early control of bacterial growth. However, mice deficient for the p19 component of IL-23 (Il23a(-/-)) exhibit increased bacterial growth late in infection that is temporally associated with smaller B cell follicles in the lungs. Cxcl13 is required for B cell follicle formation and immunity during tuberculosis. The absence of IL-23 results in decreased expression of Cxcl13 within M. tuberculosis-induced lymphocyte follicles in the lungs, and this deficiency was associated with increased cuffing of T cells around the vessels in the lungs of these mice. Il23a(-/-) mice also poorly expressed IL-17A and IL-22 mRNA. These cytokines were able to induce Cxcl13 in mouse primary lung fibroblasts, suggesting that these cytokines are likely involved in B cell follicle formation. Indeed, IL-17RA-deficient mice generated smaller B cell follicles early in the response, whereas IL-22-deficient mice had smaller B cell follicles at an intermediate time postinfection; however, only Il23a(-/-) mice had a sustained deficiency in B cell follicle formation and reduced immunity. We propose that in the absence of IL-23, expression of long-term immunity to tuberculosis is compromised due to reduced expression of Cxcl13 in B cell follicles and reduced ability of T cells to migrate from the vessels and into the lesion. Further, although IL-17 and IL-22 can both contribute to Cxcl13 production and B cell follicle formation, it is IL-23 that is critical in this regard.


Assuntos
Centro Germinativo/imunologia , Centro Germinativo/patologia , Interleucina-23/fisiologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia , Animais , Células Cultivadas , Quimiocina CXCL13/biossíntese , Centro Germinativo/microbiologia , Interleucina-23/deficiência , Interleucina-23/genética , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/crescimento & desenvolvimento , Fatores de Tempo , Tuberculose Pulmonar/microbiologia
13.
Immunohorizons ; 7(12): 861-871, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38112660

RESUMO

Influenza is a highly contagious, acute respiratory disease that causes significant public health and economic threats. Influenza infection induces various inflammatory mediators, IFNs, and recruitment of inflammatory cells in the host. This inflammatory "cytokine storm" is thought to play a role in influenza-induced lung pathogenesis. Empagliflozin is a drug primarily used to lower blood glucose in type II diabetes patients by inhibiting the sodium-glucose cotransporter-2 (SGLT-2) found in the proximal tubules in the kidneys. In this study, we have investigated the effects of empagliflozin on the pulmonary immune response to influenza infection. C57BL/6 mice (wild type) were infected with influenza A/PR/8/34 and treated with empagliflozin, and the disease outcomes were analyzed. Empagliflozin treatment decreased the expression of the inflammatory cytokines IL-1ß, IL-6, and CCL2; the percentage of inflammatory monocytes and inducible NO synthase-positive macrophages; and IFN response genes Stat1 and CXCL9 during influenza infection. Further, empagliflozin treatment decreases the expression of IL-6, CCL2, and CCL5 in RAW264.7 macrophages and bone marrow-derived macrophages. However, empagliflozin treatment increased influenza viral titer during infection. Despite fostering an increased viral burden, treatment with empagliflozin decreases the mortality in wild type and high fat diet-induced atherosclerotic LDLR-/- mice. Based on our findings, empagliflozin may have therapeutic implications for use in patients to prevent lung damage and acute respiratory illness.


Assuntos
Diabetes Mellitus Tipo 2 , Influenza Humana , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Camundongos , Animais , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Influenza Humana/tratamento farmacológico , Interleucina-6 , Camundongos Endogâmicos C57BL , Glicemia , Imunidade , Sódio/uso terapêutico
14.
PLoS One ; 16(10): e0255309, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34618816

RESUMO

BACKGROUND: Type III interferon, or interferon lambda (IFNλ) is a crucial antiviral cytokine induced by influenza infection. While IFNλ is important for anti-viral host defense, published data demonstrate that IFNλ is pathogenic during influenza/bacterial super-infection. It is known that polymorphisms in specific IFNλ genes affect influenza responses, but the effect of IFNλ subtypes on bacterial super-infection is unknown. METHODS: Using an established model of influenza, Staphylococcus aureus super-infection, we studied IFNλ3-/- and control mice to model a physiologically relevant reduction in IFNλ and to address its role in super-infection. RESULTS: Surprisingly, IFNλ3-/- mice did not have significantly lower total IFNλ than co-housed controls, and displayed no change in viral or bacterial clearance. Importantly, both control and IFNλ3-/- mice displayed a positive correlation between viral burden and total IFNλ in the bronchoalveolar lavage during influenza/bacterial super-infection, suggesting that higher influenza viral burden drives a similar total IFNλ response regardless of IFNλ3 gene integrity. Interestingly, total IFNλ levels positively correlated with bacterial burden, while viral burden and bronchoalveolar lavage cellularity did not. CONCLUSIONS: These data suggest IFNλ2 can compensate for IFNλ3 to mount an effective antiviral and defense, revealing a functional redundancy in these highly similar IFNλ subtypes. Further, the IFNλ response to influenza, as opposed to changes in cellular inflammation or viral load, significantly correlates with susceptibility to bacterial super-infection. Moreover, the IFNλ response is regulated and involves redundant subtypes, suggesting it is of high importance to pulmonary pathogen defense.


Assuntos
Interferons/análise , Interferons/imunologia , Interleucinas/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Animais , Linhagem Celular , Coinfecção/imunologia , Coinfecção/microbiologia , Cães , Feminino , Interferons/genética , Interleucinas/genética , Células Madin Darby de Rim Canino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/patologia , Polimorfismo Genético/genética , Infecções Estafilocócicas/prevenção & controle , Superinfecção/imunologia , Superinfecção/microbiologia , Carga Viral/imunologia , Interferon lambda
15.
Front Immunol ; 11: 570681, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193350

RESUMO

Influenza virus infection causes 3-5 million cases of severe illness and 250,000-500,000 deaths worldwide annually. Although pneumonia is the most common complication associated with influenza, there are several reports demonstrating increased risk for cardiovascular diseases. Several clinical case reports, as well as both prospective and retrospective studies, have shown that influenza can trigger cardiovascular events including myocardial infarction (MI), myocarditis, ventricular arrhythmia, and heart failure. A recent study has demonstrated that influenza-infected patients are at highest risk of having MI during the first seven days of diagnosis. Influenza virus infection induces a variety of pro-inflammatory cytokines and chemokines and recruitment of immune cells as part of the host immune response. Understanding the cellular and molecular mechanisms involved in influenza-associated cardiovascular diseases will help to improve treatment plans. This review discusses the direct and indirect effects of influenza virus infection on triggering cardiovascular events. Further, we discussed the similarities and differences in epidemiological and pathogenic mechanisms involved in cardiovascular events associated with coronavirus disease 2019 (COVID-19) compared to influenza infection.


Assuntos
COVID-19/imunologia , Doenças Cardiovasculares/imunologia , Orthomyxoviridae/fisiologia , SARS-CoV-2/fisiologia , Animais , COVID-19/genética , COVID-19/virologia , Doenças Cardiovasculares/virologia , Citocinas/genética , Citocinas/imunologia , Humanos , Influenza Humana/genética , Influenza Humana/imunologia , Influenza Humana/virologia , Orthomyxoviridae/genética , SARS-CoV-2/genética
16.
Viruses ; 11(6)2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31159430

RESUMO

Influenza virus is among the most common causes of respiratory illness worldwide and can be complicated by secondary bacterial pneumonia, a frequent cause of mortality. When influenza virus infects the lung, the innate immune response is activated, and interferons and inflammatory mediators are released. This "cytokine storm" is thought to play a role in influenza-induced lung pathogenesis. Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor super-family. PPARγ has numerous functions including enhancing lipid and glucose metabolism and cellular differentiation and suppressing inflammation. Synthetic PPARγagonists (thiazolidinediones or glitazones) have been used clinically in the treatment of type II diabetes. Using data from the National Health and Nutrition Examination Survey (NHANES), diabetic participants taking rosiglitazone had an increased risk of mortality from influenza/pneumonia compared to those not taking the drug. We examined the effect of rosiglitazone treatment during influenza and secondary bacterial (Methicillin resistant Staphylococcus aureus) pneumonia in mice. We found decreased influenza viral burden, decreased numbers of neutrophils and macrophages in bronchoalveolar lavage, and decreased production of cytokines and chemokines in influenza infected, rosiglitazone-treated mice when compared to controls. However, rosiglitazone treatment compromised bacterial clearance during influenza-bacterial super-infection. Both human and mouse data suggest that rosiglitazone treatment worsens the outcome of influenza-associated pneumonia.


Assuntos
Infecções Bacterianas , Coinfecção/tratamento farmacológico , Inflamação/patologia , Influenza Humana , Rosiglitazona/efeitos adversos , Animais , Infecções Bacterianas/complicações , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/imunologia , Coinfecção/imunologia , Coinfecção/microbiologia , Coinfecção/virologia , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/microbiologia , Diabetes Mellitus Tipo 2/virologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/microbiologia , Inflamação/virologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/crescimento & desenvolvimento , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/complicações , Influenza Humana/tratamento farmacológico , Influenza Humana/imunologia , Interferons/efeitos dos fármacos , Interferons/metabolismo , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Pulmão/virologia , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Staphylococcus aureus Resistente à Meticilina/imunologia , Camundongos , PPAR gama/agonistas , Rosiglitazona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Carga Viral/efeitos dos fármacos
17.
Front Immunol ; 9: 2151, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30337919

RESUMO

Influenza is a common respiratory virus that infects between 5 and 20% of the US population and results in 30,000 deaths annually. A primary cause of influenza-associated death is secondary bacterial pneumonia. We have previously shown that influenza induces type I interferon (IFN)-mediated inhibition of Type 17 immune responses, resulting in exacerbation of bacterial burden during influenza and Staphylococcus aureus super-infection. In this study, we investigated the role of STAT2 signaling during influenza and influenza-bacterial super-infection in mice. Influenza-infected STAT2-/- mice had increased morbidity, viral burden, and inflammation when compared to wild-type mice. Despite an exaggerated inflammatory response to influenza infection, we found increased bacterial control and survival in STAT2 deficient mice during influenza-MRSA super-infection compared to controls. Further, we found that increased bacterial clearance during influenza-MRSA super-infection is not due to rescue of Type 17 immunity. Absence of STAT2 was associated with increased accumulation of M1, M2 and M1/M2 co-expressing macrophages during influenza-bacterial super-infection. Neutralization of IFNγ (M1) and/or Arginase 1 (M2) impaired bacterial clearance in Stat2-/- mice during super-infection, demonstrating that pulmonary macrophages expressing a mixed M1/M2 phenotype promote bacterial control during influenza-bacterial super-infection. Together, these results suggest that the STAT2 signaling is involved in suppressing macrophage activation and bacterial control during influenza-bacterial super-infection. Further, these studies reveal novel mechanistic insight into the roles of macrophage subpopulations in pulmonary host defense.


Assuntos
Influenza Humana/imunologia , Macrófagos Alveolares/imunologia , Pneumonia Estafilocócica/imunologia , Fator de Transcrição STAT2/metabolismo , Superinfecção/imunologia , Animais , Transplante de Medula Óssea , Embrião de Galinha , Modelos Animais de Doenças , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/diagnóstico , Influenza Humana/microbiologia , Influenza Humana/mortalidade , Ativação de Macrófagos/imunologia , Macrófagos Alveolares/metabolismo , Masculino , Células-Tronco Mesenquimais , Staphylococcus aureus Resistente à Meticilina/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia Estafilocócica/diagnóstico , Pneumonia Estafilocócica/microbiologia , Pneumonia Estafilocócica/mortalidade , Cultura Primária de Células , Fator de Transcrição STAT2/genética , Fator de Transcrição STAT2/imunologia , Índice de Gravidade de Doença , Transdução de Sinais/imunologia , Superinfecção/diagnóstico , Superinfecção/microbiologia , Superinfecção/mortalidade , Quimeras de Transplante
18.
Eur Respir Rev ; 26(143)2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28049128

RESUMO

Immune reconstitution inflammatory syndrome (IRIS) is an exaggerated immune response to a variety of pathogens in response to antiretroviral therapy-mediated recovery of the immune system in HIV-infected patients. Although IRIS can occur in many organs, pulmonary IRIS, associated with opportunistic infections such as Mycobacterium tuberculosis and Pneumocystis jirovecii, is particularly associated with high morbidity and mortality. The pathology of IRIS is associated with a variety of innate and adaptive immune factors, including CD4+ T-cells, CD8+ T-cells, γδ T-cells, natural killer cells, macrophages, the complement system and surfactant proteins, Toll-like receptors and pro-inflammatory cytokines and chemokines. Although there are numerous reports about the immune factors involved in IRIS, the mechanisms involved in the development of pulmonary IRIS are poorly understood. Here, we propose that studies using gene-deficient murine and nonhuman primate models will help to identify the specific molecular targets associated with the development of IRIS. An improved understanding of the mechanisms involved in the pathology of pulmonary IRIS will help to identify potential biomarkers and therapeutic targets in this syndrome.


Assuntos
Imunidade Adaptativa , Interações Hospedeiro-Patógeno/imunologia , Síndrome Inflamatória da Reconstituição Imune/imunologia , Imunidade Inata , Infecções Respiratórias/imunologia , Animais , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Síndrome Inflamatória da Reconstituição Imune/diagnóstico , Síndrome Inflamatória da Reconstituição Imune/genética , Síndrome Inflamatória da Reconstituição Imune/metabolismo , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Camundongos Knockout , Primatas , Prognóstico , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/genética , Infecções Respiratórias/metabolismo , Transdução de Sinais , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismo
19.
Sci Rep ; 7(1): 4924, 2017 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-28687773

RESUMO

The surface states of a 3D topological insulator (TI) exhibit topological protection against backscattering. However, the contribution of bulk electrons to the transport data is an impediment to the topological protection of surface states. We report the tuning of the chemical potential in the bulk in Bi2Se2Te TI thin films, pinning it near the center of the bulk band gap, thereby suppressing the bulk carriers. The temperature dependent resistance of these films show activated behavior down to 50 K, followed by a metallic transition at lower temperatures, a hallmark of robustness of TI surface states. Manifestation of topological protection and surface dominated transport is explained by 2D weak antilocalization phenomenon. We further explore the effect of surface to bulk coupling in TI in this work, which is captured by the number of effective conducting surface channels that participate in the transport. The presence of a single conducting channel indicates a strong surface to bulk coupling which is detrimental to purely topological transport. We demonstrate the decoupling of topological surface states on opposite surfaces of thin films, thereby suppressing the bulk transport. Our findings provide a deeper understanding of surface to bulk coupling along with topological transport behavior and their respective tunability.

20.
Immunohorizons ; 1(6): 81-91, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29577113

RESUMO

Influenza is an annual, global health care concern. Secondary bacterial pneumonia is a severe complication associated with primary influenza virus infection, often resulting in critical morbidity and mortality. Our laboratory has identified influenza-induced suppression of anti-bacterial Type 17 immunity as a mechanism for enhanced susceptibility to bacterial super-infection. We have shown that influenza-induced type I interferon impairs Type 17 activation. STAT1 is a transcription factor involved in interferon signaling, shared by type I, II, and III interferon. In this work, we investigated the role of STAT1 signaling during influenza, methicillin-resistant Staphylococcus aureus (MRSA) super-infection. STAT1-/- mice had increased morbidity and airway inflammation compared to control mice during influenza mono-infection. Despite this worsened anti-viral response, STAT1-/- mice were protected from super-infection bacterial burden and mortality compared to controls. Type 17 immune activation was increased in lymphocytes in STAT1-/- mice during super-infection. The elevation in Type 17 immunity was not related to increased IL-23 production, as type I interferon could inhibit IL-23 expression in a STAT1 independent manner. STAT1-/- antigen presenting cells were inherently biased towards Type 17 polarization compared to control cells. Further, STAT1-/- dendritic cells produced attenuated IL-6 and TNFα upon heat-killed S. aureus stimulation compared to control. Overall, these data indicate that STAT1 signaling plays a detrimental role in influenza, MRSA super-infection by controlling the magnitude of Type 17 immune activation.

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